research areas in stem cells

Appointments at Mayo Clinic

Stem cells: what they are and what they do.

Stem cells offer promise for new medical treatments. Learn about stem cell types, current and possible uses, and the state of research and practice.

You've heard about stem cells in the news, and perhaps you've wondered if they might help you or a loved one with a serious disease. Here are some answers to frequently asked questions about stem cells.

What are stem cells?

Stem cells: The body's master cells

Stem cells are the body's master cells. All other cells arise from stem cells, including blood cells, nerve cells and other cells.

Stem cells are a special type of cells that have two important properties. They are able to make more cells like themselves. That is, they self-renew. And they can become other cells that do different things in a process known as differentiation. Stem cells are found in almost all tissues of the body. And they are needed for the maintenance of tissue as well as for repair after injury.

Depending on where the stem cells are, they can develop into different tissues. For example, hematopoietic stem cells reside in the bone marrow and can produce all the cells that function in the blood. Stem cells also can become brain cells, heart muscle cells, bone cells or other cell types.

There are various types of stem cells. Embryonic stem cells are the most versatile since they can develop into all the cells of the developing fetus. The majority of stem cells in the body have fewer abilities to give rise to cells and may only help maintain and repair the tissues and organs in which they reside.

No other cell in the body has the natural ability to generate new cell types.

Why is there such an interest in stem cells?

Researchers are studying stem cells to see if they can help to:

• Increase understanding of how diseases occur. By watching stem cells mature into cells in bones, heart muscle, nerves, and other organs and tissue, researchers may better understand how diseases and conditions develop.

Generate healthy cells to replace cells affected by disease (regenerative medicine). Stem cells can be guided into becoming specific cells that can be used in people to regenerate and repair tissues that have been damaged or affected by disease.

People who might benefit from stem cell therapies include those with leukemia, Hodgkin disease, non-Hodgkin lymphoma and some solid tumor cancers. Stem cell therapies also might benefit people who have aplastic anemia, immunodeficiencies and inherited conditions of metabolism.

Stem cells are being studied to treat type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, heart failure, osteoarthritis and other conditions.

Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine.

Test new drugs for safety and effectiveness. Before giving drugs in development to people, researchers can use some types of stem cells to test the drugs for safety and quality. This type of testing may help assess drugs in development for toxicity to the heart.

New areas of study include the effectiveness of using human stem cells that have been programmed into tissue-specific cells to test new drugs. For the testing of new drugs to be accurate, the cells must be programmed to acquire properties of the type of cells targeted by the drug. Techniques to program cells into specific cells are under study.

Where do stem cells come from?

There are several sources of stem cells:

Embryonic stem cells. These stem cells come from embryos that are 3 to 5 days old. At this stage, an embryo is called a blastocyst and has about 150 cells.

These are pluripotent (ploo-RIP-uh-tunt) stem cells, meaning they can divide into more stem cells or can become any type of cell in the body. This allows embryonic stem cells to be used to regenerate or repair diseased tissue and organs.

• Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow or fat. Compared with embryonic stem cells, adult stem cells have a more limited ability to give rise to various cells of the body.

Adult cells altered to have properties of embryonic stem cells. Scientists have transformed regular adult cells into stem cells using genetic reprogramming. By altering the genes in the adult cells, researchers can make the cells act similarly to embryonic stem cells. These cells are called induced pluripotent stem cells (iPSCs).

This new technique may allow use of reprogrammed cells instead of embryonic stem cells and prevent immune system rejection of the new stem cells. However, scientists don't yet know whether using altered adult cells will cause adverse effects in humans.

Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells had better heart function and survival time.

Perinatal stem cells. Researchers have discovered stem cells in amniotic fluid as well as umbilical cord blood. These stem cells can change into specialized cells.

Amniotic fluid fills the sac that surrounds and protects a developing fetus in the uterus. Researchers have identified stem cells in samples of amniotic fluid drawn from pregnant women for testing or treatment — a procedure called amniocentesis.

Why is there controversy about using embryonic stem cells?

The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research and include recommendations for the donation of embryonic stem cells. Also, the guidelines state that embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.

Where do these embryos come from?

The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in women's uteruses. The stem cells are donated with informed consent from donors. The stem cells can live and grow in special solutions in test tubes or petri dishes in laboratories.

Why can't researchers use adult stem cells instead?

Progress in cell reprogramming and the formation of iPSCs has greatly enhanced research in this field. However, reprogramming is an inefficient process. When possible, iPSCs are used instead of embryonic stem cells since this avoids the ethical issues about use of embryonic stem cells that may be morally objectionable for some people.

Although research into adult stem cells is promising, adult stem cells may not be as versatile and durable as are embryonic stem cells. Adult stem cells may not be able to be manipulated to produce all cell types, which limits how adult stem cells can be used to treat diseases.

Adult stem cells are also more likely to contain irregularities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, researchers have found that adult stem cells are more adaptable than was first thought.

What are stem cell lines, and why do researchers want to use them?

A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don't become specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.

What is stem cell therapy (regenerative medicine), and how does it work?

Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next chapter in organ transplantation and uses cells instead of donor organs, which are limited in supply.

Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells.

The specialized cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the heart muscle. The healthy transplanted heart muscle cells could then contribute to repairing the injured heart muscle.

Researchers have already shown that adult bone marrow cells guided to become heart-like cells can repair heart tissue in people, and more research is ongoing.

Have stem cells already been used to treat diseases?

Yes. Doctors have performed stem cell transplants, also known as bone marrow transplants, for many decades. In hematopoietic stem cell transplants, stem cells replace cells damaged by chemotherapy or disease or serve as a way for the donor's immune system to fight some types of cancer and blood-related diseases. Leukemia, lymphoma, neuroblastoma and multiple myeloma often are treated this way. These transplants use adult stem cells or umbilical cord blood.

Researchers are testing adult stem cells to treat other conditions, including some degenerative diseases such as heart failure.

What are the potential problems with using embryonic stem cells in humans?

For embryonic stem cells to be useful, researchers must be certain that the stem cells will differentiate into the specific cell types desired.

Researchers have discovered ways to direct stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. Research is ongoing in this area.

Embryonic stem cells also can grow irregularly or specialize in different cell types spontaneously. Researchers are studying how to control the growth and development of embryonic stem cells.

Embryonic stem cells also might trigger an immune response in which the recipient's body attacks the stem cells as foreign invaders, or the stem cells might simply fail to function as expected, with unknown consequences. Researchers continue to study how to avoid these possible complications.

What is therapeutic cloning, and what benefits might it offer?

Therapeutic cloning, also called somatic cell nuclear transfer, is a way to create versatile stem cells independent of fertilized eggs. In this technique, the nucleus is removed from an unfertilized egg. This nucleus contains the genetic material. The nucleus also is removed from the cell of a donor.

This donor nucleus is then injected into the egg, replacing the nucleus that was removed, in a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This process creates a line of stem cells that is genetically identical to the donor's cells — in essence, a clone.

Some researchers believe that stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because cloned cells are less likely to be rejected once transplanted back into the donor. And it may allow researchers to see exactly how a disease develops.

Has therapeutic cloning in people been successful?

No. Researchers haven't been able to successfully perform therapeutic cloning with humans despite success in a number of other species.

Researchers continue to study the potential of therapeutic cloning in people.

There is a problem with information submitted for this request. Review/update the information highlighted below and resubmit the form.

From Mayo Clinic to your inbox

Sign up for free and stay up to date on research advancements, health tips, current health topics, and expertise on managing health. Click here for an email preview.

Error Email field is required

Error Include a valid email address

To provide you with the most relevant and helpful information, and understand which information is beneficial, we may combine your email and website usage information with other information we have about you. If you are a Mayo Clinic patient, this could include protected health information. If we combine this information with your protected health information, we will treat all of that information as protected health information and will only use or disclose that information as set forth in our notice of privacy practices. You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail.

Thank you for subscribing!

You'll soon start receiving the latest Mayo Clinic health information you requested in your inbox.

Sorry something went wrong with your subscription

Please, try again in a couple of minutes

• Stem cell basics. National Institutes of Health. https://stemcells.nih.gov/info/basics/stc-basics/#stc-I. Accessed March 21, 2024.
• Lovell-Badge R, et al. ISSCR guidelines for stem cell research and clinical translation: The 2021 update. Stem Cell Reports. 2021; doi:10.1016/j.stemcr.2021.05.012.
• AskMayoExpert. Hematopoietic stem cell transplant. Mayo Clinic; 2024.
• Stem cell transplants in cancer treatment. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant/. Accessed March 21, 2024.
• Townsend CM Jr, et al. Regenerative medicine. In: Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 21st ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed March 21, 2024.
• Kumar D, et al. Stem cell based preclinical drug development and toxicity prediction. Current Pharmaceutical Design. 2021; doi:10.2174/1381612826666201019104712.
• NIH guidelines for human stem cell research. National Institutes of Health. https://stemcells.nih.gov/research-policy/guidelines-for-human-stem-cell-research. Accessed March 21, 2024.
• De la Torre P, et al. Current status and future prospects of perinatal stem cells. Genes. 2020; doi:10.3390/genes12010006.
• Yen Ling Wang A. Human induced pluripotent stem cell-derived exosomes as a new therapeutic strategy for various diseases. International Journal of Molecular Sciences. 2021; doi:10.3390/ijms22041769.
• Alessandrini M, et al. Stem cell therapy for neurological disorders. South African Medical Journal. 2019; doi:10.7196/SAMJ.2019.v109i8b.14009.
• Goldenberg D, et al. Regenerative engineering: Current applications and future perspectives. Frontiers in Surgery. 2021; doi:10.3389/fsurg.2021.731031.
• Brown MA, et al. Update on stem cell technologies in congenital heart disease. Journal of Cardiac Surgery. 2020; doi:10.1111/jocs.14312.
• Li M, et al. Brachyury engineers cardiac repair competent stem cells. Stem Cells Translational Medicine. 2021; doi:10.1002/sctm.20-0193.
• Augustine R, et al. Stem cell-based approaches in cardiac tissue engineering: Controlling the microenvironment for autologous cells. Biomedical Pharmacotherapy. 2021; doi:10.1016/j.biopha.2021.111425.
• Cloning fact sheet. National Human Genome Research Institute. https://www.genome.gov/about-genomics/fact-sheets/Cloning-Fact-Sheet. Accessed March 21, 2024.
• Dingli D (expert opinion). Mayo Clinic. Nov. 17, 2023.

Products and Services

• A Book: Living Medicine
• Give today to find cancer cures for tomorrow
• Acute lymphocytic leukemia
• Acute myelogenous leukemia
• Adjuvant therapy for cancer
• Amyloidosis
• Aplastic anemia
• Atypical cells: Are they cancer?
• Biopsy procedures
• Blood Cancers and Disorders
• Bone marrow transplant
• Cancer blood tests
• Myths about cancer causes
• Infographic: Cancer Clinical Trials Offer Many Benefits
• Cancer diagnosis: 11 tips for coping
• Cancer-related fatigue
• Cancer pain: Relief is possible
• Cancer risk: What the numbers mean
• Cancer surgery
• Cancer survival rate
• Cancer survivors: Care for your body after treatment
• Cancer survivors: Late effects of cancer treatment
• Cancer survivors: Managing your emotions after cancer treatment
• Cancer treatment myths
• Chemotherapy side effects: A cause of heart disease?
• Chronic lymphocytic leukemia
• Chronic myelogenous leukemia
• Curcumin: Can it slow cancer growth?
• What is type 1 diabetes? A Mayo Clinic expert explains
• Type 1 diabetes FAQs
• Cancer-related diarrhea
• DiGeorge syndrome (22q11.2 deletion syndrome)
• Eating during cancer treatment: Tips to make food tastier
• Epidermolysis bullosa
• Gaucher disease
• Heart cancer: Is there such a thing?
• High-dose vitamin C: Can it kill cancer cells?
• Hodgkin lymphoma (Hodgkin disease)
• Hodgkin's vs. non-Hodgkin's lymphoma: What's the difference?
• Low blood counts
• Measles Virus as a Cancer Fighter
• Monoclonal antibody drugs
• Mort Crim and Cancer
• Mouth sores caused by cancer treatment: How to cope
• Multiple myeloma
• Infographic: Multiple Myeloma
• Myelofibrosis
• Neuroblastoma
• No appetite? How to get nutrition during cancer treatment
• Non-Hodgkin's lymphoma
• Scleroderma
• Self-Image During Cancer
• Sickle cell anemia
• Sisters' Bone Marrow Transplant
• Small cell, large cell cancer: What this means
• Stem Cells 101
• Thalassemia
• Tumor vs. cyst: What's the difference?
• Type 1 diabetes
• Stem cell transplant
• How cancer spreads
• PICC line placement
• When cancer returns: How to cope with cancer recurrence

Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission.

• Opportunities

Mayo Clinic Press

Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press .

• Mayo Clinic on Incontinence - Mayo Clinic Press Mayo Clinic on Incontinence
• The Essential Diabetes Book - Mayo Clinic Press The Essential Diabetes Book
• Mayo Clinic on Hearing and Balance - Mayo Clinic Press Mayo Clinic on Hearing and Balance
• FREE Mayo Clinic Diet Assessment - Mayo Clinic Press FREE Mayo Clinic Diet Assessment
• Mayo Clinic Health Letter - FREE book - Mayo Clinic Press Mayo Clinic Health Letter - FREE book
• Stem cells What they are and what they do

Help transform healthcare

Your donation can make a difference in the future of healthcare. Give now to support Mayo Clinic's research.

Stem Cell Biology

View Principal Investigators in Stem Cell Biology

Stem cells are a specific type of cell capable of evolving into many different types of specialized cells within the body. There are three primary types of stem cells: embryonic stem cells are characterized as pluripotent in nature—capable of developing into the two hundred or so specialized cells of the adult organism; adult stem cells exist within certain tissues of the body (for example, blood and bone marrow) and carry out repair and regenerative functions; and induced pluripotent stem cells (iPSCs) are adult stem cells that have been genetically reprogrammed to behave like embryonic stem cells.

Due to their ability to repair, regenerate, and develop into certain specialized cell types, stem cells offer great promise as therapy for a number of diseases. Many of the Institutes and Centers of the Intramural Research Program (IRP) have a dedicated stem cell research program, including the National Heart, Lung and Blood Institute (NHLBI), National Institute of Dental Craniofacial Research (NIDCR), National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), and the National Institute of Neurological Disorders and Stroke (NINDS).

Areas of active research on stem cell biology within these programs include:

• Treating liver disease with stem cells that have been manipulated to become specialized liver cells
• Creating stem cell-derived neurons for the study of motor neuron disease
• Creating insulin-producing pancreatic beta cells for clinical trials in diabetes
• Stimulating an anti-brain tumor immune response via manipulated stem cells
• Investigating the use of stem cells to study and treat Gaucher disease and parkinsonism
• Reprogramming tumor-specific immune cells from stem cells for cancer immunotherapy
• Manipulating stem cells to become bone and cartilage

Additionally, the NIH Regenerative Medicine Program (RMP) is a resource that provides infrastructure to accelerate the clinical translation of stem cell-based therapies—at any one time, around 100 clinical trials investigating the use of stem cells as therapies are ongoing at the NIH Clinical Center.

In addition to the research programs within the IRP, the NIH Stem Cell Interest Group was established to enhance communication and collaboration among scientist interested in stem cells. Visit the Stem Cell Interest Group Web site to learn more.

This page was last updated on Tuesday, January 11, 2022

Masks Strongly Recommended but Not Required in Maryland, Starting Immediately

Due to the downward trend in respiratory viruses in Maryland, masking is no longer required but remains strongly recommended in Johns Hopkins Medicine clinical locations in Maryland. Read more .

• Vaccines  
• Masking Guidelines
• Visitor Guidelines  

Institute for Basic Biomedical Sciences

Stem cell research at johns hopkins institute of basic biomedical sciences.

Researchers at the IBBS are studying stem cells to figure out how they can give rise to a complex body, how cells of the body can revert back to stem cells and how this knowledge can be used to develop therapies for diseases and injuries.

Stem cells are cells that don’t have an identity but have the potential to develop into many types of cells for many purposes, liking building a complete organism, healing a wound or replacing old, worn-out cells in a tissue.

Embryonic stem cells can become any of the cells in the body and can form entire animals.

Not all stem cells come from embryos, adult stem cells are found throughout the body too. These cells don’t have the ability to become any cell in the body, but can transform into many different cell types. For instance, there are stem cells in our bone marrow that can become fat cells, cartilage cells or bone cells, but they can’t become eye cells or skin cells. Researchers have also figured out how to make adult cells, like a skin cell, turn back into cells with the properties of embryonic stem cells, called induced pluripotent stem cells or iPS cells for short.

Erika Matunis ,  in the Department of Cell Biology , studies in fruit flies how testis stem cells decide to stay stem cells and not become other cell types, like sperm. She has also discovered how cells that are turning into other cell types can revert back to stem cells if the permanent reservoir of stem cells is depleted and she is exploring the mechanism of how this happens. Her research, learning more about the most fundamental aspects of stem cell biology, helps all stem cell researchers better understand the cells they work with.

Jennifer Elisseeff ,  of the Department of Biomedical Engineering , studies the differences between embryonic stem cells and adult stem cells. She has found that embryonic stem cells are better at forming new tissues, whereas adult stem cells are better at secreting therapeutic molecules that promote healing of damaged tissue. Elisseeff is particularly interested in the factors released by stem cells that can help a tissue heal. She uses this information in the development of biosynthetic (part-natural and part-man-made) materials used for therapies. One of the materials her lab has developed is a bio-adhesive—essentially a glue that can be used in the body that is made of part synthetic and part natural components. The glue is used in conjunction with stitches to help prevent leakage of blood or fluids, but it’s flexible enough to allow cells to move in and heal the incision. Also, Elisseeff is collaborating with the military to develop a treatment for soft tissue facial reconstruction for people who have suffered severe trauma. They are developing tissue blueprints that can be transplanted in the face—or any other place in the body for that matter— that would allow a person’s own cells to move into a region to heal and restructure the tissue.

Warren Grayson ,  of the Department of Biomedical Engineering , takes stem cells from fat and bone marrow as well as stem cells that have the potential to become many different cell types, known as pluripotent stem cells, and coaxes them to regenerate bone or skeletal muscle in the lab. He does this by incubating stem cells in biosynthetic structures to give the cells a structured three-dimensional volume to grow in, and then places these either in bioreactors that provide heat, nutrients, movement, mechanical stress or control of any other condition like oxygen concentration to guide the stem cell to become a specific cell type or within a defect in animals to study the regenerative process. He hopes to one day be able to take a person’s own stem cells and grow tissues, like bone or muscle, to be implanted into their body to replace damaged tissue. Using a person’s own cells and tissues will reduce the likelihood that the transplanted tissue will be rejected by the immune system.

Related Links :  Stem Cell Research at Johns Hopkins

The future of medicine lies in understanding how the body creates itself out of a single cell and the mechanisms by which it renews itself throughout life.

When we achieve this goal, we will be able to replace damaged tissues and help the body regenerate itself, potentially curing or easing the suffering of those afflicted by disorders like heart disease, Alzheimers, Parkinsons, diabetes, spinal cord injury and cancer.

Research at the institute leverages Stanford’s many strengths in a way that promotes that goal. The institute brings together experts from a wide range of scientific and medical fields to create a fertile, multidisciplinary research environment.

There are four major research areas of emphasis at the institute:

• Mature tissue or organ stem cells:  Researchers are expanding their understanding of known stem cells that continue to function through life, the so called “adult” stem cells, the mature tissue or organ cells that include blood-forming, neural, skin and skeletal muscle stem cells. Research in this area is also aimed at understanding the clinical applications of these stem cells, such as regenerating sick or injured organs and tissues.  More »
• Human embryonic and induced-pluripotent stem (iPS) cells.  Researchers are studying how embryonic cells are created and how they specialize to become various tissues in the body. Understanding the mechanics of embryonic stem cells may well be the key to the most dramatic breakthroughs in regeneration medicine. We also now have the  capability to produce embryonic-like cells (iPS cells) from mature cells, and even to create stem cells directly from mature cells without going through the iPS stage.  More »
• New Stem Cell Lines:  The institute is exploring how stem cells can be created out of specialized cells that have grown out of the stem cell stage. This research includes the use of NT (nuclear transfer) technology and iPS (induced pluripotent stem cell) technology to create new stem cell lines, which serve as models for studying and treating disorders such as cancer, diabetes, cardiovascular disease, autoimmune disease, and neurodegenerative disorders such as Alzheimer's, Parkinson's, and Lou Gehrig's diseases.  More »
• Cancer Stem Cells:  Scientist at the institute have played a key role in discovering and studying cancer stem cells, which are believed to lie at the core of cancer’s destructive potential. The institute continues to be the global epicenter of the hunt for cancer stem cells. Researchers aim to conduct preclinical research to develop new therapeutic approaches to killing cancer stem cells, with the goal of moving these findings into clinical trials.  More »

Learn about the many ways to support the institute for Stem Cell Biology and Regenerative Medicine

Support Biology

Dei council and dei faculty committee, biology diversity community, mit biology catalyst symposium, honors and awards, employment opportunities, faculty and research, current faculty, in memoriam, areas of research, biochemistry, biophysics, and structural biology, cancer biology, cell biology, computational biology, human disease, microbiology, neurobiology, stem cell and developmental biology, core facilities, video gallery, faculty resources, undergraduate, why biology, undergraduate testimonials, major/minor requirements, general institute requirement, advanced standing exam, transfer credit, current students, subject offerings, research opportunities, biology undergraduate student association, career development, why mit biology, diversity in the graduate program, nih training grant, career outcomes, graduate testimonials, prospective students, application process, interdisciplinary and joint degree programs, living in cambridge, graduate manual: key program info, graduate teaching, career development resources, biology graduate student council, biopals program, postdoctoral, life as a postdoc, postdoc associations, postdoc testimonials, workshops for mit biology postdocs entering the academic job market, responsible conduct of research, postdoc resources, non-mit undergraduates, bernard s. and sophie g. gould mit summer research program in biology (bsg-msrp-bio), bsg-msrp-bio gould fellows, quantitative methods workshop, high school students and teachers, summer workshop for teachers, mit field trips, leah knox scholars program, additional resources, mitx biology, department calendar, ehs and facilities, graduate manual, resources for md/phd students, preliminary exam guidelines, thesis committee meetings, guidelines for graduating, mentoring students and early-career scientists, remembering stephen goldman (1962 – 2022).

stem cell biology • regeneration • disease modeling • pattern formation • differentiation • gametogenesis • morphogenesis • organ development • cell migration • cell-cell and cell-environment interactions • aging • cancer

Laurie A. Boyer

Eliezer calo, mary gehring, leonard p. guarente, h. robert horvitz, richard o. hynes, rudolf jaenisch, kristin knouse, jacqueline lees, ruth lehmann, harvey f. lodish, adam c. martin, elly nedivi, peter reddien, yadira soto-feliciano, robert a. weinberg, brandon (brady) weissbourd, yukiko yamashita, omer h. yilmaz, richard a. young.

Before closing his lab, Harvey F. Lodish studied the development of red blood cells and the use of modified red cells for the introduction of novel therapeutics into the human body, as well as the development of brown and white fat cells.

New approach enables a closer look at brain cell organelle

“Vaults” within germ cells offer more than safekeeping

Microscope system sharpens scientists’ view of neural circuit connections

Q&A: Pulin Li on recreating development in the lab

New findings activate a better understanding of Rett syndrome’s causes

Evolution in Action Series: Birth of a species

News brief: Calo Lab

How early-stage cancer cells hide from the immune system

Research areas

Aging & Healthspan

Bioengineering & Nanotechnology

Blood & Immune Diseases

Bone & Muscle Diseases & Injuries

Cancer & Immunotherapy

Cell & Gene Therapy

Eye Diseases

Gastrointestinal & Metabolic Diseases

Genetics & Genomics

Heart & Lung Diseases

Infectious Diseases

Neurological Diseases, Disorders & Injuries

Reproduction & Infertility

Stem Cell Biology

• Knowledge Library Hub

Stem Cells: Exploring Their Diversity, Applications and Future

Introduction to stem cells.

Stem cells can differentiate into various cell types, making them crucial for therapeutic and research applications. They can be found in various tissues and organs, including bone marrow, umbilical cord blood and embryonic tissue.

Stem cells hold great promise in the regenerative medicine field for their potential to replace, repair or regenerate damaged or diseased cells, tissues and organs. They also have the potential to be used for the treatment of a wide range of diseases, including cancer, neurodegenerative disorders and cardiovascular disease.

Research on stem cells is challenging and has limits. Not all stem cells can divide indefinitely or give rise to every cell type. Nor are all stem cells ubiquitously distributed throughout the body. New research continues to elucidate the basic mechanisms of stem cell biology.

Types of Stem Cells

Stem cells are undifferentiated or progenitor cells that have the capacity to give rise to specialized cells. There are three main types of stem cells: embryonic, adult and induced pluripotent.

Embryonic stem cells are derived from the inner cell mass of a blastocyst. These cells have the unique ability to differentiate into all cell types found in the human body and have therefore been considered a potential source for regenerative medicine.

Adult stem cells are found in various tissues and organs throughout the body and have more limited differentiation potential. They serve as a sort of internal repair system, replenishing other cells as they die or are damaged. For example, hematopoietic stem cells in bone marrow can give rise to all blood cell types, while mesenchymal stem cells in bone marrow can differentiate into bone, cartilage and fat cells.

Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem cell-like state. iPSCs have the same capacity to differentiate into various cell types as embryonic stem cells but are derived from a patient's own cells, which eliminates the need for a matched donor and reduces the risk of rejection.

Embryonic Stem Cells

There are two types of embryonic stem cells: Totipotent & Pluripotent.

Totipotent Stem Cells are embryonic stem cells that are present in the initial embryo development. A totipotent stem cell can divide and produce all the cells in the body, including extraembryonic cells (placenta and embryo).

Pluripotent Stem Cells are derived from the inner cell mass of a blastocyst and can differentiate into any cell type in the body but cannot form a new organism.

Adult Stem Cells

Adult stem cells are found in various tissues throughout the body and typically give rise to cell types specific to that tissue.

• Hematopoietic Stem Cells used in bone marrow transplants give rise to all blood cell types.
• Mesenchymal Stem Cells (MSCs) are a type of adult stem cell that can be found in many tissues throughout the body, including the bone marrow, adipose tissue and cord blood. MSCs can differentiate into various types of cells, including osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells). Mesenchymal stem cells have been used for immunomodulation in clinical trials to treat autoimmune diseases and graft-versus-host disease.

See how Danaher Life Sciences can help

Talk to an expert

Induced Pluripotent Stem Cells

Induced pluripotent stem cells (iPSCs) can be derived from mature cells in the body and have been used to generate many different types of cells and tissues for research and therapeutic purposes.

The main advantage of iPSCs over other types of stem cells is that they can be generated from a patient's own cells, which reduces the risk of immune rejection. Additionally, iPSCs can be used to create models of diseases that can then be utilized for drug discovery and testing.

Producing iPSCs involves several steps.

• Cell isolation: The first step is to obtain the adult cells that will be reprogrammed into iPSCs. This is typically done by isolating cells from a tissue sample, such as skin or blood.
• Reprogramming: The adult cells are then reprogrammed into iPSCs by introducing specific genes with viral vectors or molecules that can ‘reprogram’ the cells to a pluripotent state. Direct reprogramming with the Yamanaka factors (Oct4, Sox2, Klf4, c-Myc) has traditionally been used to generate iPSCs but additional reprogramming genes have been utilized.
• Culturing: Once the cells have been reprogrammed, they are placed in a culture dish and grown under specific conditions to promote the growth and proliferation of the iPSCs.
• Characterization: The resulting iPSCs are then characterized and verified for pluripotency, including testing the ability of the iPSCs to differentiate into multiple cell types.

Stem Cell Therapy Research

Stem cell therapy is a rapidly growing field of research with the potential to treat various medical conditions. Stem cells can differentiate into a wide range of cell types and are an attractive option for regenerative medicine and personalized therapies.

Regenerative Medicine

One of the key benefits of stem cell therapy is its potential to replace or repair damaged tissues and organs. For example, researchers are exploring the use of stem cells to treat conditions such as heart disease, Parkinson's disease and spinal cord injury. When a tissue is damaged, stem cells can be recruited to the site of injury, where they proliferate and differentiate into the specific cell type(s) needed for repair. Some injury sites have local progenitor populations or recruit mature cells to sites of damage to facilitate repair.

Applications in Cancer Treatment

In addition to regenerative medicine, stem cell therapy also shows potential in research for cancer treatment. Researchers are exploring the use of stem cells to deliver therapeutic agents directly to the tumor site in a strategy known as stem cell-mediated drug delivery. This approach has the potential to increase the effectiveness of cancer treatments while reducing their toxicity, leading to improved outcomes for patients.

Improved Treatments for Genetic Disorders

Stem cell therapy also has the potential to contribute to the development of new and improved treatments for genetic disorders. By using stem cells to study the underlying mechanisms of these conditions, researchers can gain a deeper understanding of the diseases and identify new targets for therapy. Additionally, stem cell-based screening assays can be used to test the efficacy and safety of new drugs in a controlled and reproducible manner, reducing the time and cost of drug development.

Stem Cell Engineering

Stem cell engineering refers to the use of various techniques to manipulate and control the behavior of stem cells to achieve specific goals, such as producing specific cell types or treating diseases. Some of the methods used in stem cell engineering include:

• Gene Editing: Using tools such as CRISPR-Cas9 to introduce specific genetic changes in the stem cells. This can be used to correct genetic mutations that cause diseases or to introduce new genetic traits that could be useful for therapy.
• Directed Differentiation: Using various chemical and physical cues, such as specific growth factors or extracellular matrix proteins, to coax stem cells to differentiate into specific cell types. This can be used to produce specific types of cells for use in research or therapy.
• Tissue Engineering: Using stem cells in combination with other materials, such as hydrogels or scaffolds to create replacement tissues and organs.

Stem Cells: Future Applications

There are many potential future applications for stem cells as scientists continue to explore their vast potential to improve human health. Some of the most promising areas of new and continuing research include:

• Regenerative Medicine: New research continues to investigate the use of stem cells to affect repair or regeneration in a wide range of tissues and organs, including the heart, liver, lungs and skin.
• Organ Transplants: Scientists are working to develop techniques for growing replacement organs using iPSCs. This could potentially help lower the need for organ donors and reduce the risk of rejection of transplanted organs.
• Drug Development and Toxicity Testing: Stem cells can be used to create 3D cell cultures (organoids) that more closely mimic the physiology of tissues in the body. This can be used to test the safety and efficacy of new drugs and identify potential side effects
• Disease Modeling: Stem cells are being used to create in vitro models of human diseases, which can be used to study the underlying causes to develop new treatments
• Personalized Medicine: Stem cells can potentially be used to create patient-specific cell lines that can be used to test the effectiveness of different treatments for a particular individual.

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Review Article
• Published: 17 June 2019

Advances in stem cell research and therapeutic development

• Michele De Luca   ORCID: orcid.org/0000-0002-0850-8445 1   na1 ,
• Alessandro Aiuti 2 , 3   na1 ,
• Giulio Cossu 4   na1 ,
• Malin Parmar   ORCID: orcid.org/0000-0001-5002-4199 5 , 6   na1 ,
• Graziella Pellegrini 7   na1 &
• Pamela Gehron Robey 8   na1  

Nature Cell Biology volume  21 ,  pages 801–811 ( 2019 ) Cite this article

18k Accesses

149 Citations

58 Altmetric

Metrics details

• Disease model
• Stem-cell therapies

Despite many reports of putative stem-cell-based treatments in genetic and degenerative disorders or severe injuries, the number of proven stem cell therapies has remained small. In this Review, we survey advances in stem cell research and describe the cell types that are currently being used in the clinic or are close to clinical trials. Finally, we analyse the scientific rationale, experimental approaches, caveats and results underpinning the clinical use of such stem cells.

This is a preview of subscription content, access via your institution

Access options

Access Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

24,99 € / 30 days

cancel any time

Subscribe to this journal

Receive 12 print issues and online access

195,33 € per year

only 16,28 € per issue

Buy this article

• Purchase on SpringerLink
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Next-generation stem cells — ushering in a new era of cell-based therapies

Mesenchymal stem cell perspective: cell biology to clinical progress

Cell-based therapies for neurological disorders — the bioreactor hypothesis

Sipp, D. et al. Marketing of unproven stem cell-based interventions: a call to action. Sci. Transl. Med. 9 , eaag0426 (2017).

PubMed   Google Scholar  

Thomas, E. D., Lochte, H. L. Jr., Lu, W. C. & Ferrebee, J. W. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 257 , 491–496 (1957).

CAS   PubMed   Google Scholar  

Thomas, E. D. et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49 , 511–533 (1977).

Gatti, R. A., Meuwissen, H. J., Allen, H. D., Hong, R. & Good, R. A. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet 2 , 1366–1369 (1968).

Chabannon, C. et al. Hematopoietic stem cell transplantation in its 60s: a platform for cellular therapies. Sci. Transl. Med. 10 , eaap9630 (2018).

Dunbar, C. E. et al. Gene therapy comes of age. Science 359 , eaan4672 (2018).

Aiuti, A. et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N. Engl. J. Med. 360 , 447–458 (2009).

Naldini, L. Gene therapy returns to centre stage. Nature 526 , 351–360 (2015).

Bernardo, M. E. & Aiuti, A. The role of conditioning in hematopoietic stem-cell gene therapy. Hum. Gene Ther. 27 , 741–748 (2016).

Aiuti, A. et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296 , 2410–2413 (2002).

Cicalese, M. P. et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood 128 , 45–54 (2016).

CAS   PubMed   PubMed Central   Google Scholar  

Kohn, D. B. et al. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J. Allergy Clin. Immunol. 143 , 852–863 (2018).

Tucci, F. et al. Successful treatment with ledipasvir/sofosbuvir in an infant with severe combined immunodeficiency caused by adenosine deaminase deficiency with HCV allowed gene therapy with strimvelis. Hepatology 68 , 2434–2437 (2018).

Hacein-Bey-Abina, S. et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348 , 255–256 (2003).

Braun, C. J. et al. Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity. Sci. Transl. Med. 6 , 227ra33 (2014).

Cavazzana, M., Bushman, F.D., Miccio, A., André-Schmutz, I. & Six, E. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat. Rev. Drug Discov. https://doi.org/10.1038/s41573-019-0020-9 (2019).

Cartier, N. et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326 , 818–823 (2009).

Sessa, M. et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 388 , 476–487 (2016).

Biffi, A. et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341 , 1233158 (2013).

De Ravin, S. S. et al. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci. Transl. Med. 8 , 335ra57 (2016).

PubMed   PubMed Central   Google Scholar  

Aiuti, A. et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341 , 1233151 (2013).

Ferrua, F. et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 6 , e239–e253 (2019).

Hacein-Bey Abina, S. et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. J. Am. Med. Assoc. 313 , 1550–1563 (2015).

Google Scholar  

Thompson, A. A. et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 378 , 1479–1493 (2018).

Marktel, S. et al. Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia. Nat. Med. 25 , 234–241 (2019).

Scala, S. et al. Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nat. Med. 24 , 1683–1690 (2018).

Vakulskas, C. A. et al. A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells. Nat. Med. 24 , 1216–1224 (2018).

Wu, Y. et al. Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat. Med. 25 , 776–783 (2019).

Biasco, L. et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell 19 , 107–119 (2016).

Rheinwald, J. G. & Green, H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6 , 331–343 (1975).

Green, H., Kehinde, O. & Thomas, J. Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. Proc. Natl Acad. Sci. USA 76 , 5665–5668 (1979).

Gallico, G. G. III, O’Connor, N. E., Compton, C. C., Kehinde, O. & Green, H. Permanent coverage of large burn wounds with autologous cultured human epithelium. N. Engl. J. Med. 311 , 448–451 (1984).

De Luca, M., Pellegrini, G. & Green, H. Regeneration of squamous epithelia from stem cells of cultured grafts. Regen. Med. 1 , 45–57 (2006).

Barrandon, Y. & Green, H. Three clonal types of keratinocyte with different capacities for multiplication. Proc. Natl Acad. Sci. USA 84 , 2302–2306 (1987).

Pellegrini, G. et al. The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin. Transplantation 68 , 868–879 (1999).

Ronfard, V., Rives, J. M., Neveux, Y., Carsin, H. & Barrandon, Y. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation 70 , 1588–1598 (2000).

Rama, P. et al. Limbal stem-cell therapy and long-term corneal regeneration. N. Engl. J. Med. 363 , 147–155 (2010).

Hirsch, T. et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature 551 , 327–332 (2017).

Pellegrini, G. et al. Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface. J. Cell Biol. 145 , 769–782 (1999).

Schermer, A., Galvin, S. & Sun, T. T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. J. Cell Biol. 103 , 49–62 (1986).

Cotsarelis, G., Cheng, S. Z., Dong, G., Sun, T. T. & Lavker, R. M. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 57 , 201–209 (1989).

Lehrer, M. S., Sun, T. T. & Lavker, R. M. Strategies of epithelial repair: modulation of stem cell and transit amplifying cell proliferation. J. Cell Sci. 111 , 2867–2875 (1998).

Majo, F., Rochat, A., Nicolas, M., Jaoudé, G. A. & Barrandon, Y. Oligopotent stem cells are distributed throughout the mammalian ocular surface. Nature 456 , 250–254 (2008).

Pellegrini, G., Rama, P., Mavilio, F. & De Luca, M. Epithelial stem cells in corneal regeneration and epidermal gene therapy. J. Pathol. 217 , 217–228 (2009).

Kenyon, K. R. & Tseng, S. C. Limbal autograft transplantation for ocular surface disorders. Ophthalmology 96 , 709–723 (1989).

Lindberg, K., Brown, M. E., Chaves, H. V., Kenyon, K. R. & Rheinwald, J. G. In vitro propagation of human ocular surface epithelial cells for transplantation. Invest. Ophthalmol. Vis. Sci. 34 , 2672–2679 (1993).

Pellegrini, G. et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 349 , 990–993 (1997).

Rama, P. et al. Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation 72 , 1478–1485 (2001).

Pellegrini, G. et al. Biological parameters determining the clinical outcome of autologous cultures of limbal stem cells. Regen. Med. 8 , 553–567 (2013).

Hsu, Y. C., Li, L. & Fuchs, E. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157 , 935–949 (2014).

Yang, A. et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell 2 , 305–316 (1998).

Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398 , 714–718 (1999).

Mills, A. A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398 , 708–713 (1999).

Senoo, M., Pinto, F., Crum, C. P. & McKeon, F. p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129 , 523–536 (2007).

Pellegrini, G. et al. p63 identifies keratinocyte stem cells. Proc. Natl Acad. Sci. USA 98 , 3156–3161 (2001).

Di Iorio, E. et al. Isoforms of DeltaNp63 and the migration of ocular limbal cells in human corneal regeneration. Proc. Natl Acad. Sci. USA 102 , 9523–9528 (2005).

Di Iorio, E. et al. Q-FIHC: quantification of fluorescence immunohistochemistry to analyse p63 isoforms and cell cycle phases in human limbal stem cells. Microsc. Res. Tech. 69 , 983–991 (2006).

Le, Q., Xu, J. & Deng, S. X. The diagnosis of limbal stem cell deficiency. Ocul. Surf. 16 , 58–69 (2018).

Dong, Y., Peng, H. & Lavker, R. M. Emerging therapeutic strategies for limbal stem cell deficiency. J. Ophthalmol. 2018 , 7894647 (2018).

Fine, J. D. et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J. Am. Acad. Dermatol. 70 , 1103–1126 (2014).

Carulli, S., Contin, R., De Rosa, L., Pellegrini, G. & De Luca, M. The long and winding road that leads to a cure for epidermolysis bullosa. Regen. Med. 8 , 467–481 (2013).

Mavilio, F. et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat. Med. 12 , 1397–1402 (2006).

Bauer, J. W. et al. Closure of a large chronic wound through transplantation of gene-corrected epidermal stem cells. J. Invest. Dermatol. 137 , 778–781 (2017).

Siprashvili, Z. et al. Safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with recessive dystrophic epidermolysis bullosa. J. Am. Med. Assoc. 316 , 1808–1817 (2016).

Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446 , 185–189 (2007).

Mascré, G. et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489 , 257–262 (2012).

Comai, G. & Tajbakhsh, S. Molecular and cellular regulation of skeletal myogenesis. Curr. Top. Dev. Biol. 110 , 1–73 (2014).

Miquerol, L. & Kelly, R. G. Organogenesis of the vertebrate heart. Wiley Interdiscip. Rev. Dev. Biol. 2 , 17–29 (2013).

Buckingham, M. Tissue differentiation: a personal account of research on myogenesis and cardiogenesis. Curr. Top. Dev. Biol. 116 , 135–151 (2016).

Chang, N. C. & Rudnicki, M. A. Satellite cells: the architects of skeletal muscle. Curr. Top. Dev. Biol. 107 , 161–181 (2014).

Mercola, M., Ruiz-Lozano, P. & Schneider, M. D. Cardiac muscle regeneration: lessons from development. Genes Dev. 25 , 299–309 (2011).

Chong, J. J., Forte, E. & Harvey, R. P. Developmental origins and lineage descendants of endogenous adult cardiac progenitor cells. Stem Cell Res. 13 , 592–614 (2014).

Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331 , 1078–1080 (2011).

Chien, K. R. et al. Regenerating the field of cardiovascular cell therapy. Nat. Biotechnol. 37 , 232–237 (2019).

Mauro, A. Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol. 9 , 493–495 (1961).

Buckingham, M. & Rigby, P. W. Gene regulatory networks and transcriptional mechanisms that control myogenesis. Dev. Cell 28 , 225–238 (2014).

Zammit, P. S. et al. Muscle satellite cells adopt divergent fates: a mechanism for self-renewal? J. Cell Biol. 166 , 347–357 (2004).

Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M. A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148 , 112–125 (2012).

Guiraud, S. et al. The pathogenesis and therapy of muscular dystrophies. Annu. Rev. Genomics Hum. Genet. 16 , 281–308 (2015).

Partridge, T. A., Morgan, J. E., Coulton, G. R., Hoffman, E. P. & Kunkel, L. M. Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature 337 , 176–179 (1989).

Miller, R. G. et al. Myoblast implantation in Duchenne muscular dystrophy: the San Francisco study. Muscle Nerve 20 , 469–478 (1997).

Gussoni, E. et al. Normal dystrophin transcripts detected in Duchenne muscular dystrophy patients after myoblast transplantation. Nature 356 , 435–438 (1992).

Péault, B. et al. Stem and progenitor cells in skeletal muscle development, maintenance, and therapy. Mol. Ther. 15 , 867–877 (2007).

Périé, S. et al. Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study. Mol. Ther. 22 , 219–225 (2014).

Boyer, O. et al. Autologous myoblasts for the treatment of fecal incontinence: results of a phase 2 randomized placebo-controlled study (MIAS). Ann. Surg. 267 , 443–450 (2018).

Peters, K. M. et al. Autologous muscle derived cells for treatment of stress urinary incontinence in women. J. Urol. 192 , 469–476 (2014).

Lin, C. S. & Lue, T. F. Stem cell therapy for stress urinary incontinence: a critical review. Stem Cells Dev. 21 , 834–843 (2012).

Mitchell, K. J. et al. Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development. Nat. Cell Biol. 12 , 257–266 (2010).

Joe, A. W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12 , 153–163 (2010).

Dellavalle, A. et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat. Cell Biol. 9 , 255–267 (2007).

Dellavalle, A. et al. Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nat. Commun. 2 , 499 (2011).

Cossu, G. et al. Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy. EMBO Mol. Med. 7 , 1513–1528 (2015).

Clifford, D. M. et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst. Rev. 2012 , CD006536 (2012).

Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410 , 701–705 (2001).

Zhang, Y., Mignone, J. & MacLellan, W. R. Cardiac Regeneration and Stem Cells. Physiol. Rev. 95 , 1189–1204 (2015).

Harvey, R. P., Graham, R. M. & Pu, W. T. Introduction to the special issue on heart regeneration and rejuvenation. Stem Cell Res. 13 , 521–522 (2014).

Gerbin, K. A. & Murry, C. E. The winding road to regenerating the human heart. Cardiovasc. Pathol. 24 , 133–140 (2015).

Li, Y. et al. Genetic lineage tracing of non-myocyte population by dual recombinases. Circulation 138 , 793–805 (2018).

Lee, J. H., Protze, S. I., Laksman, Z., Backx, P. H. & Keller, G. M. Human pluripotent stem cell-derived atrial and ventricular cardiomyocytes develop from distinct mesoderm populations. Cell Stem Cell 21 , 179–194.e174 (2017).

Giacomelli, E., Mummery, C. L. & Bellin, M. Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes. Cell. Mol. Life Sci. 74 , 3711–3739 (2017).

Yang, X., Pabon, L. & Murry, C. E. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114 , 511–523 (2014).

Liu, Y. W. et al. Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat. Biotechnol. 36 , 597–605 (2018).

Veerman, C. C. et al. Immaturity of human stem-cell-derived cardiomyocytes in culture: fatal flaw or soluble problem? Stem Cells Dev. 24 , 1035–1052 (2015).

Coulombe, K. L., Bajpai, V. K., Andreadis, S. T. & Murry, C. E. Heart regeneration with engineered myocardial tissue. Annu. Rev. Biomed. Eng. 16 , 1–28 (2014).

Fu, J. D. & Srivastava, D. Direct reprogramming of fibroblasts into cardiomyocytes for cardiac regenerative medicine. Circ. J. 79 , 245–254 (2015).

Farouz, Y., Chen, Y., Terzic, A. & Menasché, P. Concise review: growing hearts in the right place: on the design of biomimetic materials for cardiac stem cell differentiation. Stem Cells 33 , 1021–1035 (2015).

D’Uva, G. et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat. Cell Biol. 17 , 627–638 (2015).

Mikkers, H. M., Freund, C., Mummery, C. L. & Hoeben, R. C. Cell replacement therapies: is it time to reprogram? Hum. Gene Ther. 25 , 866–874 (2014).

Bianco, P. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19 , 35–42 (2013).

Bianco, P., Robey, P. G. & Simmons, P. J. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2 , 313–319 (2008).

Owen, M. & Friedenstein, A. J. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found. Symp. 136 , 42–60 (1988).

Bianco, P. & Robey, P.G. in Handbook of Adult and Fetal Stem Cells (eds Lanza, R. et al.) 415–424 (San Diego, Academic Press, 2004).

Caplan, A. I. Mesenchymal stem cells. J. Orthop. Res. 9 , 641–650 (1991).

Bianco, P. & Robey, P. G. Skeletal stem cells. Development 142 , 1023–1027 (2015).

Galipeau, J. & Sensébé, L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22 , 824–833 (2018).

Kuriyan, A. E. et al. Vision loss after intravitreal injection of autologous “stem cells” for AMD. N. Engl. J. Med. 376 , 1047–1053 (2017).

Caplan, A. I. & Correa, D. The MSC: an injury drugstore. Cell Stem Cell 9 , 11–15 (2011).

Phinney, D. G. & Prockop, D. J. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views. Stem Cells 25 , 2896–2902 (2007).

Bianco, P. et al. Regulation of stem cell therapies under attack in Europe: for whom the bell tolls. EMBO J. 32 , 1489–1495 (2013).

Bartunek, J. et al. Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. Eur. Heart J. 38 , 648–660 (2017).

Herreros, M. D., Garcia-Arranz, M., Guadalajara, H., De-La-Quintana, P. & Garcia-Olmo, D. Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. Dis. Colon Rectum 55 , 762–772 (2012).

Sipp, D., Robey, P. G. & Turner, L. Clear up this stem-cell mess. Nature 561 , 455–457 (2018).

Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8 , 315–317 (2006).

Sacchetti, B. et al. No identical “mesenchymal stem cells” at different times and sites: human committed progenitors of distinct origin and differentiation potential are incorporated as adventitial cells in microvessels. Stem Cell Reports 6 , 897–913 (2016).

Shi, S. & Gronthos, S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J. Bone Miner. Res. 18 , 696–704 (2003).

Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131 , 324–336 (2007).

Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G. & Morrison, S. J. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15 , 154–168 (2014).

Guimaraes-Camboa, N. et al. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20 , 345–359.e345 (2017).

Quarto, R. et al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N. Engl. J. Med. 344 , 385–386 (2001).

Lee, J. et al. Successful reconstruction of 15-cm segmental defects by bone marrow stem cells and resected autogenous bone graft in central hemangioma. J. Oral Maxillofac. Surg. 68 , 188–194 (2010).

Yamada, Y., Ueda, M., Hibi, H. & Baba, S. A novel approach to periodontal tissue regeneration with mesenchymal stem cells and platelet-rich plasma using tissue engineering technology: a clinical case report. Int. J. Periodontics Restorative Dent. 26 , 363–369 (2006).

Robey, P. G. Cell sources for bone regeneration: the good, the bad, and the ugly (but promising). Tissue Eng. Part B Rev. 17 , 423–430 (2011).

Nakashima, M. et al. Pulp regeneration by transplantation of dental pulp stem cells in pulpitis: a pilot clinical study. Stem Cell Res. Ther. 8 , 61 (2017).

Bachoud-Lévi, A. C. From open to large-scale randomized cell transplantation trials in Huntington’s disease: lessons from the multicentric intracerebral grafting in Huntington’s disease trial (MIG-HD) and previous pilot studies. Prog. Brain Res. 230 , 227–261 (2017).

Barker, R. A., Drouin-Ouellet, J. & Parmar, M. Cell-based therapies for Parkinson disease—past insights and future potential. Nat. Rev. Neurol. 11 , 492–503 (2015).

Barker, R. A., Parmar, M., Studer, L. & Takahashi, J. Human trials of stem cell-derived dopamine neurons for Parkinson’s disease: dawn of a new era. Cell Stem Cell 21 , 569–573 (2017).

Kalladka, D. et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet 388 , 787–796 (2016).

Lindvall, O. & Kokaia, Z. Stem cell research in stroke: how far from the clinic? Stroke 42 , 2369–2375 (2011).

Shirai, H. et al. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration. Proc. Natl Acad. Sci. USA 113 , E81–E90 (2016).

Whiting, P., Kerby, J., Coffey, P., da Cruz, L. & McKernan, R. Progressing a human embryonic stem-cell-based regenerative medicine therapy towards the clinic. Phil. Trans. R. Soc. Lond. B 370 , 20140375 (2015).

Priest, C. A., Manley, N. C., Denham, J., Wirth, E. D. III & Lebkowski, J. S. Preclinical safety of human embryonic stem cell-derived oligodendrocyte progenitors supporting clinical trials in spinal cord injury. Regen. Med. 10 , 939–958 (2015).

da Cruz, L. et al. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat. Biotechnol. 36 , 328–337 (2018).

Mandai, M., Kurimoto, Y. & Takahashi, M. Autologous induced stem-cell-derived retinal cells for macular degeneration. N. Engl. J. Med. 377 , 792–793 (2017).

Damier, P., Hirsch, E. C., Agid, Y. & Graybiel, A. M. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 122 , 1437–1448 (1999).

Jenner, P. Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson’s disease. Curr. Opin. Neurol. 16 Suppl 1 , S3–S7 (2003).

Huot, P., Johnston, T. H., Koprich, J. B., Fox, S. H. & Brotchie, J. M. The pharmacology of L-DOPA-induced dyskinesia in Parkinson’s disease. Pharmacol. Rev. 65 , 171–222 (2013).

Lindvall, O. et al. Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease. A detailed account of methodology and a 6-month follow-up. Arch. Neurol. 46 , 615–631 (1989).

Lindvall, O. et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 247 , 574–577 (1990).

Kefalopoulou, Z. et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 71 , 83–87 (2014).

Piccini, P. et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nat. Neurosci. 2 , 1137–1140 (1999).

Kordower, J. H. et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N. Engl. J. Med. 332 , 1118–1124 (1995).

Li, W. et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc. Natl Acad. Sci. USA 113 , 6544–6549 (2016).

Li, J. Y. et al. Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson’s disease. Mov. Disord. 25 , 1091–1096 (2010).

Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 14 , 504–506 (2008).

Ribeiro, D. et al. Efficient expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells by midbrain morphogens. Neurobiol. Dis. 49 , 118–127 (2013).

Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282 , 1145–1147 (1998).

Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131 , 861–872 (2007).

Kriks, S. et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 480 , 547–551 (2011).

Kirkeby, A. et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 1 , 703–714 (2012).

Grealish, S. et al. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson’s disease. Cell Stem Cell 15 , 653–665 (2014).

Kikuchi, T. et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature 548 , 592–596 (2017).

Kirkeby, A., Parmar, M. & Barker, R. A. Strategies for bringing stem cell-derived dopamine neurons to the clinic: a European approach (STEM-PD). Prog. Brain Res. 230 , 165–190 (2017).

Studer, L. Strategies for bringing stem cell-derived dopamine neurons to the clinic-The NYSTEM trial. Prog. Brain Res. 230 , 191–212 (2017).

Takahashi, J. Strategies for bringing stem cell-derived dopamine neurons to the clinic: the Kyoto trial. Prog. Brain Res. 230 , 213–226 (2017).

Abbott, A. Fetal-cell revival for Parkinson’s. Nature 510 , 195–196 (2014).

Download references

Acknowledgements

The authors would to thank the following parties, from whose work elements of our figures were modified; F. Aiuti (Fig. 2a ), A. De Luca (Fig. 3a ), and J. Drouin-Ouellet (Fig. 4 ). This work was partially supported by Regione Emilia-Romagna, Asse 1 POR-FESR 2007-13 to M.D.L. and G.P.; Italian Telethon Foundation to A.A.; Division of Intramural Research, National Institute of Dental Research, a part of the Intramural Research Program, the National Institutes of Health, Department of Health and Humman Services (ZIA DE000380 to P.G.R.), the Wellcome Trust (ME070401A1), the MRC (MR/P016006/1) the GOSH-SPARKS charity (V4618) to G.C.

Author information

These authors contributed equally: Michele De Luca, Alessandro Aiuti, Giulio Cossu, Malin Parmar, Graziella Pellegrini, Pamela Gehron Robey.

Authors and Affiliations

Center for Regenerative Medicine “Stefano Ferrari”, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

Michele De Luca

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

Alessandro Aiuti

Vita-Salute San Raffaele University, Milan, Italy

Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Giulio Cossu

Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund, Sweden

Malin Parmar

Lund Stem Cell Center, Lund University, Lund, Sweden

Center for Regenerative Medicine “Stefano Ferrari”, Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy

Graziella Pellegrini

National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA

Pamela Gehron Robey

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Michele De Luca .

Ethics declarations

Competing interests.

M.D.L. and G.P. are members of the Board of Directors of Holostem Terapie Avanzate Srl and consultant at J-TEC Ltd, Japan Tissue Engineering. A.A. is the principal investigator of clinical trials of HSC-GT for ADA-SCID, MLD and Wiskott–Aldrich, sponsored by Orchard Therapeutics. Orchard Therapeutic is the marketing authorization holder of Strimvelis in the European Union. M.P. is the owner of Parmar Cells AB and co-inventor of the US patent application 15/093,927 owned by Biolamina AB and EP17181588 owned by Miltenyi Biotec. M.P. is a New York Stem Cell Foundation Robertson Investigator.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Cite this article.

De Luca, M., Aiuti, A., Cossu, G. et al. Advances in stem cell research and therapeutic development. Nat Cell Biol 21 , 801–811 (2019). https://doi.org/10.1038/s41556-019-0344-z

Download citation

Received : 06 August 2018

Accepted : 09 May 2019

Published : 17 June 2019

Issue Date : July 2019

DOI : https://doi.org/10.1038/s41556-019-0344-z

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Gene-edited cells: novel allogeneic gene/cell therapy for epidermolysis bullosa.

• Fatemeh Gila
• Vahab Alamdari-Palangi
• Jafar Fallahi

Journal of Applied Genetics (2024)

Effect of Metformin on Epidermal Neural Crest Stem Cells and Their Potential Application in Ameliorating Paclitaxel-induced Neurotoxicity Phenotype

• Pariya Khodabakhsh
• Afsaneh Asgari Taei
• Leila Dargahi

Stem Cell Reviews and Reports (2024)

Mesenchymal Stem Cell-based Scaffolds in Regenerative Medicine of Dental Diseases

• Mohammad Kiarashi
• Hannaneh Bayat
• Saman Yasamineh

Single-cell sequencing advances in research on mesenchymal stem/stromal cells

• Qingxi Long
• Pingshu Zhang
• Xiaodong Yuan

Human Cell (2024)

Efficient expansion and delayed senescence of hUC-MSCs by microcarrier–bioreactor system

• Liming Ouyang
• Lixin Zhang

Stem Cell Research & Therapy (2023)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

• USC Stem Cell
• Stem Cell FAQs
• Mission and History
• California’s Leadership in Stem Cell Research
• Founding Supporters and Ambassadors
• Impact Reports and Newsletters
• Department Faculty
• Eli and Edythe Broad Center Faculty
• Research Facilities
• Translational Research Committee
• USC Stem Cell Research Oversight Committee (SCRO)
• USC+CHLA Alpha Clinic
• Apply to Become Center Faculty
• Undergraduate
• Master’s Program
• PhD Program
• Medical Education
• Postdoctoral Opportunities
• Our Trainees
• DEI Overview
• DEI Committee
• DEI News and Videos
• DEI Programs and Resources at USC Stem Cell
• DEI Programs and Resources at USC
• Additional DEI Programs and Resources

USC Stem Cell study maps how genes instruct kidneys to develop differently in mice and humans

By   cristy lytal, in this section, read this next.

USC Stem Cell’s journey towards 1,000 mini-kidneys begins with $1 million from KidneyX

• Subscribe to our enewsletter Subscribe Do Not Fill This Out
• Follow us on

How similar is kidney development in humans and in the lab mice that form the foundation of basic medical research? In a new study published in Developmental Cell , USC Stem Cell scientists probe this question by comparing the activity and regulation of the genes that drive kidney development in lab mice and humans.

“While we do have a lot in common with lab mice, our evolutionary paths diverged around 80 million years ago,” said corresponding author Andy McMahon , director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, and W.M. Keck Provost and University Professor of Stem Cell Biology and Regenerative Medicine, and Biological Sciences. “On the anatomical level, there are obvious differences in mouse and human kidneys in terms of the overall organ size, number of filtering units, and patterning of the ducts and lobes. We wanted to deepen our understanding of these fundamental differences to the level of the underlying genes and gene regulators that orchestrate kidney development.”

To accomplish this, first author Sunghyun Kim in the McMahon lab worked with his colleagues to build atlases comparing gene activity and regulation in different cell types in developing mouse and human kidneys. The scientists could then pinpoint similarities and differences between the two species and identify cell type- and species-specific genetic and gene regulatory programs relevant to kidney development and disease.

Many genes, such as the one that encodes the molecule PCDH15 , which helps cells adhere to each other, showed human-specific patterns of activity. These genes tended to be associated with cell interaction and migration, and might be necessary for building a complex, human-sized kidney during the relatively long period of embryonic development.

Other genes, including NTNG1 , a gene normally associated with nerve cell development, may be used specifically in the human kidney to guide human developmental processes.

Many gene regulators were also human-specific. Some of these have been associated with chronic kidney disease or congenital anomalies of kidney and urinary tract.

“By identifying human-specific gene regulatory regions, we were able to link these to regions previously associated with kidney disease, showing a potential for our research to provide clinical insight,” said Kim, a recent PhD graduate from USC currently pursuing postdoctoral studies at the Massachusetts General Hospital in Boston.

Additional co-authors are Kari Koppitch, Riana K. Parvez, Jinjin Guo, MaryAnne Achieng, Jack Schnell, and Nils O. Lindström from USC.

The work was federally funded by the National Institute of Diabetes and Digestive and Kidney Diseases (grants R37DK054364 and UC2DK126024), and privately funded by the Chan Zuckerberg Initiative (grant WU-20-101) as part of the Seed Network of the Human Cell Atlas consortium.

McMahon is currently or has recently been a consultant or scientific advisor to Novartis, eGENESIS, Trestle Biotherapeutics, and IVIVA Medical. All authors declare that they have no conflicts of interest.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Philos Trans R Soc Lond B Biol Sci
• v.365(1537); 2010 Jan 12

The therapeutic potential of stem cells

In recent years, there has been an explosion of interest in stem cells, not just within the scientific and medical communities but also among politicians, religious groups and ethicists. Here, we summarize the different types of stem cells that have been described: their origins in embryonic and adult tissues and their differentiation potential in vivo and in culture. We review some current clinical applications of stem cells, highlighting the problems encountered when going from proof-of-principle in the laboratory to widespread clinical practice. While some of the key genetic and epigenetic factors that determine stem cell properties have been identified, there is still much to be learned about how these factors interact. There is a growing realization of the importance of environmental factors in regulating stem cell behaviour and this is being explored by imaging stem cells in vivo and recreating artificial niches in vitro . New therapies, based on stem cell transplantation or endogenous stem cells, are emerging areas, as is drug discovery based on patient-specific pluripotent cells and cancer stem cells. What makes stem cell research so exciting is its tremendous potential to benefit human health and the opportunities for interdisciplinary research that it presents.

1. Introduction: what are stem cells?

The human body comprises over 200 different cell types that are organized into tissues and organs to provide all the functions required for viability and reproduction. Historically, biologists have been interested primarily in the events that occur prior to birth. The second half of the twentieth century was a golden era for developmental biology, since the key regulatory pathways that control specification and morphogenesis of tissues were defined at the molecular level ( Arias 2008 ). The origins of stem cell research lie in a desire to understand how tissues are maintained in adult life, rather than how different cell types arise in the embryo. An interest in adult tissues fell, historically, within the remit of pathologists and thus tended to be considered in the context of disease, particularly cancer.

It was appreciated long ago that within a given tissue there is cellular heterogeneity: in some tissues, such as the blood, skin and intestinal epithelium, the differentiated cells have a short lifespan and are unable to self-renew. This led to the concept that such tissues are maintained by stem cells, defined as cells with extensive renewal capacity and the ability to generate daughter cells that undergo further differentiation ( Lajtha 1979 ). Such cells generate only the differentiated lineages appropriate for the tissue in which they reside and are thus referred to as multipotent or unipotent ( figure 1 ).

Origin of stem cells. Cells are described as pluripotent if they can form all the cell types of the adult organism. If, in addition, they can form the extraembryonic tissues of the embryo, they are described as totipotent. Multipotent stem cells have the ability to form all the differentiated cell types of a given tissue. In some cases, a tissue contains only one differentiated lineage and the stem cells that maintain the lineage are described as unipotent . Postnatal spermatogonial stem cells, which are unipotent in vivo but pluripotent in culture, are not shown ( Jaenisch & Young 2008 ). CNS, central nervous system; ICM, inner cell mass.

In the early days of stem cell research, a distinction was generally made between three types of tissue: those, such as epidermis, with rapid turnover of differentiated cells; those, such as brain, in which there appeared to be no self-renewal; and those, such as liver, in which cells divided to give two daughter cells that were functionally equivalent ( Leblond 1964 ; Hall & Watt 1989 ). While it remains true that different adult tissues differ in terms of the proportion of proliferative cells and the nature of the differentiation compartment, in recent years it has become apparent that some tissues that appeared to lack self-renewal ability do indeed contain stem cells ( Zhao et al . 2008 ) and others contain a previously unrecognized cellular heterogeneity ( Zaret & Grompe 2008 ). That is not to say that all tissues are maintained by stem cells; for example, in the pancreas, there is evidence against the existence of a distinct stem cell compartment ( Dor et al . 2004 ).

One reason why it took so long for stem cells to become a well-established research field is that in the early years too much time and energy were expended in trying to define stem cells and in arguing about whether or not a particular cell was truly a stem cell ( Watt 1999 ). Additional putative characteristics of stem cells, such as rarity, capacity for asymmetric division or tendency to divide infrequently, were incorporated into the definition, so that if a cell did not exhibit these additional properties it tended to be excluded from the stem cell ‘list’. Some researchers still remain anxious about the definitions and try to hedge their bets by describing a cell as a stem/progenitor cell. However, this is not useful. The use of the term progenitor, or transit amplifying, cell should be reserved for a cell that has left the stem cell compartment but still retains the ability to undergo cell division and further differentiation ( Potten & Loeffler 2008 ).

Looking back at some of the early collections of reviews written as the proceedings of stem cell conferences, one regularly finds articles on the topic of cancer stem cells ( McCulloch et al . 1988 ). However, these cells have only recently received widespread attention ( Reya et al . 2001 ; Clarke et al . 2006 ; Dick 2008 ). The concept is very similar to the concept of normal tissue stem cells, namely that cells in tumours are heterogeneous, with only some, the cancer stem cells, or tumour initiating cells, being capable of tumour maintenance or regrowth following chemotherapy. The cancer stem cell concept is important because it suggests new approaches to anti-cancer therapies ( figure 2 ).

The cancer stem cell hypothesis. The upper tumour is shown as comprising a uniform population of cells, while the lower tumour contains both cancer stem cells and more differentiated cells. Successful or unsuccessful chemotherapy is interpreted according to the behaviour of cells within the tumour.

As in the case of tissue stem cells, it is important that cancer stem cell research is not sidetracked by arguments about definitions. It is quite likely that in some tumours all the cells are functionally equivalent, and there is no doubt that tumour cells, like normal stem cells, can behave differently under different assay conditions ( Quintana et al . 2008 ). The oncogene dogma ( Hahn & Weinberg 2002 ), that tumours arise through step-wise accumulation of oncogenic mutations, does not adequately account for cellular heterogeneity, and markers of stem cells in specific cancers have already been described ( Singh et al . 2004 ; Barabé et al . 2007 ; O'Brien et al . 2007 ). While the (rediscovered) cancer stem cell field is currently in its infancy, it is already evident that a cancer stem cell is not necessarily a normal stem cell that has acquired oncogenic mutations. Indeed, there is experimental evidence that cancer initiating cells can be genetically altered progenitor cells ( Clarke et al . 2006 ).

In addition to adult tissue stem cells, stem cells can be isolated from pre-implantation mouse and human embryos and maintained in culture as undifferentiated cells ( figure 1 ). Such embryonic stem (ES) cells have the ability to generate all the differentiated cells of the adult and are thus described as being pluripotent ( figure 1 ). Mouse ES cells are derived from the inner cell mass of the blastocyst, and following their discovery in 1981 ( Evans & Kaufman 1981 ; Martin 1981 ) have been used for gene targeting, revolutionizing the field of mouse genetics. In 1998, it was first reported that stem cells could be derived from human blastocysts ( Thomson et al . 1998 ), opening up great opportunities for stem cell-based therapies, but also provoking controversy because the cells are derived from ‘spare’ in vitro fertilization embryos that have the potential to produce a human being. It is interesting to note that, just as research on adult tissue stem cells is intimately linked to research on disease states, particularly cancer, the same is true for ES cells. Many years before the development of ES cells, the in vitro differentiation of cells derived from teratocarcinomas, known as embryonal carcinoma cells, provided an important model for studying lineage selection ( Andrews et al . 2005 ).

Blastocysts are not the only source of pluripotent ES cells ( figure 1 ). Pluripotent epiblast stem cells, known as epiSC, can be derived from the post-implantation epiblast of mouse embryos ( Brons et al . 2007 ; Tesar et al . 2007 ). Recent gene expression profiling studies suggest that human ES cells are more similar to epiSC than to mouse ES cells ( Tesar et al . 2007 ). Pluripotent stem cells can also be derived from primordial germ cells (EG cells), progenitors of adult gametes, which diverge from the somatic lineage at late embryonic to early foetal development ( Kerr et al . 2006 ).

Although in the past the tendency has been to describe ES cells as pluripotent and adult stem cells as having a more restricted range of differentiation options, adult cells can, in some circumstances, produce progeny that differentiate across the three primary germ layers (ectoderm, mesoderm and endoderm). Adult cells can be reprogrammed to a pluripotent state by transfer of the adult nucleus into the cytoplasm of an oocyte ( Gurdon et al . 1958 ; Gurdon & Melton 2008 ) or by fusion with a pluripotent cell ( Miller & Ruddle 1976 ). The most famous example of cloning by transfer of a somatic nucleus into an oocyte is the creation of Dolly the sheep ( Wilmut et al . 1997 ). While the process remains inefficient, it has found some unexpected applications, such as cloning endangered species and domestic pets.

A flurry of reports almost 10 years ago suggested that adult cells from many tissues could differentiate into other cell types if placed in a new tissue environment. Such studies are now largely discredited, although there are still some bona fide examples of transdifferentiation of adult cells, such as occurs when blood cells fuse with hepatocytes during repair of damaged liver ( Anderson et al . 2001 ; Jaenisch & Young 2008 ). In addition, it has been known for many years that adult urodele amphibians can regenerate limbs or the eye lens following injury; this involves dedifferentiation and subsequent transdifferentiation steps ( Brockes & Kumar 2005 ).

The early studies involving somatic nuclear transfer indicated that adult cells can be reprogrammed to pluripotency. However, the mechanistic and practical applications of inducing pluripotency in adult cells have only become apparent in the last 2 or 3 years, with the emergence of a new research area: induced pluripotent stem cells (iPS cells). The original report demonstrated that retrovirus-mediated transduction of mouse fibroblasts with four transcription factors (Oct-3/4, Sox2, KLF4 and c-Myc; figure 1 ) that are highly expressed in ES cells could induce the fibroblasts to become pluripotent ( Takahashi & Yamanaka 2006 ). Since then, rapid progress has been made: iPS cells can be generated from adult human cells ( Takahashi et al . 2007 ; Yu et al . 2007 ; Park et al . 2008 a ); cells from a range of tissues can be reprogrammed ( Aasen et al . 2008 ; Aoi et al . 2008 ); and iPS cells can be generated from patients with specific diseases ( Dimos et al . 2008 ; Park et al . 2008 b ). The number of transcription factors required to generate iPS cells has been reduced ( Kim et al . 2008 ); the efficiency of iPS cell generation increased ( Wernig et al . 2007 ); and techniques devised that obviate the need for retroviral vectors ( Okita et al . 2008 ; Stadtfeld et al . 2008 ). These latter developments are very important for future clinical applications, since the early mice generated from iPS cells developed tumours at high frequency ( Takahashi & Yamanaka 2006 ; Yamanaka 2007 ). Without a doubt, this is currently the most exciting and rapidly moving area of stem cell research.

2. Current clinical applications of stem cells

In all the publicity that surrounds embryonic and iPS cells, people tend to forget that stem cell-based therapies are already in clinical use and have been for decades. It is instructive to think about these treatments, because they provide important caveats about the journey from proof-of-principle in the laboratory to real patient benefit in the clinic. These caveats include efficacy, patient safety, government legislation and the costs and potential profits involved in patient treatment.

Haemopoietic stem cell transplantation is the oldest stem cell therapy and is the treatment that is most widely available ( Perry & Linch 1996 ; Austin et al . 2008 ). The stem cells come from bone marrow, peripheral blood or cord blood. For some applications, the patient's own cells are engrafted. However, allogeneic stem cell transplantation is now a common procedure for the treatment of bone marrow failure and haematological malignancies, such as leukaemia. Donor stem cells are used to reconstitute immune function in such patients following radiation and/or chemotherapy. In the UK, the regulatory framework put in place for bone marrow transplantation has now an extended remit, covering the use of other tissues and organs ( Austin et al . 2008 ).

Advances in immunology research greatly increased the utility of bone marrow transplantation, allowing allograft donors to be screened for the best match in order to prevent rejection and graft-versus-host disease ( Perry & Linch 1996 ). It is worth remembering that organ transplantation programmes have also depended on an understanding of immune rejection, and drugs are available to provide effective long-term immunosuppression for recipients of donor organs. Thus, while it is obviously desirable for new stem cell treatments to involve the patient's own cells, it is certainly not essential.

Two major advantages of haemopoietic stem cell therapy are that there is no need to expand the cells in culture or to reconstitute a multicellular tissue architecture prior to transplantation. These hurdles have been overcome to generate cultured epidermis to provide autologous grafts for patients with full-thickness wounds, such as third-degree burns. Proof-of-principle was established in the mid-1970s, with clinical and commercial applications following rapidly ( Green 2008 ). Using a similar approach, limbal stem cells have been used successfully to restore vision in patients suffering from chemical destruction of the cornea ( De Luca et al . 2006 ).

Ex vivo expansion of human epidermal and corneal stem cells frequently involves culture on a feeder layer of mouse fibroblastic cells in medium containing bovine serum. While it would obviously be preferable to avoid animal products, there has been no evidence over the past 30 years that exposure to them has had adverse effects on patients receiving the grafts. The ongoing challenges posed by epithelial stem cell treatments include improved functionality of the graft (e.g. through generation of epidermal hair follicles) and improved surfaces on which to culture the cells and apply them to the patients. The need to optimize stem cell delivery is leading to close interactions between the stem cell community and bioengineers. In a recent example, a patient's trachea was repaired by transplanting a new tissue constructed in culture from donor decellularized trachea seeded with the patient's own bone marrow cells that had been differentiated into cartilage cells ( Macchiarini et al . 2008 ).

Whereas haemopoietic stem cell therapies are widely available, treatments involving cultured epidermis and cornea are not. In countries where cultured epithelial grafts are available, the number of potential patients is relatively small and the treatment costly. Commercial organizations that sell cultured epidermis for grafting have found that it is not particularly profitable, while in countries with publicly funded healthcare the need to set up a dedicated laboratory to generate the grafts tends to make the financial cost–benefit ratio too high ( Green 2008 ).

Clinical studies over the last 10 years suggest that stem cell transplantation also has potential as a therapy for neurodegenerative diseases. Clinical trials have involved grafting brain tissue from aborted foetuses into patients with Parkinson's disease and Huntington's disease ( Dunnett et al . 2001 ; Wright & Barker 2007 ). While some successes have been noted, the outcomes have not been uniform and further clinical trials will involve more refined patient selection, in an attempt to predict who will benefit and who will not. Obviously, aside from the opposition in many quarters to using foetal material, there are practical challenges associated with availability and uniformity of the grafted cells and so therapies with pure populations of stem cells are an important, and achievable ( Conti et al . 2005 ; Lowell et al . 2006 ), goal.

No consideration of currently available stem cell therapies is complete without reference to gene therapy. Here, there have been some major achievements, including the successful treatment of children with X-linked severe combined immunodeficiency. However, the entire gene therapy field stalled when several of the children developed leukaemia as a result of integration of the therapeutic retroviral vector close to the LMO2 oncogene locus ( Gaspar & Thrasher 2005 ; Pike-Overzet et al . 2007 ). Clinical trials have since restarted, and in an interesting example of combined gene/stem cell therapy, a patient with an epidermal blistering disorder received an autologous graft of cultured epidermis in which the defective gene had been corrected ex vivo ( Mavilio et al . 2006 ).

These are just some examples of treatments involving stem cells that are already in the clinic. They show how the field of stem cell transplantation is interlinked with the fields of gene therapy and bioengineering, and how it has benefited from progress in other fields, such as immunology. Stem cells undoubtedly offer tremendous potential to treat many human diseases and to repair tissue damage resulting from injury or ageing. The danger, of course, lies in the potentially lethal cocktail of desperate patients, enthusiastic scientists, ambitious clinicians and commercial pressures ( Lau et al . 2008 ). Internationally agreed, and enforced, regulations are essential in order to protect patients from the dangers of stem cell tourism, whereby treatments that have not been approved in one country are freely available in another ( Hyun et al . 2008 ).

3. What are the big questions in the field?

Three questions in stem cell research are being hotly pursued at present. What are the core genetic and epigenetic regulators of stem cells? What are the extrinsic, environmental factors that influence stem cell renewal and differentiation? And how can the answers to the first two questions be harnessed for clinical benefit?

4. Core genetic and epigenetic regulators

Considerable progress has already been made in defining the transcriptional circuitry and epigenetic modifications associated with pluripotency ( Jaenisch & Young 2008 ). This research area is moving very rapidly as a result of tremendous advances in DNA sequencing technology, bioinformatics and computational biology. Chromatin immunoprecipitation combined with microarray hybridization or DNA sequencing ( Mathur et al . 2008 ) is being used to identify transcription factor-binding sites, and bioinformatics techniques have been developed to allow integration of data obtained by the different approaches. It is clear that pluripotency is also subject to complex epigenetic regulation, and high throughput genome-scale DNA methylation profiling has been developed for epigenetic profiling of ES cells and other cell types ( Meissner et al . 2008 ).

Oct4, Nanog and Sox2 are core transcription factors that maintain pluripotency of ES cells. These factors bind to their own promoters, forming an autoregulatory loop. They occupy overlapping sets of target genes, one set being actively expressed and the other, comprising genes that positively regulate lineage selection, being actively silenced ( Jaenisch & Young 2008 ; Mathur et al . 2008 ; Silva & Smith 2008 ). Nanog stabilizes pluripotency by limiting the frequency with which cells commit to differentiation ( Chambers et al . 2007 ; Torres & Watt 2008 ). The core pluripotency transcription factors also regulate, again positively and negatively, the microRNAs that are involved in controlling ES cell self-renewal and differentiation ( Marson et al . 2008 ).

As the basic mechanisms that maintain the pluripotent state of ES cells are delineated, there is considerable interest in understanding how pluripotency is re-established in adult stem cells. It appears that some cell types are more readily reprogrammed to iPS cells than others ( Aasen et al . 2008 ; Aoi et al . 2008 ), and it is interesting to speculate that this reflects differences in endogenous expression of the genes required for reprogramming or in responsiveness to overexpression of those genes ( Hochedlinger et al . 2005 ; Markoulaki et al . 2009 ). Another emerging area of investigation is the relationship between the epigenome of pluripotent stem cells and cancer cells ( Meissner et al . 2008 ).

Initial attempts at defining ‘stemness’ by comparing the transcriptional profiles of ES cells, neural and haemopoietic stem cells ( Ivanova et al . 2002 ; Ramalho-Santos et al . 2002 ) have paved the way for more refined comparisons. For example, by comparing the gene expression profiles of adult neural stem cells, ES-derived and iPS-derived neural stem cells and brain tumour stem cells, it should be possible both to validate the use of ES-derived stem cells for brain repair and to establish the cell of origin of brain tumour initiating cells. Furthermore, it is anticipated that new therapeutic targets will be identified from molecular profiling studies of different stem cell populations.

As gene expression profiling becomes more sophisticated, the question of ‘what is a stem cell?’ can be addressed in new ways. Several studies have used single cell expression microarrays to identify new stem cell markers ( Jensen & Watt 2006 ). Stem cells are well known to exhibit different proliferative and differentiation properties in culture, during tissue injury and in normal tissue homeostasis, raising the question of which elements of the stem cell phenotype are hard-wired versus a response to environmental conditions.

One of the growing trends in stem cell research is the contribution of mathematical modelling. This is illustrated in the concept of transcriptional noise: the hypothesis that intercellular variability is a manifestation of ‘noise’ in gene expression levels, rather than stable phenotypic variation ( Chang et al . 2008 ). Studies with clonal populations of haemopoietic progenitor cells have shown that slow fluctuations in protein levels can produce cellular heterogeneity that is sufficient to affect whether a given cell will differentiate along the myeloid or erythroid lineage ( Chang et al . 2008 ). Mathematical approaches are also used increasingly to model observed differences in cell behaviour in vivo . In studies of adult mouse interfollicular epidermis, it is observed that cells can divide to produce two undifferentiated cells, two differentiated cells or one of each ( figure 3 ); it turns out that this can be explained in terms of the stochastic behaviour of a single population of cells rather than by invoking the existence of discrete types of stem and progenitor cell ( Clayton et al . 2007 ).

The stem cell niche. Stem cells (S) are shown dividing symmetrically to produce two stem cells (1) or two differentiated cells (D) (2), or undergoing asymmetric division to produce one stem cell and one differentiated cell (3). Under some circumstances, a differentiated cell can re-enter the niche and become a stem cell (4). Different components of the stem cell niche are illustrated: extracellular matrix (ECM), cells in close proximity to stem cells (niche cells), secreted factors (such as growth factors) and physical factors (such as oxygen tension, stiffness and stretch).

5. Extrinsic regulators

There is strong evidence that the behaviour of stem cells is strongly affected by their local environment or niche ( figure 3 ). Some aspects of the stem cell environment that are known to influence self-renewal and stem cell fate are adhesion to extracellular matrix proteins, direct contact with neighbouring cells, exposure to secreted factors and physical factors, such as oxygen tension and sheer stress ( Watt & Hogan 2000 ; Morrison & Spradling 2008 ). It is important to identify the environmental signals that control stem cell expansion and differentiation in order to harness those signals to optimize delivery of stem cell therapies.

Considerable progress has been made in directing ES cells to differentiate along specific lineages in vitro ( Conti et al . 2005 ; Lowell et al . 2006 ; Izumi et al . 2007 ) and there are many in vitro and murine models of lineage selection by adult tissue stem cells (e.g. Watt & Collins 2008 ). It is clear that in many contexts the Erk and Akt pathways are key regulators of cell proliferation and survival, while pathways that were originally defined through their effects in embryonic development, such as Wnt, Notch and Shh, are reused in adult tissues to influence stem cell renewal and lineage selection. Furthermore, these core pathways are frequently deregulated in cancer ( Reya et al . 2001 ; Watt & Collins 2008 ). In investigating how differentiation is controlled, it is not only the signalling pathways themselves that need to be considered, but also the timing, level and duration of a particular signal, as these variables profoundly influence cellular responses ( Silva-Vargas et al . 2005 ). A further issue is the extent to which directed ES cell differentiation in vitro recapitulates the events that occur during normal embryogenesis and whether this affects the functionality of the differentiated cells ( Izumi et al . 2007 ).

For a more complete definition of the stem cell niche, researchers are taking two opposite and complementary approaches: recreating the niche in vitro at the single cell level and observing stem cells in vivo. In vivo tracking of cells is possible because of advances in high-resolution confocal microscopy and two-photon imaging, which have greatly increased the sensitivity of detecting cells and the depth of the tissue at which they can be observed. Studies of green fluorescent protein-labelled haemopoietic stem cells have shown that their relationship with the bone marrow niche, comprising blood vessels, osteoblasts and the inner bone surface, differs in normal, irradiated and c-Kit-receptor-deficient mice ( Lo Celso et al . 2009 ; Xie et al . 2009 ). In a different approach, in vivo bioluminescence imaging of luciferase-tagged muscle stem cells has been used to reveal their role in muscle repair in a way that is impossible when relying on retrospective analysis of fixed tissue ( Sacco et al . 2008 ).

The advantage of recreating the stem cell niche in vitro is that it is possible to precisely control individual aspects of the niche and measure responses at the single cell level. Artificial niches are constructed by plating cells on micropatterned surfaces or capturing them in three-dimensional hydrogel matrices. In this way, parameters such as cell spreading and substrate mechanics can be precisely controlled ( Watt et al . 1988 ; Théry et al . 2005 ; Chen 2008 ). Cells can be exposed to specific combinations of soluble factors or to tethered recombinant adhesive proteins. Cell behaviour can be monitored in real time by time-lapse microscopy, and activation of specific signalling pathways can be viewed using fluorescence resonance energy transfer probes and fluorescent reporters of transcriptional activity. It is also possible to recover cells from the in vitro environment, transplant them in vivo and monitor their subsequent behaviour. One of the exciting aspects of the reductionist approach to studying the niche is that it is highly interdisciplinary, bringing together stem cell researchers and bioengineers, and also offering opportunities for interactions with chemists, physicists and materials scientists.

6. Future clinical applications of stem cell research

Almost every day there are reports in the media of new stem cell therapies. There is no doubt that stem cells have the potential to treat many human afflictions, including ageing, cancer, diabetes, blindness and neurodegeneration. Nevertheless, it is essential to be realistic about the time and steps required to take new therapies into the clinic: it is exciting to be able to induce ES cells to differentiate into cardiomyocytes in a culture dish, but that is only one very small step towards effecting cardiac repair. The overriding concerns for any new treatment are the same: efficacy, safety and affordability.

In January 2009, the US Food and Drug Administration approved the first clinical trial involving human ES cells, just over 10 years after they were first isolated. In this trial, the safety of ES cell-derived oligodendrocytes in repair of spinal cord injury will be evaluated ( http://www.geron.com ). There are a large number of human ES cell lines now in existence and banking of clinical grade cells is underway, offering the opportunity for optimal immunological matching of donors and recipients. Nevertheless, one of the attractions of transplanting iPS cells is that the patient's own cells can be used, obviating the need for immunosuppression. Discovering how the pluripotent state can be efficiently and stably induced and maintained by treating cells with pharmacologically active compounds rather than by genetic manipulation is an important goal ( Silva et al . 2008 ).

An alternative strategy to stem cell transplantation is to stimulate a patient's endogenous stem cells to divide or differentiate, as happens naturally during skin wound healing. It has recently been shown that pancreatic exocrine cells in adult mice can be reprogrammed to become functional, insulin-producing beta cells by expression of transcription factors that regulate pancreatic development ( Zhou et al . 2008 ). The idea of repairing tissue through a process of cellular reprogramming in situ is an attractive paradigm to be explored further.

A range of biomaterials are already in clinical use for tissue repair, in particular to repair defects in cartilage and bone ( Kamitakahara et al . 2008 ). These can be considered as practical applications of our knowledge of the stem cell microenvironment. Advances in tissue engineering and materials science offer new opportunities to manipulate the stem niche and either facilitate expansion/differentiation of endogenous stem cells or deliver exogenous cells. Resorbable scaffolds can be exploited for controlled delivery and release of small molecules, growth factors and peptides. Conversely, scaffolds can be designed that are able to capture unwanted tissue debris that might impede repair. Hydrogels that can undergo controlled sol–gel transitions could be used to release stem cells once they have integrated within the target tissue.

Although most of the new clinical applications of stem cells have a long lead time, applications of stem cells in drug discovery are available immediately. Adult tissue stem cells, ES cells and iPS cells can all be used to screen for compounds that stimulate self-renewal or promote specific differentiation programmes. Finding drugs that selectively target cancer stem cells offers the potential to develop cancer treatments that are not only more effective, but also cause less collateral damage to the patient's normal tissues than drugs currently in use. In addition, patient-specific iPS cells provide a new tool to identify underlying disease mechanisms. Thus stem cell-based assays are already enhancing drug discovery efforts.

7. Conclusion

Amid all the hype surrounding stem cells, there are strong grounds for believing that over the next 50 years our understanding of stem cells will revolutionize medicine. One of the most exciting aspects of working in the stem cell field is that it is truly multidisciplinary and translational. It brings together biologists, clinicians and researchers across the physical sciences and mathematics, and it fosters partnerships between academics and the biotech and pharmaceutical industries. In contrast to the golden era of developmental biology, one of stem cell research's defining characteristics is the motivation to benefit human health.

Acknowledgements

We thank all members of our lab, past and present, for their energy, fearlessness and intellectual curiosity in the pursuit of stem cells. We are grateful to Cancer Research UK, the Wellcome Trust, MRC and European Union for financial support and to members of the Cambridge Stem Cell Initiative for sharing their ideas.

One contribution of 19 to a Theme Issue ‘ Personal perspectives in the life sciences for the Royal Society's 350th anniversary ’.

• Aasen T., et al.2008 Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes . Nat. Biotechnol. 26 , 1276–1284 ( doi:10.1038/nbt.1503 ) [ PubMed ] [ Google Scholar ]
• Anderson D. J., Gage F. H., Weissman I. L.2001 Can stem cells cross lineage boundaries? Nat. Med. 7 , 393–395 ( doi:10.1038/86439 ) [ PubMed ] [ Google Scholar ]
• Andrews P., Matin M., Bahrami A., Damjanov I., Gokhale P., Draper J.2005 Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin . Biochem. Soc. Trans. 33 , 1526–1530 ( doi:10.1042/BST20051526 ) [ PubMed ] [ Google Scholar ]
• Aoi T., Yae K., Nakagawa M., Ichisaka T., Okita K., Takahashi K., Chiba T., Yamanaka S.2008 Generation of pluripotent stem cells from adult mouse liver and stomach cells . Science 321 , 699–702 ( doi:10.1126/science.1154884 ) [ PubMed ] [ Google Scholar ]
• Arias A. M.2008 Drosophila melanogaster and the development of biology in the 20th century . Methods Mol. Biol. 420 , 1–25 ( doi:10.1007/978-1-59745-583-1_1 ) [ PubMed ] [ Google Scholar ]
• Austin E. B., Guttridge M., Pamphilon D., Watt S. M.2008 The role of blood services and regulatory bodies in stem cell transplantation . Vox Sang. 94 , 6–17 [ PubMed ] [ Google Scholar ]
• Barabé F., Kennedy J. A., Hope K. J., Dick J. E.2007 Modeling the initiation and progression of human acute leukemia in mice . Science 316 , 600–604 ( doi:10.1126/science.1139851 ) [ PubMed ] [ Google Scholar ]
• Brockes J. P., Kumar A.2005 Appendage regeneration in adult vertebrates and implications for regenerative medicine . Science 310 , 1919–1922 ( doi:10.1126/science.1115200 ) [ PubMed ] [ Google Scholar ]
• Brons I. G., et al.2007 Derivation of pluripotent epiblast stem cells from mammalian embryos . Nature 448 , 191–195 ( doi:10.1038/nature05950 ) [ PubMed ] [ Google Scholar ]
• Chambers I., et al.2007 Nanog safeguards pluripotency and mediates germline development . Nature 450 , 1230–1234 ( doi:10.1038/nature06403 ) [ PubMed ] [ Google Scholar ]
• Chang H. H., Hemberg M., Barahona M., Ingber D. E., Huang S.2008 Transcriptome-wide noise controls lineage choice in mammalian progenitor cells . Nature 453 , 544–457 ( doi:10.1038/nature06965 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen C. S.2008 Mechanotransduction—a field pulling together? J. Cell Sci. 121 , 3285–3292 ( doi:10.1242/jcs.023507 ) [ PubMed ] [ Google Scholar ]
• Clarke M. F., Dick J. E., Dirks P. B., Eaves C. J., Jamieson C. H., Jones D. L., Visvader J., Weissman I. L., Wahl G. M.2006 Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells . Cancer Res. 66 , 9339–9344 ( doi:10.1158/0008-5472.CAN-06-3126 ) [ PubMed ] [ Google Scholar ]
• Clayton E., Doupé D. P., Klein A. M., Winton D. J., Simons B. D., Jones P. H.2007 A single type of progenitor cell maintains normal epidermis . Nature 446 , 185–189 ( doi:10.1038/nature05574 ) [ PubMed ] [ Google Scholar ]
• Conti L., et al.2005 Niche-independent symmetrical self-renewal of a mammalian tissue stem cell . PLoS Biol. 3 , e283 ( doi:10.1371/journal.pbio.0030283 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• De Luca M., Pellegrini G., Green H.2006 Regeneration of squamous epithelia from stem cells of cultured grafts. Review . Regen. Med. 1 , 45–57 ( doi:10.2217/17460751.1.1.45 ) [ PubMed ] [ Google Scholar ]
• Dick J. E.2008 Stem cell concepts renew cancer research . Blood 112 , 4793–4807 ( doi:10.1182/blood-2008-08-077941 ) [ PubMed ] [ Google Scholar ]
• Dimos J. T., et al.2008 Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons . Science 321 , 1218–1221 ( doi:10.1126/science.1158799 ) [ PubMed ] [ Google Scholar ]
• Dor Y., Brown J., Martinez O. I., Melton D. A.2004 Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation . Nature 429 , 41–46 ( doi:10.1038/nature02520 ) [ PubMed ] [ Google Scholar ]
• Dunnett S. B., Björklund A., Lindvall O.2001 Cell therapy in Parkinson's disease—stop or go? Review . Nat. Rev. Neurosci. 2 , 365–369 ( doi:10.1038/35072572 ) [ PubMed ] [ Google Scholar ]
• Evans M., Kaufman M.1981 Establishment in culture of pluripotential cells from mouse embryos . Nature 292 , 154–156 ( doi:10.1038/292154a0 ) [ PubMed ] [ Google Scholar ]
• Gaspar H. B., Thrasher A. J.2005 Gene therapy for severe combined immunodeficiencies . Expert Opin. Biol. Ther. 5 , 1175–1182 ( doi:10.1517/14712598.5.9.1175 ) [ PubMed ] [ Google Scholar ]
• Green H.2008 The birth of therapy with cultured cells . Bioessays 30 , 897–903 ( doi:10.1002/bies.20797 ) [ PubMed ] [ Google Scholar ]
• Gurdon J. B., Melton D. A.2008 Nuclear reprogramming in cells. Review . Science 322 , 1811–1815 ( doi:10.1126/science.1160810 ) [ PubMed ] [ Google Scholar ]
• Gurdon J. B., Elsdale T. R., Fischberg M.1958 Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei . Nature 182 , 64–65 ( doi:10.1038/182064a0 ) [ PubMed ] [ Google Scholar ]
• Hahn W. C., Weinberg R. A.2002 Modelling the molecular circuitry of cancer . Nat. Rev. Cancer 2 , 331–341 ( doi:10.1038/nrc795 ) [ PubMed ] [ Google Scholar ]
• Hall P. A., Watt F. M.1989 Stem cells: the generation and maintenance of cellular diversity . Development 106 , 619–633 [ PubMed ] [ Google Scholar ]
• Hochedlinger K., Yamada Y., Beard C., Jaenisch R.2005 Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues . Cell 121 , 465–477 ( doi:10.1016/j.cell.2005.02.018 ) [ PubMed ] [ Google Scholar ]
• Hyun I., et al.2008 New ISSCR guidelines underscore major principles for responsible translational stem cell research . Cell Stem Cell 3 , 607–609 ( doi:10.1016/j.stem.2008.11.009 ) [ PubMed ] [ Google Scholar ]
• Ivanova N. B., Dimos J. T., Schaniel C., Hackney J. A., Moore K. A., Lemischka I. R.2002 A stem cell molecular signature . Science 298 , 601–604 ( doi:10.1126/science.1073823 ) [ PubMed ] [ Google Scholar ]
• Izumi N., Era T., Akimaru H., Yasunaga M., Nishikawa S.2007 Dissecting the molecular hierarchy for mesendoderm differentiation through a combination of embryonic stem cell culture and RNA interference . Stem Cells 25 , 1664–1674 ( doi:10.1634/stemcells.2006-0681 ) [ PubMed ] [ Google Scholar ]
• Jaenisch R., Young R.2008 Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming . Cell 132 , 567–582 ( doi:10.1016/j.cell.2008.01.015 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Jensen K. B., Watt F. M.2006 Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence . Proc. Natl. Acad. Sci. USA 103 , 11958–11963 ( doi:10.1073/pnas.0601886103 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kamitakahara M., Ohtsuki C., Miyazaki T.2008 Review paper: behavior of ceramic biomaterials derived from tricalcium phosphate in physiological condition . J. Biomater. Appl. 23 , 197–212 ( doi:10.1177/0885328208096798 ) [ PubMed ] [ Google Scholar ]
• Kerr C. L., Gearhart J. D., Elliott A. M., Donovan P. J.2006 Embryonic germ cells: when germ cells become stem cells . Semin. Reprod. Med. 24 , 304–313 ( doi:10.1055/s-2006-952152 ) [ PubMed ] [ Google Scholar ]
• Kim J. B., et al.2008 Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors . Nature 454 , 646–650 ( doi:10.1038/nature07061 ) [ PubMed ] [ Google Scholar ]
• Lajtha L. G.1979 Stem cell concepts . Nouv. Rev. Fr. Hematol. 21 , 59–65 [ PubMed ] [ Google Scholar ]
• Lau D., Ogbogu U., Taylor B., Stafinski T., Menon D., Caulfield T.2008 Stem cell clinics online: the direct-to-consumer portrayal of stem cell medicine . Cell Stem Cell 3 , 591–594 ( doi:10.1016/j.stem.2008.11.001 ) [ PubMed ] [ Google Scholar ]
• Leblond C. P.1964 Classification of cell populations on the basis of their proliferative behavior . Natl. Cancer Inst. Monogr. 14 , 119–150 [ PubMed ] [ Google Scholar ]
• Lo Celso C., et al.2009 Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche . Nature 457 , 92–96 ( doi:10.1038/nature07434 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Lowell S., Benchoua A., Heavey B., Smith A. G.2006 Notch promotes neural lineage entry by pluripotent embryonic stem cells . PLoS Biol. 4 , e121 ( doi:10.1371/journal.pbio.0040121 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Macchiarini P., et al.2008 Clinical transplantation of a tissue-engineered airway . Lancet 372 , 2023–2030 ( doi:10.1016/S0140-6736(08)61598-6 ) [ PubMed ] [ Google Scholar ]
• Markoulaki S., et al.2009 Transgenic mice with defined combinations of drug-inducible reprogramming factors . Nat. Biotechnol. 27 , 169–171 ( doi:10.1038/nbt.1520 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Marson A., et al.2008 Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells . Cell 134 , 521–533 ( doi:10.1016/j.cell.2008.07.020 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Martin G.1981 Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells . Proc. Natl. Acad. Sci. USA 78 , 7634–7638 ( doi:10.1073/pnas.78.12.7634 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Mathur D., Danford T. W., Boyer L. A., Young R. A., Gifford D. K., Jaenisch R.2008 Analysis of the mouse embryonic stem cell regulatory networks obtained by ChIP-chip and ChIP-PET . Genome Biol. 9 , R126 ( doi:10.1186/gb-2008-9-8-r126 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Mavilio F., et al.2006 Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells . Nat. Med. 12 , 1397–1402 ( doi:10.1038/nm1504 ) [ PubMed ] [ Google Scholar ]
• McCulloch E. A., Minden M. D., Miyauchi J., Kelleher C. A., Wang C.1988 Stem cell renewal and differentiation in acute myeloblastic leukaemia. Review . J. Cell Sci. Suppl. 10 , 267–281 [ PubMed ] [ Google Scholar ]
• Meissner A., et al.2008 Genome-scale DNA methylation maps of pluripotent and differentiated cells . Nature 454 , 766–770 [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Miller R. A., Ruddle F. H.1976 Pluripotent teratocarcinoma-thymus somatic cell hybrids . Cell 9 , 45–55 ( doi:10.1016/0092-8674(76)90051-9 ) [ PubMed ] [ Google Scholar ]
• Morrison S. J., Spradling A. C.2008 Stem cells and niches: mechanisms that promote stem cell maintenance throughout life . Cell 132 , 598–611 ( doi:10.1016/j.cell.2008.01.038 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• O'Brien C. A., Pollett A., Gallinger S., Dick J. E.2007 A human colon cancer cell capable of initiating tumour growth in immunodeficient mice . Nature 445 , 106–110 ( doi:10.1038/nature05372 ) [ PubMed ] [ Google Scholar ]
• Okita K., Nakagawa M., Hyenjong H., Ichisaka T., Yamanaka S.2008 Generation of mouse induced pluripotent stem cells without viral vectors . Science 322 , 949–953 ( doi:10.1126/science.1164270 ) [ PubMed ] [ Google Scholar ]
• Park I. H., Zhao R., West J. A., Yabuuchi A., Huo H., Ince T. A., Lerou P. H., Lensch M. W., Daley G. Q.2008a Reprogramming of human somatic cells to pluripotency with defined factors . Nature 451 , 141–146 ( doi:10.1038/nature06534 ) [ PubMed ] [ Google Scholar ]
• Park I. H., et al.2008b Disease-specific induced pluripotent stem cells . Cell 134 , 877–886 ( doi:10.1016/j.cell.2008.07.041 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Perry A. R., Linch D. C.1996 The history of bone-marrow transplantation . Blood Rev. 10 , 215–219 ( doi:10.1016/S0268-960X(96)90004-1 ) [ PubMed ] [ Google Scholar ]
• Pike-Overzet K., van der Burg M., Wagemaker G., van Dongen J. J., Staal F. J.2007 New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy . Mol. Ther. 15 , 1910–1916 ( doi:10.1038/sj.mt.6300297 ) [ PubMed ] [ Google Scholar ]
• Potten C. S., Loeffler M.2008 Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt . Development 110 , 1001–1020 [ PubMed ] [ Google Scholar ]
• Quintana E., Shackleton M., Sabel M. S., Fullen D. R., Johnson T. M., Morrison S. J.2008 Efficient tumour formation by single human melanoma cells . Nature 456 , 593–598 ( doi:10.1038/nature07567 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Ramalho-Santos M., Yoon S., Matsuzaki Y., Mulligan R. C., Melton D. A.2002 ‘Stemness’: transcriptional profiling of embryonic and adult stem cells . Science 298 , 597–600 ( doi:10.1126/science.1072530 ) [ PubMed ] [ Google Scholar ]
• Reya T., Morrison S. J., Clarke M. F., Weissman I. L.2001 Stem cells, cancer, and cancer stem cells . Nature 414 , 105–111 ( doi:10.1038/35102167 ) [ PubMed ] [ Google Scholar ]
• Sacco A., Doyonnas R., Kraft P., Vitorovic S., Blau H. M.2008 Self-renewal and expansion of single transplanted muscle stem cells . Nature 456 , 502–506 ( doi:10.1038/nature07384 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Silva J., Smith A.2008 Capturing pluripotency . Cell 132 , 532–536 ( doi:10.1016/j.cell.2008.02.006 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Silva J., Barrandon O., Nichols J., Kawaguchi J., Theunissen T. W., Smith A.2008 Promotion of reprogramming to ground state pluripotency by signal inhibition . PLoS Biol. 6 , e253 ( doi:10.1371/journal.pbio.0060253 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Silva-Vargas V., Lo Celso C., Giangreco A., Ofstad T., Prowse D. M., Braun K. M., Watt F. M.2005 β -Catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells . Dev. Cell 9 , 121–131 ( doi:10.1016/j.devcel.2005.04.013 ) [ PubMed ] [ Google Scholar ]
• Singh S. K., Clarke I. D., Hide T., Dirks P. B.2004 Cancer stem cells in nervous system tumors . Oncogene 23 , 7267–7273 ( doi:10.1038/sj.onc.1207946 ) [ PubMed ] [ Google Scholar ]
• Stadtfeld M., Nagaya M., Utikal J., Weir G., Hochedlinger K.2008 Induced pluripotent stem cells generated without viral integration . Science 322 , 945–949 ( doi:10.1126/science.1162494 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Takahashi K., Yamanaka S.2006 Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors . Cell 126 , 663–676 ( doi:10.1016/j.cell.2006.07.024 ) [ PubMed ] [ Google Scholar ]
• Takahashi K., Tanabe K., Ohnuki M., Narita M., Ichisaka T., Tomoda K., Yamanaka S.2007 Induction of pluripotent stem cells from adult human fibroblasts by defined factors . Cell 131 , 861–872 ( doi:10.1016/j.cell.2007.11.019 ) [ PubMed ] [ Google Scholar ]
• Tesar P. J., Chenoweth J. G., Brook F. A., Davies T. J., Evans E. P., Mack D. L., Gardner R. L., Mckay R. D.2007 New cell lines from mouse epiblast share defining features with human embryonic stem cells . Nature 448 , 196–199 ( doi:10.1038/nature05972 ) [ PubMed ] [ Google Scholar ]
• Théry M., Racine V., Pépin A., Piel M., Chen Y., Sibarita J. B., Bornens M.2005 The extracellular matrix guides the orientation of the cell division axis . Nat. Cell Biol. 7 , 947–953 ( doi:10.1038/ncb1307 ) [ PubMed ] [ Google Scholar ]
• Thomson J., Itskovitz-Eldor J., Shapiro S., Waknitz M., Swiergiel J., Marshall V., Jones J.1998 Embryonic stem cell lines derived from human blastocysts . Science 282 , 1145–1147 ( doi:10.1126/science.282.5391.1145 ) [ PubMed ] [ Google Scholar ]
• Torres J., Watt F. M.2008 Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFkappaB and cooperating with Stat3 . Nat. Cell Biol. 10 , 194–201 ( doi:10.1038/ncb1680 ) [ PubMed ] [ Google Scholar ]
• Watt F. M.1999 Stem cell manifesto. Book review . Cell 96 , 470–473 ( doi:10.1016/S0092-8674(00)80643-1 ) [ Google Scholar ]
• Watt F. M., Collins C. A.2008 Role of β -catenin in epidermal stem cell expansion, lineage selection, and cancer . Cold Spring Harb. Symp. Quant. Biol. 73 , 503–512 ( doi:10.1101/sqb.2008.73.011 ) [ PubMed ] [ Google Scholar ]
• Watt F. M., Hogan B. L.2000 Out of Eden: stem cells and their niches . Science 287 , 1427–1430 ( doi:10.1126/science.287.5457.1427 ) [ PubMed ] [ Google Scholar ]
• Watt F. M., Jordan P. W., O'Neill C. H.1988 Cell shape controls terminal differentiation of human epidermal keratinocytes . Proc. Natl. Acad. Sci. USA 85 , 5576–5580 ( doi:10.1073/pnas.85.15.5576 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wernig M., Meissner A., Foreman R., Brambrink T., Ku M., Hochedlinger K., Bernstein B. E., Jaenisch R.2007 In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state . Nature 448 , 318–324 ( doi:10.1038/nature05944 ) [ PubMed ] [ Google Scholar ]
• Wilmut I., Schnieke A. E., McWhir J., Kind A. J., Campbell K. H.1997 Viable offspring derived from fetal and adult mammalian cells . Nature 385 , 810–813 [Erratum in Nature 1997 386 , 200.] ( doi:10.1038/385810a0 ) [ PubMed ] [ Google Scholar ]
• Wright B. L., Barker R. A.2007 Established and emerging therapies for Huntington's disease . Curr. Mol. Med. 7 , 579–587 ( doi:10.2174/156652407781695738 ) [ PubMed ] [ Google Scholar ]
• Xie Y., et al.2009 Detection of functional haematopoietic stem cell niche using real-time imaging . Nature 457 , 97–101 ( doi:10.1038/nature07639 ) [ PubMed ] [ Google Scholar ]
• Yamanaka S.2007 Strategies and new developments in the generation of patient-specific pluripotent stem cells . Cell Stem Cell 1 , 39–49 ( doi:10.1016/j.stem.2007.05.012 ) [ PubMed ] [ Google Scholar ]
• Yu J., et al.2007 Induced pluripotent stem cell lines derived from human somatic cells . Science 318 , 1917–1920 ( doi:10.1126/science.1151526 ) [ PubMed ] [ Google Scholar ]
• Zaret K. S., Grompe M.2008 Generation and regeneration of cells of the liver and pancreas . Science 322 , 1490–1494 ( doi:10.1126/science.1161431 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Zhao C., Deng W., Gage F. H.2008 Mechanisms and functional implications of adult neurogenesis . Cell 132 , 645–660 ( doi:10.1016/j.cell.2008.01.033 ) [ PubMed ] [ Google Scholar ]
• Zhou Q., Brown J., Kanarek A., Rajagopal J., Melton D. A.2008 In vivo reprogramming of adult pancreatic exocrine cells to beta-cells . Nature 455 , 627–632 ( doi:10.1038/nature07314 ) [ PMC free article ] [ PubMed ] [ Google Scholar ]

• Open access
• Published: 15 August 2024

Clinical and preclinical approach in AGA treatment: a review of current and new therapies in the regenerative field

• Lorena Pozo-Pérez   ORCID: orcid.org/0009-0000-8208-6669 1 , 2 ,
• Pilar Tornero-Esteban 3 &
• Eduardo López-Bran 1  

Stem Cell Research & Therapy volume  15 , Article number:  260 ( 2024 ) Cite this article

159 Accesses

Metrics details

Androgenetic alopecia (AGA) is the most prevalent type of hair loss. Its morbility is mainly psychological although an increased incidence in melanoma has also been observed in affected subjects. Current drug based therapies and physical treatments are either unsuccessful in the long term or have relevant side effects that limit their application. Therefore, a new therapeutic approach is needed to promote regenerative enhancement alternatives. These treatment options, focused on the cellular niche restoration, could be the solution to the impact of dihydrotestosterone in the hair follicle microenvironment. In this context emerging regenerative therapies such as Platelet-rich plasma or Platelet-rich fibrine as well as hair follicle stem cells and mesenchymal stem cell based therapies and their derivatives (conditioned medium CM or exoxomes) are highlighting in the evolving landscape of hair restoration. Nanotechnology is also leading the way in AGA treatment through the design of bioinks and nanobiomaterials whose structures are being configuring in a huge range of cases by means of 3D bioprinting. Due to the increasing number and the rapid creation of new advanced therapies alternatives in the AGA field, an extended review of the current state of art is needed. In addition this review provides a general insight in current and emerging AGA therapies which is intented to be a guidance for researchers highlighting the cutting edge treatments which are recently gaining ground.

Introduction

AGA is a dynamic and progressive hair loss disorder which affects men and women around the world. The incidence of AGA increases with age, affecting 80% of Caucasian men population and 30–50% bellow the age of 50 years old [ 1 , 2 ]. A similar prevalence is observed in elderly women [ 3 ] . Although AGA is often considered a minor dermatological condition, hair loss has a huge impact on self-esteem and quality of life, hence its frequent association with anxiety and depression [ 4 ].

The etiology of AGA entails an intricate interplay among different genetic and hormonal factors, resulting in the miniaturization of hair follicles and alterations in the dynamics of the hair growth cycle, specifically the shortening of the anagen phase. AGA hormonal etiology is caused by DHT, an androgen derived from testosterone by 5-alpha reductase enzyme action. This hormone has a higher affinity towards androgen receptors (ARs) in the hair follicles. In fact, individuals with AGA have an overexpressed AR gene compared to controls [ 5 , 6 ]. This situation leads to follicle miniaturisation after the expression of senescence genes [ 6 , 7 ].

AR locus is located in the X cromosome hence it shows a X-linked inheritance. In addition several AR polimorfisms are known to be linked to a higher probability to suffer AGA [ 8 ]. Although 5α-reductase enzime is also a key factor in AGA development, SRD5A1 and SRD5A2 (5-αreductase genes) association studies do not showed any relation between them and AGA [ 9 ].

Although male AGA etiology is well known to be caused by DHT action in hair follicles, female AGA is related to a huge range of trigger factors, hence observed clinical differences between both sexes. For example women have a diffuse hair loss patron whereas all men keep their hair density in occipital areas. Female AGA cases are in many cases linked to hirsutism patients and in menopause period [ 10 , 11 ] Estrogens exerts a protective impact probably due to their capacity to participate in androgen metabolism in the dermal papilla cells (DPCs).

Hair cycle includes three phases: hair growth phase (anagen) [ 12 ], regression phase (catagen) [ 13 ] and relative rest phase (telogen) [ 14 ]. In AGA patients, a shortening of the anagen phase is observed, so that the telogen phase sets in progressively. Hair becomes thinner and eventually the anagen phase turns so short that hair is not long enough to reach the skin surface [ 15 ] Testosterone and DHT act on the ARs in the DPCs by negatively modulating growth factors genes transcription and positively growth factor suppressors such as Transforming Growth Factor Beta (TGF-β) and Dickkopf-1 (DKK-1), both inducers of the catagen phase [ 16 , 17 ]. It is well known that anagen phase is characterised by the proliferation of follicular cells, mainly epithelial cells and DPCs. The latter, together with bulge stem cells (BSCs), are the two main types of hair follicle stem cells involved in hair growth. Their importance has been documented detecting changes in their functionality in AGA patients [ 18 , 19 ]. Inflammation is also one of the pathophysiological characteristics of AGA, as evidenced by the lymphocytes and mast cells infiltration around the bulge area [ 20 , 21 , 22 ].

Material and methods

A systematic clinical trials review was conducted in ClinicalTrials.gov ( https://clinicaltrials.gov/ ). The keywords “AGA” as Condition or disease and “CELL THERAPY” were used. A literature search about preclinical studies was conducted using Pubmed ( https://pubmed.ncbi.nlm.nih.gov/ ) and introducing various combinations of the following terms: FINASTERIDE, AGA, CELL THERAPY, ASCs (Adipose derived Stem Cells), ASCs-CM (ASCs Conditioned Medium), MESOTHERAPY, PRP, MINOXIDIL, KETOKENAZOL, BICALUTAMIDE, CORTEXOLONE 17A-PROPIONATE, LASER THERAPY, HAIR TRANSPLANT, MURINE MODEL, MICE, MICRONEEDLING, WNT PATHWAY, JAK-STAT PATHWAY, MSCs and SVF (Stromal Vascular Fraction), REGENERATIVE THERAPIES, NANOPARTICLES, BIOINKS, GREEN NANOMATERIALS, HERBAL EXTRACTS, PHYTOMEDICINE amd 3D BIOPRINTING. The electronic databases were systematically searched until May, 2024.

Conventional therapies

Antiandrogens.

Finasteride 1 mg/day is the only one oral FDA and EMA approved drugs for AGA treatment. This drug is a potent and specific inhibitor of the 5-alpha reductase (type II) which shows benefitial effects stopping hair loss in the 80% of the patients after one year-treatment [ 23 ]. Its primary action, which involves halting DHT production is responsible of adverse effects such as reduced eyaculation volume, loss of libido and erectile dysfunction. Furthermore, although prolonged treatments with Finasteride do not produce drastic semen alterations in healthy men, it may impact patients experiencing infertility symptoms, leading to controversial prescription in young men [ 24 ]. In general Finasteride levels are very low in semen hence its use is not restricted [ 25 ]. Moreover, Finasteride is also contraindicated in women due to its teratogenic effects during pregnancy and its potential risk of developing breast cancer [ 26 ].

Thus, efforts have been led to develop various topical formulations of Finasteride to mitigate systemic side effects associated with oral administration, such as sprays or nano-transferosomal gels. Studies indicate that topical Finasteride increases hair count, is well tolerated and is as effective as oral Finasteride [ 27 , 28 , 29 , 30 ].

Nevertheless, despite its effectiveness and minimal adverse effects, further research is essential to evaluate the long-term efficacy of hair regrowth, therapeutic safety, cost-effectiveness, patient tolerability and satisfaction with topical Finasteride among individuals with androgenetic alopecia. Although oral is the only Finateride formulation approved for AGA treatment in Europe, also recommmended as concomitant therapy after follicular unit transplantation procedure, topical solution is expected to be approved proximately due to the numerous ongoing and completed phase III clinical trials (NCT03004469/EUDRACT2015-002877–40).

Concomitantly Ketoconazole, a topical antifungal shampoo for the treatment of seborrhoeic dermatitis can be applied. Its anti-inflammatory and anti-androgenic properties by affecting steroid genesis enhance Finasteride effect by decreasing DHT levels in the male scalp [ 31 , 32 ]. An improvement in the progression of AGA and hirsutism conditions in women was also observed [ 33 ].

On the other hand, Dutasteride, another selective inhibitor of both type-1 and type-2 5-alpha reductase enzymes was assessed as Dutasteride 0,5 mg showing superior outcomes in terms of hair density and hair width compared to Finasteride 1 mg treatment [ 34 ]. However, its clinical use remains limited as it is only approved in Mexico and Korea [ 26 ]. Currently its topical formulation is being tested in Europe (EUDRACT2022-001802–23).

A topical application of these inhibitor drugs is expected to be approved proximately if clinical trials continue showing as effective results as oral ones.

Other drugs that avoid AR activation are its antagonists such as Cortexolone 17a-propionate, Spironolactone or Cyproterone. In general these drugs do not achieve better results than approved ones (oral Finasteride and topical Minoxidil) and cause several adverse effects .

As aforementioned, Minoxidil is currently the only topical drug approved for AGA. Its application for hair growth was discovered as an adverse effect of hypertension treatment due to its vasodilator action by opening potassium channels. Its oral formulation is not prescribed for AGA because it promotes a systemic arterial hypotension caused by vascular smooth muscle relaxation. Its topical application is completely safe and it was approved with the aim of acting only on the scalp vessels. It increases blood flow thus an extra nutrients and oxygen supply to the hair follicle. Moreover, one study found cytoprotective activity resulting from the activation of prostaglandin synthase-1, the main isoform in DPCs [ 35 ]. Doses range from 2 to 5%, and like other hair growth stimulators, Minoxidil treatment can cause telogen follicles to fall out and be replaced by new ones [ 36 ]. Nevertheless, the efficacy in the population is still low, not exceeding 40% of treated patients after 24 weeks of treatment [ 23 ].

In order to improve Minoxidil outcomes several oral doses and sulphate compositions are being tested. Recently, a clinical study of 30 male participants has shown efficacy and safety of 5 mg daily dose of oral Minoxidil after being administered to patients for 24 weeks [ 37 ]. Lower oral doses such as 1.25 mg/day for 24 weeks, daily capsules containing minoxidil 0.25 mg and spironolactone 25 mg as well as a dose range of 0.25–2.5 mg in female hair loss also showed a clinical improvement and a hair shedding reduction in AGA patients [ 38 , 39 , 40 ] as well as the sublingual daily dose of 0.45 mg, tested in female and male AGA subjects with an acceptable safety and efficacy profile [ 41 ]. The most common adverse effects are irritant and allergic contact dermatitis on the scalp and facial hypertrichosis [ 26 ].

Throughout the years, several studies have pointed out the importance of sulphate as an effective supplement to Minoxidil treatment. In particular Minoxidil sulphate is known to be fourteen times more potent than Minoxidil tested in vitro follicles [ 42 ]. These results have been supported over the years. In 2019, Maekawa et al. reported hair growth promoting effects in an in vivo murine study after treatment with sodium thiosulphate without significant adverse effects [ 43 ]. These results were tested as a single treatment and in combination therapy with Minoxidil. They supported the additional effect of sulphate in Minoxidil therapy due to the cysteine supply. Minoxidil bio-activation by sulfotransferase enzymes has also been highlighted as an important clinical outcome predictor in female hair loss [ 44 ]. With the aim of improving topical Minoxidil penetrability, tissue retention and a side effects reduction lecithin-based microparticles has been tested as a vehicle in combination to sulphate [ 45 ].

Nowadays, different minoxidil formulations have not showed enough efficacy in all patients and this is the principal cause of the ongoing new therapies research. Specially since there is only indicated treatment for females (topical Minoxidil), nowadays, efforts are being undertaken in order to promote other alternative therapies. Other clinical trials performed with prostaglandin F2 analogues and Cetirizine, that we will address, has the same purpose. AR receptor antagonists outcomes such as from Bicalutamide or Flutamide applications have also been assessed showing mild favourable results in females and hepatotoxicity risk hence its not recomended use [ 26 , 46 ].

Prostagladins analogues and antagonists receptors

In general in order to avoid Finasteride and Minoxidil side effects, other topical drugs have been tested (Table 1 ). Prostaglandin F2 analogues such as Bimatoprost, approved for eyelashes hypotrichosis and Latanoprost, known to induce anagen phase in hair follicles, have been tested. Clinical trials reported are both effective comparing to placebo [ 47 , 48 , 49 , 50 , 51 , 52 ].

Setipiprant is also an oral prostaglandin D2 (PG D2) receptor antagonist which is overexpressed in AGA patients and related to follicle miniaturization [ 53 ]. A clinical trial testing a Setipiprant dose of 2000 mg/day was also conducted with slightly better results in hair density versus control [ 54 ]. In order to inhibite PG D2 receptor activation, topical Cetirizine, H1 antihistaminic and PG D2 production reducer, was also tested in a clinical study of 60 subjects. Experimental group showed significantly higher results in hair growth and patient satisfaction than control [ 55 ]. Recently Bassiouny et al. (2023) had performed a clinical trial testing topical Cetirizine as a concomitant medication with topical Minoxidil therapy in the treatment of female AGA. Results showed an increase in the hair shaft thickness and a higher clinical improvement. Its anti-inflammatory action can be also responsible of an improvement in AGA conditions [ 56 ].

Although prostaglandin F2 analogues are known to cause hair lightening and prostaglandin D2 antagonists to be related to atrophy and alopecia conditions, none of them achieve enough efficacy to be considered as promising therapeutical options.

Wnt and JAK-STAT regulators

Other pathways such as Wnt and JAK-STAT are known to regulate the hair cycle. Wnt activator and JAK-STAT inhibitor drugs have been tested in the light of in vivo and in vitro experimental studies with favourable results in hair growth [ 57 , 58 ]. Current clinical trials results are positive for SM04554, a Wnt pathway activator, promoting hair growth and Ki67 expression in the hair bulb [ 47 , 59 , 60 ]. Other such as Valproic acid and Ciclosporine A have also shown an enhancer hair growth effect. Regarding JAK-STAT inhibitor drugs, a JAK inhibitor 1/3 was clinically tested but no significant differences were observed [ 61 ].

Physical treatments

Laser therapy and hair transplant hightlight among physical treatments. In order to stop hair loss in AGA, a wide range of wavelengths has been studied in laser therapy which could stimulate angiogenesis and inflammation possibly mediated by HSP27 leading to follicular stem cell activation [ 62 ].

Damage and hair follicle scarring derived from the difficulty in defining adjusted energy parameters are some of the laser therapy limitations [ 63 ]. Lower wavelengths are considered as optimal ones around 655 nm [ 64 ]. In 2007, Low-Level Laser (Light) Therapy was approved by the FDA as a treatment for hair loss [ 26 , 65 , 66 ]. Several devices using this technology have been applied such as the HairMax Laser Comb (Lexington International LLC, Boca Raton, FL, United States) in 2011 or iRestore Light Therapy Apparatus, tested in a clinical trial in 2015 for male and female AGA [ 26 , 62 , 65 ]. Several randomised, controlled, double-blinded studies results have shown an increased self-rated questionnaire and total hair score in daily and weekly irradiated individuals [ 67 , 68 ].

Fractionated Erbium laser studies in women with AGA have also reported an improvement in hair density [ 69 , 70 , 71 ]. A trial combining 1550 nm fractionated Erbium laser treatment with topical Minoxidil 5% compared to Minoxidil treatment was conducted in 2019. Combined treatment results were significantly higher than Minoxidil alone [ 72 ]. Another study tested 1550 nm fractionated Erbium laser and PRP alone and in combination. A synergistic effect was showed in the combinated therapy with the greatest outcome [ 73 ].

As European guidelines report, laser can be applied as an ancillary therapy with Finasteride or Minoxidil therefore single laser therapy outcomes does not show efficacy by itself.

Hair transplantation as a surgical technique is based on the sensitivity and distribution of the ARs in different scalp areas. Thus, follicles are extracted from a donor area which is not sensitive to androgen action and then are inserted into the affected scalp. In general, transplantation involves a lasting impact resulting in natural hair growth after 6 months and in a patient's self-esteem significant improvement. Low density of the donor area [ 74 ], reduced viability of the cells obtained [ 75 ] or curly hair are limitations in the process [ 76 ]. Transplantation success depends on the technique, surgeon`s skills and individual characteristics [ 77 ]. Follicular unit transplantation is the gold standard technique with a low frequency of complications [ 26 , 78 ] however AGA progression continues so adjuvant therapies are necessary hence its use in combination to oral Finasteride [ 1 , 74 ]. One of its limitations is that it provides a partial solution since the other nontransplanted follicles, which remains in the frontal and vertex area, still are contingent to DHT atrophic action.

Apparently Finasteride should show a 100% of successfull outcomes because it acts exactly in the etiologic target. However this is not a fact. Althought DHT production will stop after blocking 5-α reductase by antiandrogen therapies, minituarization process would have been triggered, afecting numerous hair follicles becoming fibrotic stellae. It is seemed that this phenomena will be mostly irreversible although DHT levels were low as clinical evidence shows. Other injury factors such as inflammation or fibrosis are needed to be treated as well. These are the reasons why new regenerative therapies are necessary in order to restore damaged follicular mechanisms caused by a prolonged DHT action. The angiogenic and anti-inflammatory growth factors release, PRP functions and the supply of different cell populations have shown to be promising therapies in a near future.

Microneedling

On one hand, microneedling is a widely used technique in dermatology in which a large number of microneedles positioned on a dermatological roller on the skin activates the healing process and thus triggers angiogenesis, platelets mobilisation and growth factors, collagen and elastin synthesis [ 79 ]. The mechanism of action is based on the aforementioned regenerative activation, the BSCs stimulation caused by scarring, and growth-related genes overexpression such as Vascular Endothelial Growth Factor (VEGF), β-catenin or Wnt pathway products [ 80 ]. Hundred cases of mild to moderate AGA were recruited and it was observed that Minoxidil microneedling was more effective than Minoxidil alone. Since then, numerous trials have supported the microneedling sessions efficacy as an adjuvant technique to pharmacological therapy with Minoxidil or Finasteride and after PRP and PRF administration procedure. In 2018, Kumar et al. [ 81 ] compared weekly microneedling plus twice-daily application of topical Minoxidil to Minoxidil-treated group. Hair density increased and patient satisfaction score was higher in the former group, although response was not macroscopically significant. Later these results were supported by Bao et al. [ 82 ]. Yu et al. [ 83 ] also tested an AGA treatment based on a topical fibroblast growth factor (FGF) solution sprayed before microneedling and topical Minoxidil. They observed in this group the most satisfactory results comparing to Minoxidil, FGF or saline alone.

Mesotherapy

On the other hand, mesotherapy is an intradermal technique which consists of administering pharmacological substances and natural active ingredients diluted in small doses at specific points on the affected scalp. Melo et al. [ 84 ] reported a case whose results showed a considerable increase in hair density after 20 treatment sessions using a mixture composed of 1 ml of Minoxidil 0.5%, 1 ml of Finasteride 0.05%, 2 ml of biotin 5 mg/ml and 2 ml of D-panthenol 50 mg/ml. Mesotherapy with natural compounds seemed to be clinically effective as an adjunctive treatment to Minoxidil and Finasteride. Although it is a minimally invasive technique adverse events may include burning, erythema, headaches, subcutaneous necrosis, scalp abscesses and edema [ 85 ].

Gajjar et al. [ 86 ] conducted a clinical trial to evaluate safety and efficacy of an amino acids, vitamins and other nutritional compounds solution, and compared it to the group treated with topical Minoxidil 5%. They observed no significant differences between groups. Recently Nassar et al. [ 87 ] compared LC hair essence serum (formulated with hyaluronic acid, stem cell extract peptides, and zinc arginine and red clover extract) and botulinum toxin A administration. Better results were obtained in LC treated group than in botox treated one although both showed a significant improvement in hair growth.

Jung et al. [ 88 ] obtained favourable results in a pilot animal study whereby botox was subcutaneously administered in a stress model mice, and Zhou et al. [ 89 ] showed promising results with an favourable safety and efficacy profiles alone and in combination with Finasteride in a clinical study of 63 patients. Aforementioned, Nassar et al. [ 87 ] also obtained significant results. Currently a clinical trial is recruiting male and female participants in order to assess its effect in mild to moderate AGA subjects [ 90 ]. It has also been studied as a preventive drug by intramuscular injection for the progressive hair loss in AGA men [ 91 ].

Simultaneously microcirculation is enhanced by both methods and consequently additional benefits, besides the active ingredient of the solution applied, are provided to the hair growth and a faster and more effective absortion as well. The needles damage along the surface promotes the activation of skin regenerative mechanisms along with angiogenesis.

Emerging therapies

The number of innovative therapies increases constantly improving or incorporating new physical techniques and active pharmaceutical or living beings extracts ingredients. Among them the most of AGA emerging therapies are regenerative-based whose main favourable actions are angiogenesis activation, growth factors supply and antiinflamatory action (Table 2 ).

Phytomedicine

Traditionally phytomedicine has been applied in AGA treatment for many years. Topical and subcutaneous administration of plant extracts has been extended in experimental studies showing a favourable hair promoting effect [ 92 , 93 ].

Nowadays some clinical trials are been performed in order to validate these preliminar results. Among them, niacin, ascorbic acid, vitamin B complex, tocopherol, grape seed, rosemary oil, sage, nettles and Hibiscus rosasinensis are used because of their capacity to improve blood supply [ 94 ] . Serenoa repens extract prevents TGF-β induction, caused by DHT, and interacts with mithocondrial signaling pathway contributing to its protective action [ 92 ]. Other are antioxidants which can act against microinflammation (grape seed) or actively inhibits 5α-reductase (green tea [ 95 ], ginkgo biloba [ 94 ], gingenoside ro [ 93 ] or curcumin [ 96 ]). Other tea extracts such as Chinese black tea has shown a higher affinity to estrogen receptors promoting also a hair growth enhancer effect [ 97 ].

Neurotoxines

In the last years the study of neurotoxines in disorders like AGA has been documented.

The mechanism of action of Botulinum toxin A particularly is based in its relaxation effect. It is known that a turgency loss can enhance hair growth. Hair follicle is considered as a mechanosensitive organ which can be affected by an increase of occipitofrontal muscle tightening which reduce blood flow. This fact is considered as a hair loss promoter but not a trigger itself [ 87 ]. Another suggested Botulinum toxin A function is the inhibition of TGF-β1 released by hair follicles and related to AGA fibrosis and which is considered as a supressor factor of the follicular keratinocyte growth [ 98 ].

Specially Botulinum toxin application has recently been considered as an effective and safe therapeutical option for AGA treatment which improves Finasteride and Finasteride plus Minoxidil outcomes as a supplement of these standard therapies [ 99 ].

All the clinical trials performed have reported an increase of hair count, clinical response or patient satisfaction [ 98 , 99 , 100 , 101 , 102 ]. Today further neurotoxins implications in AGA clinical improvement are needed to dilucidate. The heterogenous methodology applied and the absence of control studies are some of the weakest points to be improved [ 103 ].

Nanotechnology

Nanotechnology offers innovative solutions in several areas of biomedicine. They have been widely used in wound healing, tissue regeneration, drug delivery systems and personalised medicine [ 104 , 105 , 106 ].

Its use in AGA is growing rapidly and it is establishing itself as a promising new therapeutic option. Diverse nanosystems including nanoparticles, nanostructured lipid carriers and nanotransferosomes have been proposed for the treatment of hair follicle disorders.

These systems share a common strategy: achieving a more precise control over drug release and enhancing the efficacy of drug delivery to the target niche as biocompatible complexes. Their size and design facilitate the accumulation of these nanoparticles in follicle casts, effectively serving as drug reservoirs, thereby increasing local drug concentration at the target site while minimising systemic side effects [ 107 ].

The topical use of Minoxidil using lecithin based nanoestructures has been used to enhance a percutaneous delivery and to avoid skin side effects showing yielding comparable efficacy with a reduced incidence of skin issues [ 45 ]. Polymeric nanoparticles has also been explored as carriers of topical Finasteride [ 108 ]. Whereas the reported lecithin based nanoparticles benefits were associated with an enhanced safety profile, the polymeric Finasteride carriers were found to yield a prolongued Finasteride release thereby increasing its time of residence onto the skin [ 108 , 109 ].

Other nanoparticles conformed by Molybdenum has been also applied. Molybdelum inhibits oxidative stress due to the presence in its composition of transition metal elements with rapid electron transfer. It is suggested to be a promising therapeutic approach alone and in combination with Minoxidil [ 110 ] .

Additionally, other formulations based on nano-transferosomes, widely used as drug nanocarriers across the skin [ 111 ], were also applied for Finasteride administration as a gel form [ 28 ].

A recent study has illustrated an increased efficacy of Aminexil, a keratin fibers stimulator and hair growth promoter, loaded in a nanostructured lipid carrier (NLC) in chemotherapy-induced alopecia rats showing an increase in hair growth promotion compared to the use of the commercial product alone [ 112 ].

In the context of phytomedicine, green nanomaterials such as Poly-γ-glutamic acid (PGA) nanoparticles have been widely used as delivery agents due to a high biocompatibility and a good safety profile [ 113 ]. In particular it has been shown to be an excellent carrier for an herbal mixture consisting of Phellinus linteus , Cordyceps militaris , Polygonum multiflorum , Ficus carica, and Cocos nucifera oil. PGA as a vehicle of the herbal mixture also promoted a higher hair length, an earlier anagen initiation and a more prolonged anagen phase in C57BL/6N mice. An increase in β-catenin protein expression, a stimulator of the anagen phase, was reported to improve the effect of the herbal mixture alone [ 113 ]. This herbal extract has been also carried by PGA in combination to Chitosan Hydrogel supporting these results and reporting an induction of changes in DPCs to a polygonal shape which is associated with an enlargement of the hair bulbs [ 114 ].

PGA has also been proven as a curcumic-zinc framework carrier through a microneedle patch with promising results in hair growth [ 115 ]. Therefore, nanoparticles offer an innovative approach for treating AGA, through a targeted delivery, which could potentially improve hair growth outcomes. Nevertheless, further research in this area is needed.

Hydradermabrasion

Other therapies such as hydradermabrasion, an extended method in the aesthetic field, is being clinically assessed for improving AGA outcomes and for enhancing hair quality through Hydraderm and Hydrafacial in combination to Keravive Peptide spray, an hyperconcentrated solution of biomimetic growth factors and dermal proteins. Results are not available yet [ 116 , 117 ]. This tecnique is also led to enhance microcirculation in affected scalps.

Regenerative therapies

Regenerative therapies for AGA offer a new perspective, against traditional treatments limitations, with potential long-term solutions and fewer side effects.

These regenerative therapies encompass various alternatives such as PRP and its newly generation of products called PRF, SVF, and stem cell-based therapies, including MSCs condicionated medium (MSCs-CM) and extracellular vesicles application.

Tissue engineering is also gaining ground through the development of new 3D cell structures composed by HFSCs and DPCs embebbed in specific scaffolds which pretend to evolve to functional hair follicles after being transplanted into the bald scalp.

Platelet-rich plasma (PRP) represents the main autologous alternative currently utilized in the treatment of AGA by subcutaneous administration. Although it was initially used for connective tissue regeneration in the field of orthopaedics demonstrating its efficacy in varios conditions such as bone breaks [ 118 ], ligament tears [ 119 ], osteoarthritis [ 120 ] and arthritis [ 121 ], its application in the AGA field is widespread with a primary function centered on the restoration of the niche environment. Different growth factors contained in alpha granules of platelets, such as VEGF or Plaque Derived Growth Factor (PDGF) stimulate hair regrowth by inducing the activation of genes associated to various biological processes leading to anagen phase start and proliferation, elastin and collagen synthesis and to an extracellular matrix development [ 122 ]. Additionally, its effects includes hypoxia reduction, vasoconstriction and inflammation in bald areas while promoting neoangiogenesis [ 123 , 124 , 125 ].

In 2014, Khatu et al. [ 126 ] conducted a clinical study on 11 AGA non-responders to treatment with Minoxidil or Finasteride patients for 6 months. Each dose was injected twice a month in 4 sessions. Results were evaluated after 3 months macroscopically based on clinical criteria and photography, hair pull test and satisfaction questionnaire. A significant hair density increase was observed.

In 2018, a prospective and comparative study in AGA young men obtained favourable results with an improvement of hair growth in 16 out of 20 participants [ 127 ] and in 2019 another prospective and comparative study between PRP and Minoxidil was also conducted [ 128 ]. Both groups were treated for 6 months. Standardised tests data, satisfaction surveys and correlation index between platelet concentration and clinical improvement were collected. It was concluded that PRP treatment was more effective than Minoxidil and that platelet count was proportional to hair density increase. The same year a clinical trial with 19 patients, in which PRP plasma was administered every 4 months in a total of 3 times, reported an increase in the number of hair follicles before the second session [ 129 ].

Later Pakhomova & Smirnova [ 130 ] tested PRP and Minoxidil combination obtaining promising results in male subjects. Recently Qu et al. [ 131 ] have proven the therapeutic PRP effect monthly administrated in a total of 3 times in 32 men. Results revealed that PRP treatment produced a significant increase in hair density, hair diameter and anagen hair ratio at month 6 compared to control.

PRP administration has also shown efficacy in female AGA although it is less effective than Minoxidil [ 132 , 133 ].

In spite of the extensive use of PRP, in the management of AGA its use presents important limitations. There is not an established protocol for PRP preparation and effectiveness varies due to different preparation methods so the optimal concentration of platelets, the relative centrifugal force and the possible benefits or not of the presence of leukocytes in the final composition of the PRP remains unknown. In addition, there is a restricted long term efficacy due to the relatively short half-lives of growth factors and prompt release following PRP activation.

Therefore, in an attempt to overcome these limitations, second-generation platelet concentrates, called platelet-rich fibrin (PRF), was developed. PRF is similar to PRP except that PRF naturally contains fibrin for clot scaffolding which allows the retention of small biomolecules, stem cells and high concentrations of host immune cells contributing to tissue healing and regeneration. Its formulation is entirely autologous since anticoagulants are no needed in the preparation and present a much longer release of growth factors due to its 3D scaffold structure [ 134 ].

Since its gel-based consistency nature limited its application, in 2014 an injectable generation of PRF was developed. This new injectable formulation obtained by reduction of the speed centrifugation based on the low speed centrifugation concept [ 135 ] presented the advantage of use a liquid form before being converted to a fibrin matrix (clot), which allowed a slower and more gradual release of the growth factors [ 136 ]. Also an increase release of growth factors when compared to traditional PRF was observed [ 137 ].

Numerous studies have investigated the clinical applications of PRF in different regenerative fields including odontology [ 136 ], surgery [ 138 ], traumatology [ 139 ], wound healing [ 140 ], facial esthetics [ 141 ] and in hair regrowth [ 142 , 143 , 144 , 145 ].

Different comparative studies have reported PRF to be more effective in improving fat grafting than PRP [ 141 ], when fat graft was combined with either PRP or PRF during facial lipostructure surgery or in the treatment of acne scars [ 146 ] .

In regard to hair regrowth, there is a growing interest in the application of PRF. In 2021, a study conducted by Lu et al. indicated the role of PRF in promoting hair follicule regeneration through the enhancement of cell proliferation, migration and trichogenic inductivity [ 142 ] .

In addition, recent clinical studies have highlighted the beneficial effect of PRF in the treatment of AGA. Arora et al. (2019), including three patients between 35 and 40 years of age with a varying degree of hair loss, reported an increase in hair density when treated with injectable PRF [ 143 ]. In another study conducted by Shashank et al. (2020), a 34-year-old male with hair thinning diagnosed with grade 4, experimented an increase in hair density after PRF sessions [ 147 ] and Bhoite et al. (2022) reported a clinically noticeable improvement in the hair growth in 11 out of 15 patients after receiving PRF and microneedling treatment for 4 sessions along with Minoxidil, Finasteride and multivitamin supplements [ 144 ].

To date, the largest human clinical trial (168 patients) was conducted by Schiavone et al. reporting a clinical improvement of AGA parameters at month 6 in all the participants after platelet concentrates administration sessions [ 145 ].

Currently, PRF therapy represents an effective, safe and inexpensive innovative treatment for AGA. Neverheless further investigation is required in order to optimize preparation protocols for a more effective composition.

HFSCs, DPCs and MSCs and their derivatives

MSCs has been widely used in the field of regenerative medicine and their secretoma. Derivative products such as MSCs condicionated medium (MSC-CM) and extracellular vesicles are progressively being more investigated in different pathologies. Both MSCs-CM and exosomes (nanomembranous vesicles) contain different biomolecules capable of restoring physiological conditions.

Since most of the beneficial effects associated with the utilization of MSCs arise from their paracrine action, facilitated by different components present in their secretome such as growth factors, cytokines or chemokines, there is a growing interest in investigating MSCs-CM and exosomes. Extracellular vesicles are secreted through paracrine signaling including microRNAs, mRNAs, metabolites, second messengers, adhesion proteins, growth factor receptors, ligands and long-coding RNAs [ 148 ]. Among these components, RNA and proteins are the functional ones implicated in tissue regeneration [ 149 ].

The effectiveness of MSCs derivatives treatment is atributed to their main function: organs and tissues homeostasis. Additionally, they exhibit the ability to secrete growth factors and anti-inflammatory cytokines thereby participating in inmunomodulation within the niche and in lymphocyte infiltration reduction generally observed in these patients [ 150 , 151 ]. Although MSCs are found in different anatomical locations such as periosteum, bone trabeculae, synovial membrane, muscle tissue, dermis and bone marrow [ 152 , 153 ]; it is from adipose tissue where extraction is less complex through a non-invasive process with a high cell yield [ 154 ].

For this reason, adipose-derived stem cells (ASCs) are being widely used in the dermatological field, particularly in tissue regeneration, psoriasis and alopecia. In AGA treatment, SVF, derived from adipose tissue, and stem cells (SCs) or their derivative products have demonstrated significant improvement in hair density and diameter according to the lastest reported outcomes.

The most of the publications are refered to its conditioned medium as a growth factors enriched secretome produced by MSCs metabolism but also to SVF as an easily extractable heterogenous adipose cell population composed of adipocytes, preadipocytes, adipose stem cells, endotelial progenitor cells, hematopoietic progenitors, monocytes, leukocytes and pericytes [ 155 , 156 , 157 ].

Currently, HFSCs and MSCs derivatives administration is considered as the main focus in numerous lines of hair regrowth research.

Experimental regeneration based-studies

In 2019 Gentile et al. [ 158 ] collected every hair follicle cell function, interactions among them as well as MSCs signalling impact at follicular level, extracted from in vitro experiments to date. These experiments have elucidated the mechanisms which are involved after supplying MSCs to the hair follicle and about their role as intrinsic populations.

In this context ASCs-CM is known to specifically trigger DPCs replication and hair shafts lengthening in isolated hair follicles [ 159 ]. Park et al. [ 155 ] evaluated enriched medium effects. ASCs-CM promoted DPCs differentiation and epidermal keratinocytes. They differentiated between normoxic and hypoxic conditions and unexpestedly, after 100 µl injection in each group, faster hair activation was detected in the latter.

Studies with ASCs in murids were applied by intradermal administration in the order of 10 6 cells. Positive results were obtained in 7-week-old C3H/HeN mice after 12 weeks in the 1.5· 10 6 ASCs intradermally administered and in the 1 ml of ASCs-CM topically administered groups [ 150 ]. Results suggested that ASCs and ASCs-CM promote hair growth by increasing DPCs through cell cycle modulation and anagen phase activation. In 2011, Festa et al. [ 160 ] indicated that preadipocytes played an important role in hair growth by activating the SCs follicular activity, whereas mature adipocytes did not show this capacity. They administered SVF and isolated adipogenic precursors in 7-week-old mice. This study confirmed the importance of ASCs. Hair growth was observed when isolated adipocyte precursors were administered while no such effect occurred when SVF was applied. Experimental results indicate that mature adipocytes are not the primary adipogenic cell type involved in the induction of stem cell activity in hair follicles and that adipocyte precursor cells are essential for skin epithelial stem cells activation.

Results obtained by He et al. [ 161 ] also supported this conclusion. They evaluated the puripotency of CD34 + , CD34- and SVF cells from adipose tissue in a nude mouse model. Results showed that CD34 + cells administration resulted in a higher number of hair follicles than CD34- and SVF groups. These progenitor cells would participate in hair morphogenesis by integrating into the dermal sheath. On the other hand, differentiation to blood vessel endothelial cells was observed in CD34 + and SVF cells. The former group was shown to have a high differentiation potential in skin development.

These studies were supported by other ones based on tissue regeneration such as the one performed by Zografou et al. [ 162 ] in which 10 6 ASCs, distributed in 10 spots, were administered in diabetic Spargue Dawley rats. They observed a survival and angiogenesis increase in the grafted areas. In other pathologies such as psoriasis Rokunohe et al. [ 163 ] and Lee et al. [ 164 ] applied 3·10 6 ASCs and 4·10 6 human umbilical cord-derived mesenchymal stem cells (hUCB-MSCs) respectively in the dorsal area of diseased mice and obtained favourable results in terms of expected immunosuppressive activity.

In regard to the use of exosomes in AGA although most of the investigation is still in a preclinical setting. Several case reports has shown promising results. Instead of MSC-CM use, exosomes are more resistant to degradation, citokines and growth factors half-lives are larger and according to Wu et al. (2021) exosomes show a safer and more efficient profile [ 165 ]. In hair regeneration preclinical studies, different sources of exosomes have been explored including exosomes derived from dermal papilla cells (DPCs) [ 166 ], from adipose-derived stem cells [ 165 ], from hair outer root sheath cells [ 167 ] or immune cell-derived exosomes such as macrophage extracellular vesicles [ 168 ]. In fact perifollicular macrophages are known to activate DPCs promoting anagen phase.

Commonly, results show an enhancement of hair follicle proliferation and migration, an increase of β-catenin expression via Wnt pathway and an aceleration of the anagen onset [ 168 ]. In addition exosomes reduce proinflammatory levels [ 169 ] and accelerate re-ephitelialization [ 170 ].

Clinical regeneration based-studies

Cell therapy in AGA has been applied by different procedures such as subcutaneous or intradermal administration from different types of sources in the human body, including, autologous HFSCs [ 171 ], ASCs extracted from the occipital region for hair transplantation [ 172 ] or obtained from the abdominal area, as part of autologous SVF [ 173 ].

In regard to ASCs-CM, Fukuoka and Suga [ 156 ] proved its efficacy in a clinical trial involving 22 patients, resulting in a significant increase in hair count after treatment in both male and female subjets. Positive results in hair density and thickness parameters were also observed by Shin et al. in a female cohort [ 174 ]. At present, a study including 37 participants using two different ASCs-CM concentrations has been completed with pending results [ 175 ].

The efficacy of ASCs-CM was further evaluated in a study with 38 participants over 16 weeks, showing a significant increase in hair count and thickness compared to placebo within 8 weeks of application [ 176 ]. Moreover, it was also tested female hair loss with the Hair Stimulating Complex, a derivative solution of ASCs-CM enriched with growth factors [ 177 ]. The use of HUCB-MSCs conditioned medium with paracrine factors in a experimental solution called NGF-574H was tested by a twice a day topical administration [ 178 ]. In addition, small-scale clinical studies were conducted using SVF [ 179 , 180 ]. A recent clinical trial comparing PRP versus mesotherapy containing the ASCs-CM and a mixture of recombinant growth factors in 100 participans is still awaiting results [ 181 ].

ASCs-CM has also been applied in transplantation areas [ 172 ] and formulated with several growth factors, interleukin 6 as AAPE Prostemics commercial product via microneedling administration [ 174 , 182 ].

Zanzottera et al. [ 172 ], in order to optimized the SVF extraction process, used the Rigenera® system to obtain a heterogeneous solution of the hypodermis with autologous SCs from the donor occipital area during hair transplantation procedure. The suspension was applied to the scalp areas undergoing hair transplantation in 3 AGA subjects. Monthly follow-up revealed faster healing after transplantation and improved hair growth after two months. Subsequently Gentile et al. [ 183 ] isolated HFSCs using Rigenera® Securdrill resulting in a 29% higher density in the treatment area compared to placebo.

Other researchers have suggested that autologous ASCs-enriched fat grafting could be a promising alternative for treating AGA. Hamed Kadry et al. [ 173 ] conducted a study comparing PRP and intradermal SVF treatment, showing that SVF-treated patients exhibited more marked improvements in hair count and hair thickness in both sexes. Both treatments has also been compared in a clinical trial of 22 participants [ 184 ]. Ghazally et al. also compared PRP and ASCs suspension vs PRP application in the recipient site during follicular unit extraction [ 185 ].

On the other hand, Stevens et al. [ 186 ] tested a combined treatment of PRP and SVF, resulting in a significant increase of hair density at 6 and 12 weeks after a single injection in 10 AGA subjects. In this context, safety and efficacy of using a biocellular mixture consisting of emulsified adipose-derived tissue SVF and high density PRP concentrate group is under evaluation in comparison to other groups in 60 female subjects. Experimental groups includes adipose-derived cell-enriched SVF, SVF, high density PRP concentrate and high density PRP concentrate alone [ 187 ].

Recently El-Khalawany et al. [ 188 ] conducted a clinical study with a single administration of autologous SVF in 30 patients, with positive results in terms of hair density, hair thickness, global photography and patient satisfaction.

Since 2008, researchers have showed a growing interest exploring the efficacy and safety of ex vivo-cultured, expanded and autologous cells. These isolated cells include dermal cells from the occipital region [ 189 , 190 , 191 , 192 ] or in combination with epidermal cells [ 193 , 194 , 195 , 196 , 197 , 198 , 199 ]. Currently, a clinical trial is going using autologous HFSCs extracted from occipital area [ 200 ] with a previous similar one performed using isolating and replicating HFSCs from scalp biopsies [ 201 ]. Results from both are pending. Elmaadawi et al. [ 202 ] used autologous bone marrow mononuclear cells and HFSCs in different groups to treat refractory alopecia areata and AGA. A significant improvement was observed in all treatment groups after the administration of a solution containing a total of 10 5 cells. Despite their different origins, both therapies exhibited similar safety and efficacy, presenting a higher efficacy in females.

To date, the only clinical trial detailing a clinical dose of ASCs in AGA treatment is the STYLE Transplantation [ 203 ]. They conducted a randomized study including 71 subjects in 4 groups, two of which received SCs enriched population from SVF (high dose- 1·106 ASCs/cm 2 and low dose 0.5· 10 6 ASCs/cm 2 ) while the other received Puregraft fat graft and saline respectively. Fat and enriched SVF were administered in the subdermal layer and at a rate of 0.1 ml/cm 2 over a total area of 40 cm 2 . Follow-up was performed at weeks 6, 12, 24 and 52 revealing an increase of 16 hairs in hair count at weeks 12, 24 and 52 in the low-dose group compared to baseline. In addition, more participants in this group showed a higher number of positive responses on the hair satisfaction questionnaire at week 24, followed by those who received only SVF. No severe adverse effects were reported.

According to exosomes, one clinical trial is only ongoing in order to assess eficacy and safety of exosomes versus PRP in AGA treatment [ 204 ].

Tissue engineering and 3D bioprinting techniques

Nowadays tissue engineering development is making a good progress but the construction of a functional hair follicle is still a huge challenge due to the complexe mesenchymal-epithelial interactions [ 205 ]. Three are the aims which are pursued in the context of tissue regeneration: inductive signals intake, sustitution of damaged cells or onstruction of 3D structures composed by cells on synthetic or collagen matrix [ 206 ] .

Currently the cutting edge advances are based on bioinks constituted by isolated and expanded autologous HFCs and DPCs in vitro extracted from a follicular unit extraction, the construction of spheroid cultures of both lines together and the incorporation into in a biomaterial scaffold which are contigent upon a modulation signaling [ 106 , 207 ]. An appropiate design, the use of a biocompatible material and the viability of the cells are essential points in order to achieve complete and functional hair follicles after transplantation.

3D bioprinting techniques, such as the refered one, offers the possibility of manufacturing constructs that mimic a particular tissue architecture, regardless of its complexity, facilitating the hierarchical arrangement of cells within intricate 3D biomaterials while promoting tissue regeneration. As a consequence, nanomaterials can also be integrated, creating complex biological structures with enchanced properties including biocompatibility and regeneration action [ 106 ].

Currently, 3D printing techniques have been used for the regeneration of different types of tissues, including skin [ 208 ], cartilage [ 209 ], vascular networks [ 210 ] or organs such a bioprosthetic ovary [ 211 ]. The potential use of this technology in clinical settings addressing hair loss like AGA seems promising.

In this context, a recent study using 3D printing technique incorporating magnesium silicate nanomaterials, manufactured a multicellular micropattern constituded by hair follicle cells and a vascular network which leaded to hair regrowth in an AGA immunodeficient mouse model [ 212 ].

Additionally, 3D skin equivalents with hair follicle structures and epidermal-papillary-dermal layers has been developed using skin tissue equivalents [ 213 ].

Nevertheless to success in AGA using bioprinting techniques it will be neccesary to develop biomaterials capable of mimicking the intricate structure of the hair follicle and its surrounding microenvironment, while being biocompatible, bioactive and non immunogenic. Due to the complex structure of the hair follicle considered as a dynamic miniorgan, an improved bioprinting method is required in order to replicate as similarly as possible the hair biological conformation. The presence of factors to be incorporated to the nanostructure providing to the hair follicle microenvironment the functional activity of the absent sebaceous gland is also a challenge.

Although topical Minoxidil and oral Finasteride are the only approved drugs for AGA, numerous adverse events are associated with their administration. Hair transplant is an effective option with favourable results, however long-term efficacy may diminish due to progressive miniaturization and loss of preexisting nontransplanted hairs induced by DHT chronic action. The elucidation of strategies to ameliorate the AGA hindered microenvironment is a complex challenge. Recurrent local hormonal action can jeopardize follicle funcionality and regular cycling processes. Early therapeutic intervention is crucial in order to preserve follicles and prevent irreversible damage and fibrosis.

Currently, different strategies aiming to restore physiological conditions or the hair follicle are being under investigation. Allogenic and autologous stem cells administration, along with their derivatives including ASCs-CM or exosomes, are well known for supplying essencial growth factors pivotal for the niche restoration. In addition, their immunomodulatory role plays a crucial role to ameliorate microinflammation associated with AGA and despite of the numerous advantages potentially offered by these therapies their widespread application hinders their implementation. Additionally, to support the clinical use of MSC derivatives, there is a need to standardise and optimise preparation protocols to tackle issues related to donor variability or tissue origin that influence the secretome composition and thereby their therapeutic action.

In addition, contemporary literature highlights research studies on bioinks and bionanomaterial scaffolds for 3D bioprinting techniques across different fields. Despite being in the early stages of exploration, these techniques show considerable potential and offer significant promise for the treatment of AGA. The intricate nature of biological systems, exemplified by the dynamic life cycle of the hair follicle, presents pivotal considerations in the assembly of multi-layered scaffolds. The construction of spheroidal mix cultures of HFSCs and DPCs embebbed in scaffolds has replaced isolated and expanded HFCS administration alone. The DPCs and HFCs interaction is the basis for the onset of anagen phase so an adecuate choice of trigger factors which would induce bioink grafting and transformation into a functional biological struture is essential. The adecuate scaffold biomaterial should be also biocompatible and resilient enough to persist in the dermal layers until progression to become a functional hair follicle analogue structure.

The aforementioned regenerative approaches are leading to two different pursuits. One focuses on the restoration of miniaturized hair follicles and the altered microenviroment surrounding them to rekindle inherent selfrenewal capacities whereas the other one aims to recreate from scratch a structure as complex as such as the hair follicle. It would be necessary to assess patient clinical characteristics carefully according to AGA severity and the onset of alopecic conditions in order to set a treatment which pretends to revive his own follicular regenerative mechanisms or to create de novo lost hair follicles which became fibrotic stellae.

Further investigation is needed in order to define the exogen factors that could lead to functional hair follicle development from bioinks.

Availability of data and materials

All references are included in this review.

Abbreviations

androgenetic alopecia

androgen receptor

adipose derived stem cells

adipose derived stem cells conditioned medium

dihydrotestosterone

dermal papilla cells

fibroblast growth factor

hair follicle stem cells

human umbilical cord blood-derived mesenchymal stem cells

low-level laser therapy

mesenchimal stem cells

plaque derived growth factor

platelet rich plasma

platelet rich fibrin

transforming growth factor

vascular endotelial growth factor

Blumeyer A, Tosti A, Messenger A, Reygagne P, del Marmol V, Spuls PI, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men. JDDG J der Dtsch Dermatologischen Gesellschaft. 2011;9:1–57. https://doi.org/10.1111/j.1610-0379.2011.07802.x .

Article   Google Scholar  

Hamilton JB. Patterned loss of hair in man: types and incidence. Ann N Y Acad Sci. 1951;53(3):708–28. https://doi.org/10.1111/j.1749-6632.1951.tb31971.x .

Article   CAS   PubMed   Google Scholar  

Ramos PM, Miot HA. Female pattern hair loss: a clinical and pathophysiological review. An Bras Dermatol. 2015;90(4):529–43.

Article   PubMed   PubMed Central   Google Scholar  

Gentile G. Advances in regenerative stem cell therapy in androgenic alopecia and hair loss: wnt pathway, growth-factor, and mesenchymal stem cell signaling impact analysis on cell growth and hair follicle development. Cells. 2019;8(5):466.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Ellis JA, Sinclair R, Harrap SB. Androgenetic alopecia: pathogenesis and potential for therapy. Expert Rev Mol Med. 2002;4(22):1–11.

Article   PubMed   Google Scholar  

Urysiak-Czubatka I, Kmieć ML, Broniarczyk-Dyła G. Assessment of the usefulness of dihydrotestosterone in the diagnostics of patients with androgenetic alopecia. Postep dermatologii i Alergol. 2014;31(4):207–15.

Otberg N, Finner AM, Shapiro J. Androgenetic Alopecia. Endocrinol Metab Clin North Am. 2007;36(2):379–98.

Ellis JA, Stebbing M, Harrap SB. Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol. 2001;116(3):452–5.

Ellis JA, Stebbing M, Harrap SB. Genetic analysis of male pattern baldness and the 5α-reductase genes. J Invest Dermatol. 1998;110(6):849–53.

Mirmirani P. Hormones and clocks: Do they disrupt the locks? Fluctuating estrogen levels during menopausal transition may influence clock genes and trigger chronic telogen effluvium. Dermatol Online J. 2016;22(5). https://pubmed.ncbi.nlm.nih.gov/27617515/

Bienenfeld A, Azarchi S, Lo Sicco K, Marchbein S, Shapiro J, Nagler AR. Androgens in women: Androgen-mediated skin disease and patient evaluation. J Am Acad Dermatol. 2019;80(6):1497–506. https://doi.org/10.1016/j.jaad.2018.08.062 .

Rompolas P, Greco V. Stem cell dynamics in the hair follicle niche. Semin Cell Dev Biol. 2014;25–26:34–42.

Plikus MV, Mayer JA, de la Cruz D, Baker RE, Maini PK, Maxson R, et al. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature. 2008;451(7176):340–4.

Wang AB, Jain P, Tumbar T. The hair follicle stem cell niche: the bulge and its environment. Tissue-Specific Stem Cell Niche. 2015. https://doi.org/10.1007/978-3-319-21705-5_1 .

Tsuboi R, Niiyama S, Irisawa R, Harada K, Nakazawa Y, Kishimoto J. Autologous cell–based therapy for male and female pattern hair loss using dermal sheath cup cells: a randomized placebo-controlled double-blinded dose-finding clinical study. J Am Acad Dermatol. 2020;83(1):109–16.

Kwack MH, Sung YK, Chung EJ, Im SU, Ahn JS, Kim MK, et al. Dihydrotestosterone-inducible Dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes. J Invest Dermatol. 2008;128(2):262–9.

Kitagawa T, Matsuda K-I, Inui S, Takenaka H, Katoh N, Itami S, et al. Keratinocyte growth inhibition through the modification of Wnt signaling by androgen in balding dermal papilla cells. J Clin Endocrinol Metab. 2009;94(4):1288–94.

Ohyama M, Terunuma A, Tock CL, Radonovich MF, Pise-Masison CA, Hopping SB, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest. 2006;116(1):249–60.

Mohammadi P, Youssef KK, Abbasalizadeh S, Baharvand H, Aghdami N. Human hair reconstruction: close, but yet so far. Stem Cells Dev. 2016;25(23):1767–79.

Cervelli V, Garcovich S, Bielli A, Cervelli G, Curcio BC, Scioli MG, et al. The effect of autologous activated platelet rich plasma (AA-PRP) injection on pattern hair loss: clinical and histomorphometric evaluation. Biomed Res Int. 2014;2014:760709.

Jaworsky C, Kligman AM, Murphy GF. Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis. Br J Dermatol. 1992;127(3):239–46.

Houschyar KS, Borrelli MR, Tapking C, Popp D, Puladi B, Ooms M, et al. Molecular mechanisms of hair growth and regeneration: current understanding and novel paradigms. Dermatology. 2020;236(4):271–80.

Andy G, John M, Mirna S, Rachita D, Michael K, Maja K, et al. Controversies in the treatment of androgenetic alopecia: The history of finasteride. Dermatol Ther. 2019;32(2):e12647.

Overstreet JW, Fuh VL, Gould J, Howards SS, Lieber MM, Hellstrom W, et al. Re: Chronic treatment with finasteride daily does not affect spermatogenesis or semen production in young men [5]. J Urol. 2000;164(4):1319–20.

Kanti V, Messenger A, Dobos G, Reygagne P, Finner A, Blumeyer A, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men – short version. J Eur Acad Dermatology Venereol. 2018;32(1):11–22.

Article   CAS   Google Scholar  

Kelly Y, Blanco A, Tosti A. Androgenetic Alopecia: An Update of Treatment Options. Vol. 76, Drugs. Springer International Publishing; 2016. p. 1349–64

Study to Evaluate the Efficacy and Safety of P-3074 Topical Solution in the Treatment of Androgenetic Alopecia. 2023: https://www.clinicaltrials.gov/search?term=NCT03004469

Ahmed OAA, Rizq WY. Finasteride nano-transferosomal gel formula for management of androgenetic alopecia: ex vivo investigational approach. Drug Des Devel Ther. 2018;12:2259–65.

Piraccini BM, Blume-Peytavi U, Scarci F, Jansat JM, Falqu M, Otero R, et al. Efficacy and safety of topical finasteride spray solution for male androgenetic alopecia: a phase III, randomized, controlled clinical trial. 2021; https://doi.org/10.1111/jdv.17738

Gupta AK, Talukder M. Topical finasteride for male and female pattern hair loss: is it a safe and effective alternative? J Cosmet Dermatol. 2022;21(5):1841–8. https://doi.org/10.1111/jocd.14895 .

Inui S, Itami S. Reversal of androgenetic alopecia by topical ketoconzole: Relevance of anti-androgenic activity. J Dermatol Sci. 2007;45(1):66–8.

Hugo Perez BS. Ketocazole as an adjunct to finasteride in the treatment of androgenetic alopecia in men. Med Hypotheses. 2004;62(1):112–5.

Sonino N, Scaroni C, Biason A, Boscaro M, Mantero F. Low-dose ketoconazole treatment in hirsute women. J Endocrinol Investig Off J Ital Soc Endocrinol. 1990;13(1):35–40.

Gubelin Harcha W, Barboza Martínez J, Tsai TF, Katsuoka K, Kawashima M, Tsuboi R, et al. A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia. J Am Acad Dermatol. 2014;70(3):489–98.

Mahe YF, et al. Androgenetic alopecia and microinflammation. Int J Dermatol. 2000;39:576–84.

Orasan MS, Roman II, Coneac A, Muresan A, Orasan RI. Hair loss and regeneration performed on animal models. Med Pharm Reports. 2015;89(3):327–34.

Panchaprateep R, Lueangarun S. Efficacy and safety of oral minoxidil 5 mg once daily in the treatment of male patients with androgenetic alopecia: an open-label and global photographic assessment. Dermatol Ther (Heidelb). 2020;10(6):1345–57.

Jha A, Sonthalia S, Zeeshan MD. Efficacy and safety of very-low-dose oral minoxidil 1.25 mg in male androgenetic alopecia. J Am Acad Dermatology. 2020;83(5):1491–3.

Sinclair RD. Female pattern hair loss: a pilot study investigating combination therapy with low-dose oral minoxidil and spironolactone. Int J Dermatol. 2018;57(1):104–9.

Sinclair R, Perera E. Treatment of chronic telogen effluvium with oral minoxidil: A retrospective study. F1000Research 2017 61650. 2017;6:1650.: https://f1000research.com/articles/6-1650

Sinclair R, Trindade de Carvalho L, Ferial Ismail F, Meah N. Treatment of male and female pattern hair loss with sublingual minoxidil: a retrospective case-series of 64 patients. J Eur Acad Dermatology Venereol. 2020;34(12):795–6.

Buhl AE, Waldon DJ, Baker CA, Johnson GA. Minoxidil sulfate is the active metabolite that stimulates hair follicles. J Invest Dermatol. 1990;95(5):553–7.

Maekawa M, Ohnishi T, Balan S, Hisano Y, Nozaki Y, Ohba H, et al. Thiosulfate promotes hair growth in mouse model. Biosci Biotechnol Biochem. 2019;83(1):114–22.

Ramos PM, Goren A, Sinclair R, Miot HA. Oral minoxidil bio-activation by hair follicle outer root sheath cell sulfotransferase enzymes predicts clinical efficacy in female pattern hair loss. J Eur Acad Dermatology Venereol. 2020;34(1):e40-1.

Lee HJ, Oh DW, Na MJ, Kim DW, Yuk DY, Choi HC, et al. Preparation and in vivo evaluation of lecithin-based microparticles for topical delivery of minoxidil. Arch Pharm Res. 2017;40(8):943–51.

Carvalho R de M, Santos LDN, Ramos PM, Machado CJ, Acioly P, Frattini SC, et al. Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know. J Cosmet Dermatol. 2022;21(10):4171–5

Ocampo-Garza J, Griggs J, Tosti A. New drugs under investigation for the treatment of alopecias. Expert Opin Investig Drugs. 2019;28(3):275–84.

NCT01904721. A Safety and Efficacy Study of Bimatoprost in Men With Androgenic Alopecia (AGA). 2016.: https://www.clinicaltrials.gov/study/NCT01904721?term=NCT01904721&rank=1&limit=10

NCT01325337. Safety and Efficacy Study of Bimatoprost in the Treatment of Men With Androgenic Alopecia. 2014: https://www.clinicaltrials.gov/study/NCT01325337?term=NCT01325337&rank=1

NCT0132535. Safety and Efficacy Study of Bimatoprost in the Treatment of Women With Female Pattern Hair Loss. 2014: https://www.clinicaltrials.gov/study/NCT01325350?term=NCT01325350&rank=1

Topical Bimatoprost Effect on Androgen Dependent Hair Follicles. [cited 2023 Jul 31].: https://www.clinicaltrials.gov/study/NCT02170662?term=NCT02170662&rank=1

Blume-Peytavi U, Hillmann K, Garcia Bartels N. A randomized double-blind placebo-controlled pilot study to assess the efficacy of a 24-week topical treatment by latanoprost 0.1% on hair growth and pigmentation in healthy volunteers with androgenetic alopecia. https://pubmed.ncbi.nlm.nih.gov/21875758

Nieves A, Garza LA. Does prostaglandin D2 hold the cure to male pattern baldness? Exp Dermatol. 2014 Apr [cited 2019 Jul 29];23(4):224–7.: http://www.ncbi.nlm.nih.gov/pubmed/24521203

NCT02781311. A Safety and Efficacy Study of Setipiprant Tablets in Androgenetic Alopecia in Males. clinicaltrials.gov. 2019: https://www.clinicaltrials.gov/study/NCT02781311?term=NCT02781311&rank=1

Mohamed S. Zaky MD1 | Hassan Abo Khodeir MD1 | Hebat-Allah Ahmed MD1 |, Mohamed L. Elsaie MD. Therapeutic implications of topical cetirizine 1% in treatment of male androgenetic alopecia: A case-controlled study. 2020: https://onlinelibrary.wiley.com/doi/pdfdirect/ https://doi.org/10.1111/jocd.13940

Bassiouny EA, Solwan, El-Samanoudy I, Abbassi MM, Nada HR, Samar , et al. Comparison between topical cetirizine with minoxidil versus topical placebo with minoxidil in female androgenetic alopecia: a randomized, double-blind, placebo-controlled study. 2023;315:1293–304.: https://doi.org/10.1007/s00403-022-02512-2

Lee S-H, Yoon J, Shin SH, Zahoor M, Kim HJ, Park PJ, et al. Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells. 2012: https://pubmed.ncbi.nlm.nih.gov/22506014/

Harel S, Higgins CA, Cerise JE, Dai Z, Chen JC, Clynes R, et al. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Sci Adv. 2015;1(9).: https://pubmed.ncbi.nlm.nih.gov/26601320/

A Study of the Safety, Tolerability, and Efficacy of Topical SM04554 Solution in Male Subjects With Androgenetic Alopecia (AGA) - Full Text View - ClinicalTrials.gov. [cited 2022 Sep 26].: https://clinicaltrials.gov/ct2/show/NCT02275351

A Study of SM04554 Applied Topically to the Scalp of Male Subjects With Androgenetic Alopecia Analyzed by Biopsy of the Scalp Prior To and Post Dosing - Full Text View - ClinicalTrials.gov. [cited 2022 Sep 26].: https://clinicaltrials.gov/ct2/show/NCT02503137?cond=NCT02503137&draw=2&rank=1

A Study in Male and Female Subjects With Androgenetic Alopecia Treated With ATI-50002 Topical Solution - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27].: https://clinicaltrials.gov/ct2/show/NCT03495817?term=NCT03495817&draw=2&rank=1

“iRestore” Light Therapy Apparatus - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27].: https://clinicaltrials.gov/ct2/show/NCT03331003?term=CELL+THERAPY&cond=aga&draw=2&rank=25

Wu Y-F, Wang S-H, Wu P-S, Fan SM-Y, Chiu H-Y, Tsai T-H, et al. Enhancing hair follicle regeneration by nonablative fractional laser: assessment of irradiation parameters and tissue response. Lasers Surg Med. 2015;47(4):331–41

Avci P, Gupta GK, Clark J, Wikonkal N, Hamblin MR. Low-level laser (Light) therapy (LLLT) for treatment of hair loss. Lasers Surg Med. 2014;46:144–51.

Darwin E, Heyes A, Hirt PA, Wikramanayake TC, Jimenez JJ. Low-level laser therapy for the treatment of androgenic alopecia: a review. Lasers Med Sci. 2018;33(2):425–34.

Pillai J, Mysore V. Role of low-level light therapy (LLLT) in androgenetic alopecia. Vol. 14, Journal of Cutaneous and Aesthetic Surgery. 2021. p. 385. https://pubmed.ncbi.nlm.nih.gov/35283601

Kim H, Choi JW, Kim JY, Shin JW, Lee SJ, Huh CH. Low-level light therapy for androgenetic alopecia: a 24-week, randomized, double-blind, sham device-controlled multicenter trial. Dermatol Surg. 2013;39(8):1177–83.

Lanzafame RJ, Blanche RR, Bodian AB, Chiacchierini RP, Fernandez-Obregon A, Kazmirek ER. The growth of human scalp hair mediated by visible red light laser and LED sources in males. Lasers Surg Med. 2013;45(8):487–95.

Lee GY, Lee SJ, Kim WS. The effect of a 1550 nm fractional erbium-glass laser in female pattern hair loss. J Eur Acad Dermatol Venereol. 2011;25(12):1450–4.

Meephansan J, Ungpraphakorn N, Ponnikorn S, Suchonwanit P, Poovorawan Y. Efficacy of 1,550-nm erbium-glass fractional laser treatment and its effect on the expression of insulin-like growth factor 1 and Wnt/β-catenin in androgenetic alopecia. Dermatol Surg. 2018;44(10):1295–303.

Alhattab MK, AL Abdullah MJ, Al-Janabi MH, Aljanaby WA, Alwakeel HA. The effect of 1540-nm fractional erbium-glass laser in the treatment of androgenic alopecia. J Cosmet Dermatol. 2020;19(4):878–83.

Suchonwanit P, Rojhirunsakool S, Khunkhet S. A randomized, investigator-blinded, controlled, split-scalp study of the efficacy and safety of a 1550-nm fractional erbium-glass laser, used in combination with topical 5% minoxidil versus 5% minoxidil alone, for the treatment of androgenetic alopecia. Lasers Med Sci. 2019;34(9):1857–64.

Haddad N, Arruda S, Sadick N. Evaluating the efficacy of platelet rich plasma and 1550 nm fractional laser in combination and alone for the management of androgenetic alopecia. J Drugs Dermatol. 2022;21(11):1166–9.

Leavitt M, Perez-Meza D, Rao NA, Barusco M, Kaufman KD, Ziering C. Effects of finasteride (1 mg) on hair transplant. Dermatol Surg. 2005;31(10):1268–76.

Cole JP. An analysis of follicular punches, mechanics, and dynamics in follicular unit extraction. Facial Plast Surg Clin North Am. 2013;21(3):437–47.

Rogers NE, Callender VD. Advances and challenges in hair restoration of curly Afrocentric hair. Dermatol Clin. 2014;32(2):163–71.

Rose P. The latest innovations in hair transplantation. Facial Plast Surg. 2011;27(04):366–77.

Caroli S, Pathomvanich D, Amonpattana K, Kumar A. Current status of hair restoration surgery. Int Surg. 2011;96(4):345–51.

Singh A, Yadav S. Microneedling: advances and widening horizons. Indian Dermatol Online J. 2016;7(4):244.

Dhurat R, Sukesh M, Avhad G, Dandale A, Pal A, Pund P. A randomized evaluator blinded study of effect of microneedling in androgenetic alopecia: a pilot study. Int J Trichology. 2013;5(1):6.

Kumar M, Inamadar A, Palit A. A randomized controlled, single-observer blinded study to determine the efficacy of topical minoxidil plus microneedling versus topical minoxidil alone in the treatment of androgenetic alopecia. J Cutan Aesthet Surg. 2018;11(4):211–6.

Bao L, Fang H, Zheng LLY. Randomized trial of electrodynamic microneedling combined with 5% minoxidil topical solution for treating androgenetic alopecia in Chinese males and molecular mechanistic study of the involvement of the Wnt/β-catenin signaling pathway. 2020. p. 483–93

Yu C-Q, Zhang H, Guo M-E, Li X-K, Chen H-D, Li Y-H, et al. Combination therapy with topical minoxidil and nano-microneedle-assisted fibroblast growth factor for male androgenetic alopecia: a randomized controlled trial in Chinese patients. 2021. http://links.lww.com/CM9/A373

Melo DF, de Mattos Barreto T, Plata GT, Araujo LR, Tortelly VD. Excellent response to mesotherapy as adjunctive treatment in male androgenetic alopecia. J Cosmet Dermatol. 2019; 2019; https://pubmed.ncbi.nlm.nih.gov/ 31066492/

Melo DF, Saceda-Corralo D, Tosti A, Weffort F, Carla Jorge M, de Barros CC, et al. Frontal edema due to mesotherapy for androgenetic alopecia: a case series. Dermatol Ther. 2022;35(2):8–10.

Gajjar P, Mehta H, Barvaliya M, Sonagra B. Comparative study between mesotherapy and topical 5% minoxidil by dermoscopic evaluation for androgenic alopecia in male: a randomized controlled trial. Int J Trichol. 2019;11(2):58–67.

Nassar A, Abdel-Aleem H, Samir M, Khattab FM. Efficacy of botulinum toxin A injection in the treatment of androgenic alopecia: a comparative controlled study. J Cosmet Dermatol. 2022;21(10):4261–8.

Jung BH, Song SH, Yoon SJ, Koo JH, Yoo KY. The effect of botulinum toxin on hair follicle cell regeneration under continuous stress conditions: a pilot animal study. Neurotox Res. 2022;40(1):103–10. https://doi.org/10.1007/s12640-021-00453-8 .

Zhou Y, Yu S, Zhao J, Feng X, Zhang M, Zhao Z. Effectiveness and safety of botulinum toxin type a in the treatment of androgenetic alopecia. Biomed Res Int. 2020;2020.

Use of Botulinum Toxin in the Treatment of Androgenic Alopecia. 2022 [cited 2023 Aug 2]. https://www.clinicaltrials.gov/study/NCT05456087?term=botulinum toxin&cond=aga&rank=2

Treatment of Male Pattern Baldness With Botulinum Toxin. 2009. https://www.clinicaltrials.gov/study/NCT00965640?term=botulinum toxin&cond=aga&rank=1

Zhu H-L, Gao Y-H, Yang J-Q, Li J-B, Gao J. Serenoa repens extracts promote hair regeneration and repair of hair loss mouse models by activating TGF-β and mitochondrial signaling pathway. Eur Rev Med Pharmacol Sci. 2018;22(12):4000–8.

PubMed   Google Scholar  

Murata K, Takeshita F, Samukawa K, Tani T, Matsuda H. Effects of Ginseng Rhizome and Ginsenoside Ro on Testosterone 5α-Reductase and Hair Re-growth in Testosterone-treated Mice. 2011; https://pubmed.ncbi.nlm.nih.gov/21538628

Wall D, Meah N, Fagan N, York K, Sinclair R. Advances in hair growth. Fac Rev. 2022;11. https://pubmed.ncbi.nlm.nih.gov/35156098/

Kwon OS, Han JH, Yoo HG, Chung JH, Cho KH, Eun HC, et al. Human hair growth enhancement in vitro by green tea epigallocatechin-3-gallate (EGCG). Phytomedicine. 2007;14(7–8):551–5.

Srivilai J, Rabgay K, Khorana N, Waranuch N, Nuengchamnong N, Wisuitiprot W, et al. Anti-androgenic curcumin analogues as steroid 5-alpha reductase inhibitors. Med Chem Res. 2017. https://doi.org/10.1007/s00044-017-1869-y .

Hou IC, Oi Y, Fujita H, Yano Y, Fukami H, Yoshikawa M. A hair growth-promoting effect of Chinese black tea extract in mice. Biosci Biotechnol Biochem. 2013;77(7):1606–7.

Uri Shon MD, Myung Hwa Kim MD, Dong Yoon Lee MD SHKP y BCPM. The effect of intradermal botulinum toxin on androgenetic alopecia and its possible mechanism. J Am Acad Dermatol. 2020;83(6):1838–9

Zhou Y, Yu S, Zhao J, Feng X, Zhang M, Zhao Z. Effectiveness and safety of botulinum toxin type a in the treatment of androgenetic alopecia. 2020: https://doi.org/10.1155/2020/1501893

Zhang L, Yu Q, Wang Y, Ma Y, Shi Y, Li X. A small dose of botulinum toxin A is effective for treating androgenetic alopecia in Chinese patients. Dermatol Ther. 2019;32(4).: https://pubmed.ncbi.nlm.nih.gov/30566260/

Singh S, Neema S, Vasudevan B. A pilot study to evaluate effectiveness of botulinum toxin in treatment of androgenetic alopecia in males. J Cutan Aesthet Surg. 2017;10(3):163–7.

Freund BJ, Schwartz M. Treatment of male pattern baldness with botulinum toxin: A pilot study. Plast Reconstr Surg. 2010 Nov [cited 2024 May 27];126(5).: https://journals.lww.com/plasreconsurg/fulltext/2010/11000/treatment_of_male_pattern_baldness_with_botulinum.79.aspx

English Jr Sophia Ruiz RS. Systematic Review and Meta-Analysis Use of Botulinum Toxin for Androgenic Alopecia: A Systematic Review. 2021: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8928186/

Khalilov R, Bakishzade A, Nasibova A. Future prospects of biomaterials in nanomedicine. Adv Biol Earth Sci. 2024;9:5–10.

Huseynov E, Khalilov R, Mohamed AJ. Novel nanomaterials for hepatobiliary diseases treatment and future perspectives. Adv Biol Earth Sci. 2024;9:81–91.

Salahshour P, Abdolmaleki S, Monemizadeh S, Gholizadeh S, Khaksar S. Nanobiomaterials/bioinks based scaffolds in 3d bioprinting for tissue engineering and artificial human organs. Adv Biol Earth Sci. 2024;9:97–104.

Saghir Z, Shaikh A, Ahmed B, Patel A, Patil SG, Raheem A, et al. Nanotechnology-based strategies for hair follicle regeneration in androgenetic alopecia. Mater Proc. 2023;14:57.

Google Scholar  

Roque LV, Dias IS, Cruz N, Rebelo A, Roberto A, Rijo P, et al. Design of finasteride-loaded nanoparticles for potential treatment of alopecia. Skin Pharmacol Physiol. 2017;30(4):197–204.

Kim JH, Na J, Bak DH, Lee BC, Lee E, Choi MJ, et al. Development of finasteride polymer microspheres for systemic application in androgenic alopecia. Int J Mol Med. 2019;43(6):2409–19.

CAS   PubMed   PubMed Central   Google Scholar  

Xiao Q, Lu Y, Yao W, Gong CC, Jia C, Gao J, et al. Molybdenum nanoparticles as a potential topical medication for alopecia treatment through antioxidant pathways that differ from minoxidil. J Trace Elem Med Biol. 2024;82. https://pubmed.ncbi.nlm.nih.gov/38150949/

Fernández-García R, Lalatsa A, Statts L, Bolás-Fernández F, Ballesteros MP, Serrano DR. Transferosomes as nanocarriers for drugs across the skin: quality by design from lab to industrial scale. Int J Pharm. 2020;573.: https://pubmed.ncbi.nlm.nih.gov/31678520/

Makky AMA, El-leithy E, Hussein DG, Khattab A. A full factorial design to optimize aminexil nano lipid formulation to improve skin permeation and efficacy against alopecia. AAPS PharmSciTech. 2023;24(1):1–19.

Lee HJ, Kwon HK, Kim HS, Kim M Il, Park HJ. Hair growth promoting effect of 4HGF encapsulated with PGA nanoparticles (PGA-4HGF) by β-catenin activation and its related cell cycle molecules. Int J Mol Sci. 2019;20(14). https://www.researchgate.net/publication/334461649_Hair_Growth_Promoting_Effect_of_4HGF_Encapsulated_with_PGA_Nanoparticles_PGA-4HGF_by_b-Catenin_Activation_and_Its_Related_Cell_Cycle_Molecules

Monti D, Tampucci S, Burgalassi S, Chetoni P, Lenzi C, Pirone A, et al. Topical formulations containing finasteride Part I: In vitro permeation/penetration study and in vivo pharmacokinetics in hairless rat. J Pharm Sci. 2014;103(8):2307–14.

Yang Y, Wang P, Gong Y, Yu Z, Gan Y, Li P, et al. Curcumin-zinc framework encapsulated microneedle patch for promoting hair growth. Theranostics. 2023;13(11):3675–88.

Hydraderm for Androgenic Alopecia - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27].: https://clinicaltrials.gov/ct2/show/NCT05426629?term=CELL+THERAPY&cond=aga&draw=2&rank=24

Keravive by Hydrafacial for Scalp Health and Enhanced Hair Quality - Full Text View - ClinicalTrials.gov. [cited 2024 May 31].: https://classic.clinicaltrials.gov/ct2/show/NCT06112782?term=hydradermabrasion&cond=androgenetic+alopecia&draw=2&rank=2

Utomo DN, Hernugrahanto KD, Edward M, Widhiyanto L, Mahyudin F. Combination of bone marrow aspirate, cancellous bone allograft, and platelet-rich plasma as an alternative solution to critical-sized diaphyseal bone defect: A case series. Int J Surg Case Rep. 2019;58:178–85.

Kunze KN, Pakanati JJ, Vadhera AS, Polce EM, Williams BT, Parvaresh KC, et al. The efficacy of platelet-rich plasma for ligament injuries a systematic review of basic science literature with protocol quality assessment. 2019. http://www.sagepub.com/journals-permissions .

Kon E, Buda R, Filardo G, Di Martino A, Timoncini A, Cenacchi A, et al. Platelet-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions. Knee Surgery, Sport Traumatol Arthrosc. 2010;18(4):472–9.

Filardo G, Previtali D, Napoli F, Candrian C, Zaffagnini S, Grassi A. PRP injections for the treatment of knee osteoarthritis: a meta-analysis of randomized controlled trials. Cartilage. 2021;13(1):364S-375S.

Hausauer AK, Jones DH. Evaluating the efficacy of different platelet-rich plasma regimens for management of androgenetic alopecia: a single-center, blinded, randomized clinical trial. Dermatol Surg. 2018;44(9):1191–200.

Gupta AK, Cole J, Deutsch DP, Everts PA, Niedbalski RP, Panchaprateep R, et al. Platelet-rich plasma as a treatment for androgenetic alopecia. Dermatologic Surg. 2019;1.: http://insights.ovid.com/crossref?an=00042728-900000000-98404

Gentile P, Scioli MG, Bielli A, De Angelis B, De Sio C, De Fazio D, et al. Platelet-rich plasma and micrografts enriched with autologous human follicle mesenchymal stem cells improve hair re-growth in androgenetic alopecia. biomolecular pathway analysis and clinical evaluation. Biomedicines. 2019;7(2):27

Gupta AK, Versteeg SG, Rapaport J, Hausauer AK, Shear NH, Piguet V. The efficacy of platelet-rich plasma in the field of hair restoration and facial aesthetics—a systematic review and meta-analysis. J Cutan Med Surg. 2019;23(2):185–203.

Khatu SS, More YE, Gokhale NR, Chavhan DC, Bendsure N. Platelet-rich plasma in androgenic alopecia: myth or an effective tool. J Cutan Aesthet Surg. 2014;7(2):107–10.

Shetty VH, Goel S. Dermoscopic pre‐ and posttreatment evaluation in patients with androgenetic alopecia on platelet‐rich plasma—A prospective study. J Cosmet Dermatol. 2018;jocd.12845.

Verma K, Tegta GR, Verma G, Gupta M, Negi A, Sharma R. A study to compare the efficacy of platelet-rich plasma and minoxidil therapy for the treatment of androgenetic alopecia. Int J Trichology. 2019;11(2):68–79.

Bayat M, Yazdanpanah MJ, Hamidi Alamdari D, Banihashemi M, Salehi M. The effect of platelet-rich plasma injection in the treatment of androgenetic alopecia. J Cosmet Dermatol. 2019. https://doi.org/10.1111/jocd.12907 .

Pakhomova EE, Smirnova IO. Comparative evaluation of the clinical efficacy of prp-therapy, minoxidil, and their combination with immunohistochemical study of the dynamics of cell proliferation in the treatment of men with androgenetic alopecia. Int J Mol Sci. 2020;21(18):1–16.

Qu Q, Zhou Y, Shi P, Du L, Fan Z, Wang J, et al. Platelet-rich plasma for androgenic alopecia: a randomized, placebo-controlled, double-blind study and combined mice model experiment. J Cosmet Dermatol. 2021;20(10):3227–35.

Bruce AJ, Pincelli TP, Heckman MG, Desmond CM, Arthurs JR, Diehl NN, et al. A randomized, controlled pilot trial comparing platelet-rich plasma to topical minoxidil foam for treatment of androgenic alopecia in women. Dermatol Surg. 2020;46(6):826–32.

Dubin DP, Lin MJ, Leight HM, Farberg AS, Torbeck RL, Burton WB, et al. The effect of platelet-rich plasma on female androgenetic alopecia: a randomized controlled trial. J Am Acad Dermatol. 2020;83(5):1294–7.

Pavlovic V, Ciric M, Jovanovic V, Trandafilovic M, Stojanovic P. Platelet-rich fibrin: Basics of biological actions and protocol modifications. Open Med (Warsaw, Poland). 2021;16(1):446–54.

Article   CAS   PubMed Central   Google Scholar  

Choukroun J, Ghanaati S. Reduction of relative centrifugation force within injectable platelet-rich-fibrin (PRF) concentrates advances patients’ own inflammatory cells, platelets and growth factors: the first introduction to the low speed centrifugation concept. Eur J Trauma Emerg Surg. 2018;44:87–95.

Miron RJ, Fujioka-Kobayashi M, Hernandez M, Kandalam U, Zhang Y, Ghanaati S, et al. Injectable platelet rich fibrin (i-PRF): opportunities in regenerative dentistry? 2017; https://pubmed.ncbi.nlm.nih.gov/28154995/

Kobayashi E, Flückiger L, Fujioka-Kobayashi M, Sawada K, Sculean A, Schaller B, et al. Comparative release of growth factors from PRP, PRF, and advanced-PRF. Clin Oral Investig. 2016;20(9):2353–60.

Egierska D, Perszke M, Mazur M, Duś-Ilnicka I. Platelet-rich plasma and platelet-rich fibrin in oral surgery: a narrative review. Dent Med Probl. 2023;60(1):177–86.

Celikten M, Sahin H, Senturk GE, Bilsel K, Pulatkan A, Kapicioglu M, et al. The effect of platelet-rich fibrin, platelet-rich plasma, and concentrated growth factor in the repair of full thickness rotator cuff tears. J shoulder Elb Surg. 2024;33(5):e261-77.

Domingues RB, von Rautenfeld M, Kavalco CM, Caliari C, Dellagiustina C, da Fonseca LF, et al. The role of orthobiologics in chronic wound healing. Int Wound J. 2024;21(4):e14854

Omid Keyhan S, Hemmat S, Ali Badri A, Abdeshahzadeh A, Khiabani K. Use of platelet-rich fibrin and platelet-rich plasma in combination with fat graft: which is more effective during facial lipostructure? Oral Maxillofac Surg J Oral Maxillofac Surg. 2013;71:610–21. https://doi.org/10.1016/j.joms.2012.06.176 .

Lu K, Han Q, Ma Z, Yan Q, Pei Y, Shi P, et al. Injectable platelet rich fibrin facilitates hair follicle regeneration by promoting human dermal papilla cell proliferation, migration, and trichogenic inductivity. Exp Cell Res. 2021;409(1):112888. https://doi.org/10.1016/j.yexcr.2021.112888 .

Arora R, Shukla S. Injectable-platelet-rich fibrin-smart blood with stem cells for the treatment of alopecia: a report of three patients. Int J Trichol. 2019;11(3):128–31.

Bhoite KS, Chikhalkar SB, Mishra SN, Kharkar VD. Injectable platelet rich fibrin therapy for androgenetic alopecia: a series of 15 cases. Int J Res Dermatology. 2022;8(4):398–402.

Schiavone G, Paradisi A, Ricci F, Abeni D. Injectable platelet-, leukocyte-, and fibrin-rich plasma (Il-PRF) in the management of androgenetic alopecia. Dermatol Surg. 2018;44(9):1183–90.

Ali N, Diab F, Al-Shimaa ·, Ibrahim M, Aya ·, Abdallah M. Fluid platelet-rich fibrin (PRF) versus platelet-rich plasma (PRP) in the Treatment of Atrophic Acne Scars: A Comparative Study. 2023;315:1249–55. https://doi.org/10.1007/s00403-022-02511-3

Shashank B, Bhushan M. Injectable platelet-rich fibrin (prf): the newest biomaterial and its use in various dermatological conditions in our practice: a case series. J Cosmet Dermatol. 2021;20(5):1421–6.

Shimizu Y, Ntege EH, Sunami H, Inoue Y. Regenerative medicine strategies for hair growth and regeneration: a narrative review of literature. Regen Ther. 2022;21:527–39. https://doi.org/10.1016/j.reth.2022.10.005 .

Nepal S, Venkataram A, Mysore V. The role of adipose tissue in hair regeneration: a potential tool for management? J Cutan Aesthet Surg. 2021;14(3):295–304.

Won CH, Yoo HG, Kwon OS, Sung MY, Kang YJ, Chung JH, et al. Hair growth promoting effects of adipose tissue-derived stem cells. Vol. 57, J. Dermatol Sci. 2010. p. 134–7. https://pubmed.ncbi.nlm.nih.gov/19963355/

Fukuoka H, Narita K, Suga H. Hair regeneration therapy: application of adipose-derived stem cells. Curr Stem Cell Res Ther. 2017;12(7). https://pubmed.ncbi.nlm.nih.gov/28530535/

Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyvk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues Cloning in vitro and retransplantation in vivo. Transplantation. 1974;17(4):331–40.

Tuan RS, Boland G, Tuli R. Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther. 2003;5(1):1–14.

Schäffler A, Büchler C. Concise review: adipose tissue-derived stromal cells-basic and clinical implications for novel cell-based therapies. Stem Cells. 2007;25(4):818–27.

Park B-S, Kim W-S, Choi J-S, Kim H-K, Won J-H, Ohkubo F, et al. Hair growth stimulated by conditioned medium of adipose-derived stem cells is enhanced by hypoxia: evidence of increased growth factor secretion. Biomed Res. 2010;31(1):27–34.

Fukuoka H, Suga H. Hair regeneration treatment using adipose-derived stem cell conditioned medium: follow-up with trichograms. Eplasty. 2015;15:e10.

PubMed   PubMed Central   Google Scholar  

Owczarczyk-Saczonek A, Wociór A, Placek W, Maksymowicz W, Wojtkiewicz J. The use of adipose-derived stem cells in selected skin diseases (vitiligo, alopecia, and nonhealing wounds). Stem Cells Int. 2017 Aug 21;2017:1–11. https://pubmed.ncbi.nlm.nih.gov/28904532/

Gentile P, Garcovich S. Advances in Regenerative Stem Cell Therapy in Androgenic Alopecia and Hair Loss: Wnt pathway, Growth-Factor, and Mesenchymal Stem Cell Signaling Impact Analysis on Cell Growth and Hair Follicle Development. Cells. 2019;8(5). : http://www.ncbi.nlm.nih.gov/pubmed/31100937

Zhang P, Kling RE, Ravuri SK, Kokai LE, Rubin JP, Chai JK, et al. A review of adipocyte lineage cells and dermal papilla cells in hair follicle regeneration. J Tissue Eng. 2014;5. http://www.uk.sagepub.com/aboutus/openaccess.htm

Festa E, Fretz J, Berry R, Schmidt B, Rodeheffer M, Horowitz M, et al. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell. 2011;146(5):761–71.

He J, Duan H, Xiong Y, Zhang W, Zhou G, Cao Y, et al. Participation of CD34-enriched mouse adipose cells in hair morphogenesis. Mol Med Rep. 2013;7(4):1111–6.

Zografou A, Papadopoulos O, Tsigris C, Kavantzas N, Michalopoulos E, Chatzistamatiou T, et al. Autologous transplantation of adipose-derived stem cells enhances skin graft survival and wound healing in diabetic rats. Ann Plast Surg. 2013;71(2):225–32.

Rokunohe A, Matsuzaki Y, Rokunohe D, Sakuraba Y, Fukui T, Nakano H, et al. Immunosuppressive effect of adipose-derived stromal cells on imiquimod-induced psoriasis in mice. J Dermatol Sci. 2016;82(1):50–3.

Lee YS, Sah SK, Lee JH, Seo KW, Kang KS, Kim TY. Human umbilical cord blood-derived mesenchymal stem cells ameliorate psoriasis-like skin inflammation in mice. Biochem Biophys Reports. 2016;2017(9):281–8.

Wu J, Yang Q, Wu S, Yuan R, Zhao X, Li Y, et al. Adipose-derived stem cell exosomes promoted hair regeneration. Tissue Eng Regen Med. 2021;18(4):685–91. https://doi.org/10.1007/s13770-021-00347-y .

Zhou L, Wang H, Jing J, Yu L, Wu X, Lu Z. Regulation of hair follicle development by exosomes derived from dermal papilla cells. Biochem Biophys Res Commun. 2018;500(2):325–32. https://doi.org/10.1016/j.bbrc.2018.04.067 .

Nilforoushzadeh MA, Aghdami N, Taghiabadi E. Human hair outer root sheath cells and platelet-lysis exosomes promote hair inductivity of dermal papilla cell. Tissue Eng Regen Med. https://doi.org/10.1007/s13770-020-00266-4

Rajendran RL, Gangadaran P, Seo CH, Kwack MH, Oh JM, Lee HW, et al. Macrophage-derived extracellular vesicle promotes hair growth. Cells. 2020;9(4):856.

Riazifar M, Mohammadi MR, Pone EJ, Yeri A, Lasser C, Segaliny AI, et al. Stem cell-derived exosomes as nanotherapeutics for autoimmune and neurodegenerative disorders. ACS Nano. 2019;13(6):6670–88.

Zhang B, Wang M, Gong A, Zhang X, Wu X, Zhu Y, et al. HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells. 2015;33(7):2158–68.

Gentile P, Scioli MG, Bielli A, Orlandi A, Cervelli V. Stem cells from human hair follicles: first mechanical isolation for immediate autologous clinical use in androgenetic alopecia and hair loss. Stem cell Investig. 2017;4(7):58–58.

Zanzottera F, Lavezzari E, Trovato L, Icardi A, Graziano A. Adipose derived stem cells and growth factors applied on hair transplantation. follow-up of clinical outcome. J Cosmet Dermatological Sci Appl. 2014;4(4):268–74

Hamed Kadry M, Kheir WA El, Sayed Shalaby M El, El Shahid AR, Metwally HG. Autologous Adipose Derived Stem Cell versus Platelet Rich Plasma Injection in the Treatment of Androgentic Alopecia: Efficacy, Side Effects and Safety. J Clin Exp Dermatol Res. 2018;09(03). : https://www.omicsonline.org/open-access/autologous-adipose-derived-stem-cell-versus-platelet-rich-plasma-injection-in-the-treatment-of-androgentic-alopecia-efficacy-side-2155-9570-1000447-102382.html

Shin H, Ryu HH, Kwon O, Park BS, Jo SJ. Clinical use of conditioned media of adipose tissue-derived stem cells in female pattern hair loss: A retrospective case series study. Int J Dermatol. 2015;54(6):730–5.

Adipose-derived Stem Cell Conditioned Media as a Novel Approach for Hair Regrowth in Male Androgenetic Alopecia - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 31]. : https://clinicaltrials.gov/ct2/show/NCT05296863?term=NCT05296863&draw=2&rank=1

Tak YJ, Lee SY, Cho AR, Kim YS. A randomized, double-blind, vehicle-controlled clinical study of hair regeneration using adipose-derived stem cell constituent extract in androgenetic alopecia. Stem Cells Transl Med. 2020;9(8):839–49.

Safety and Tolerability of Hair Stimulating Complex (HSC) in Female Pattern Hair Loss - Full Text View - ClinicalTrials.gov. 2018. https://clinicaltrials.gov/ct2/show/NCT03662854?term=NCT03662854&draw=2&rank=1

Hair Growth Efficacy and Safety of NGF-574H in Adult With Androgenic Alopecia - Full Text View - ClinicalTrials.gov. 2018: https://clinicaltrials.gov/ct2/show/NCT03676400?term=NCT03676400&draw=2&rank=1

Adipose-derived SVF for Treatment of Alopecia - Full Text View - ClinicalTrials.gov. 2016. https://clinicaltrials.gov/ct2/show/NCT02626780?term=adipose&cond=AGA&draw=2&rank=4

Point-of-Care Adipose-derived Cells for Hair Growth - Full Text View - ClinicalTrials.gov. 2016. https://clinicaltrials.gov/ct2/show/NCT02729415?term=NCT02729415&draw=2&rank=1

Efficacy of Platelet-Rich Plasma Versus Mesotherapy in Androgenetic Alopecia: A Retrospective Study - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT05129800?term=CELL+THERAPY&cond=aga&draw=2&rank=27

Fukuoka H, Suga H, Narita K, Watanabe R, Shintani S. The latest advance in hair regeneration therapy using proteins secreted by adipose-derived stem cells. Am J Cosmet Surg. 2015;29(4):273–82.

Gentile P, Scioli MG, Bielli A, Orlandi A, Cervelli V. Stem cells from human hair follicles: first mechanical isolation for immediate autologous clinical use in androgenetic alopecia and hair loss. Stem Cell Investig. 2017;4(7):58–58.

Mahmood S Choudhery APKEMU. Adipose tissue derived stem cell based hair restoration therapy for androgenetic alopecia - ClinicalTrials.gov. 2018. https://clinicaltrials.gov/ct2/show/NCT02865421?term=NCT02865421&draw=2&rank=1

Adipose Derived Stem Cells Versus Platelet Rich Plasma on Follicular Unit Extraction - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT03388840?term=NCT03388840&draw=2&rank=1

Stevens HP, Donners S, De Bruijn J. Introducing platelet-rich stroma: platelet-rich plasma (PRP) and stromal vascular fraction (SVF) combined for the treatment of androgenetic alopecia. Aesthetic Surg J. 2018;38(8):811–22.

Kenneth Williams. AGA Biocellular Stem/Stromal Hair Regenerative Study - Full Text View - ClinicalTrials.gov. 2021. : https://clinicaltrials.gov/ct2/show/NCT02849470?term=NCT02849470&draw=2&rank=1

El-Khalawany M, Rageh MA, Elnokrashy I, Ibrahim SMA. Efficacy of autologous stromal vascular fraction injection in the treatment of androgenic alopecia. Arch Dermatol Res. 2022;0123456789. https://doi.org/10.1007/s00403-022-02501-5

A Study to Evaluate and Compare Injections of Autologous Mixed Population of Dermal Cells Cells Into the Balding Scalp of Subjects With Hair Loss (CA-0006931) - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01669746?term=NCT01669746&draw=2&rank=1

A Study to Evaluate and Compare Injections of Autologous Mixed Population of Dermal Cells Into the Balding Scalp of Subjects With Hair Loss (CA-0004542) - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01451151?term=CELL+THERAPY&cond=aga&draw=2&rank=17

A Study to Evaluate and Compare Injections of Autologous Dermal Cells Into the Balding Scalp of Subjects With Hair Loss - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01451099?term=CELL+THERAPY&cond=aga&draw=2&rank=16

A Study to Evaluate and Compare Injections of Autologous Mixed Population of Dermal Cells Into the Balding Scalp of Subjects With Hair Loss (CA-0005995) - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01451190?term=CELL+THERAPY&cond=aga&draw=2&rank=20

A Study to Evaluate and Compare Injections of Autologous Dermal and Epidermal Cells Into the Balding Scalp of Subjects With Hair Loss (CA-0004669) - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01451177?term=NCT01451177&draw=2&rank=1

A Study to Evaluate and Compare Injections of Autologous Dermal and Epidermal Cells Into the Balding Scalp of Subjects With Hair Loss (CA-0004512) - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01451125?term=CELL+THERAPY&cond=aga&draw=2&rank=15

A Study to Evaluate and Compare Injections of Autologous Dermal and Epidermal Cells Into the Balding Scalp of Subjects With Hair Loss (CA-0004541) - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01451138?term=CELL+THERAPY&cond=aga&draw=2&rank=18

A Study to Evaluate and Compare Injections of Autologous Dermal and Epidermal Cells Into the Balding Scalp of Subjects With Hair Loss (CA-0002899) - Full Text View - ClinicalTrials.gov. 2009. : https://clinicaltrials.gov/ct2/show/NCT01451112?term=NCT01451112&draw=2&rank=1

A Study to Evaluate and Compare Injections of Autologous Dermal and Epidermal Cells Into the Balding Scalp of Subjects With Hair Loss (CA-0002012) - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01451047?term=CELL+THERAPY&cond=aga&draw=2&rank=21

A Study to Evaluate and Compare Injections of Autologous Dermal and Epidermal Cells Into the Balding Scalp of Subjects With Hair Loss - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01451021?term=CELL+THERAPY&cond=aga&draw=2&rank=22

A Study to Evaluate and Compare Injections of Autologous Dermal and Epidermal Cells Into the Balding Scalp of Subjects With Hair Loss (CA-0002013) - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 27]. : https://clinicaltrials.gov/ct2/show/NCT01451073?term=CELL+THERAPY&cond=aga&draw=2&rank=23

Autologous Hair Follicle Derived Mesenchymal Stem Cell Suspension to Treat AGA - Full Text View - ClinicalTrials.gov. [cited 2023 Mar 31]. : https://clinicaltrials.gov/ct2/show/NCT05659095?term=NCT05659095&draw=1&rank=1

Safety and Efficacy Study of Human Autologous Hair Follicle Cells to Treat Androgenetic Alopecia - Full Text View - ClinicalTrials.gov. 2021. p. ClinicalTrials.gov. : https://clinicaltrials.gov/ct2/show/NCT01286649?term=CELL+THERAPY&cond=AGA&draw=2&rank=4

Elmaadawi IH, Mohamed BM, Ibrahim ZAS, Abdou SM, El Attar YA, Youssef A, et al. Stem cell therapy as a novel therapeutic intervention for resistant cases of alopecia areata and androgenetic alopecia. J Dermatolog Treat. 2018;29(5):431–40. https://pubmed.ncbi.nlm.nih.gov/27553744/

STYLE -- A Trial of Cell Enriched Adipose For Androgenetic Alopecia. 2020. : https://www.clinicaltrials.gov/ct2/show/NCT02503852?term=kerastem&cond=androgenetic+alopecia&draw=2&rank=1

Efficacy and Safety of Exosomes Versus Platelet Rich Plasma in Patients of Androgenetic Alopecia | ClinicalTrials.gov. 2024. https://clinicaltrials.gov/study/NCT06239207?cond=androgenetic alopecia &term=Exosomes&rank=1

Llamas-Molina JM, Carrero-Castaño A, Ruiz-Villaverde R, Campos A. Tissue engineering and regeneration of the human hair follicle in androgenetic alopecia. Literature Review. 2022. https://doi.org/10.3390/life12010117 .

Fisher JP, Mikos AG, Bronzino JD. Tissue engineering. Science (80- ). 1993. https://doi.org/10.1126/science.8493529

Castro AR, Logarinho E. Tissue engineering strategies for human hair follicle regeneration: How far from a hairy goal? 2019; https://pubmed.ncbi.nlm.nih.gov/31876379/

Lee V, Singh G, Trasatti JP, Bjornsson C, Xu X, Tran TN, et al. Design and fabrication of human skin by three-dimensional bioprinting. Tissue Eng Part C Methods. 2014;20(6):473.

Markstedt K, Mantas A, Tournier I, Martínez Ávila H, Hägg D, Gatenholm P. 3D bioprinting human chondrocytes with nanocellulose-alginate bioink for cartilage tissue engineering applications. Biomacromolecules. 2015;16(5):1489–96.

Cui H, Zhu W, Nowicki M, Zhou X, Khademhosseini A, Grace Zhang L, et al. Hierarchical fabrication of engineered vascularized bone biphasic constructs via dual 3D bioprinting: integrating regional bioactive factors into architectural design. Adv Healthc Mater. 2016;5(17):2174–81. https://doi.org/10.1002/adhm.201600505 .

Laronda MM, Rutz AL, Xiao S, Whelan KA, Duncan FE, Roth EW, et al. A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nat Commun. 2017;8(1):1–10.

Ma J, Qin C, Wu J, Zhuang H, Du L, Xu J, et al. 3D multicellular micropatterning biomaterials for hair regeneration and vascularization. Mater Horizons. 2023;10(9):3773–84.

Kang MS, Kwon M, Lee SH, Kim WH, Lee GW, Jo HJ, et al. 3D printing of skin equivalents with hair follicle structures and epidermal-papillary-dermal layers using gelatin/hyaluronic acid hydrogels. Chem – An Asian J. 2022;17(18):202200620. https://doi.org/10.1002/asia.202200620

Download references

Acknowledgements

Not applicable.

No funding was requested for this review.

Author information

Authors and affiliations.

Dermatology Department, Clínico San Carlos Hospital, Madrid, Spain

Lorena Pozo-Pérez & Eduardo López-Bran

Institute for Health Research of Clinico San Carlos Hospital (IdISSC), Madrid, Spain

Lorena Pozo-Pérez

Cellular GMP Manufacturing Facility, Institute for Health Research of Clinico San Carlos Hospital (IdISSC), Madrid, Spain

Pilar Tornero-Esteban

You can also search for this author in PubMed   Google Scholar

Contributions

LLPP conducted the literature research and articles collection, wrote the review and elaborated tables. PPTE collaborated in the literature research, writing and reviewing the paper. EELB designed, reviewed and approved the final manuscript.

Corresponding author

Correspondence to Lorena Pozo-Pérez .

Ethics declarations

Ethics approval and consent to participate, consent for publication, competing interests.

They authors declare that they have no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Pozo-Pérez, L., Tornero-Esteban, P. & López-Bran, E. Clinical and preclinical approach in AGA treatment: a review of current and new therapies in the regenerative field. Stem Cell Res Ther 15 , 260 (2024). https://doi.org/10.1186/s13287-024-03801-5

Download citation

Received : 26 April 2024

Accepted : 11 June 2024

Published : 15 August 2024

DOI : https://doi.org/10.1186/s13287-024-03801-5

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Androgenetic alopecia
• Hair growth
• Cell therapy
• Conditioned medium
• Nanomaterials

Stem Cell Research & Therapy

ISSN: 1757-6512

• Submission enquiries: Access here and click Contact Us
• General enquiries: [email protected]

• Type 1 Diabetes
• Type 2 Diabetes
• RESEARCH LABS
• Clinical Studies

From Stem Cells to Blood Flow: Studying the Effects of High Cholesterol on Artery Development

A study from the Messina laboratory in the Diabetes Center of Excellence at UMass Chan Medical School was  published in JVS-Vascular Science , exploring how high cholesterol levels, known as hypercholesterolemia, can affect the growth of new blood vessels (collateral arteries), which are important for maintaining blood flow when main arteries are blocked.  This is particularly relevant for conditions including peripheral arterial disease (PAD), where clogged arteries in the legs can lead to serious complications, including limb loss.

The study, led by former Messina lab postdoc Jinglian Yan, PhD, who is currently a Senior Scientist at Astellas Pharma, focused on a specific mechanism involving hematopoietic stem cells (HSCs), that can be converted into various types of blood cells, including a type of white blood cell called monocytes.

“We hypothesized that hypercholesterolemia affects these stem cells in a way that promotes the production of inflammatory cells called Ly6Chi monocytes and limits the production of cells that help form new blood vessels, Ly6Clow monocytes,” said Louis Messina, MD, The Johnnie Ray Cox Term Chair in Biomedical Research, Professor of Surgery in the Division of Vascular and Endovascular Surgery, and the Department of Molecular Cell and Cancer Biology.

To test this, the scientists used a model in which they transplanted stem cells from both normal and hypercholesterolemic mice into other mice.  

“The mice receiving stem cells from mice with high cholesterol showed poor blood flow recovery and reduced artery enlargement, similar to what is observed in hypercholesterolemic conditions,” said Dr. Messina. 

This indicated that the problem was linked to the stem cells themselves, not just the presence of high cholesterol. When cholesterol levels are high, it changes how these stem cells work. Specifically, it reduces the activity of a protein called Tet1, which is important for guiding stem cells to become helpful types of monocytes that promote blood vessel growth.

High cholesterol causes more of the stem cells to turn into "bad" monocytes (pro-inflammatory) that can cause inflammation, instead of "good" monocytes (proangiogenic) that help grow new blood vessels.

Because of this shift, the body struggles to grow new blood vessels in response to injuries, which can lead to poor blood flow and increased risk of serious conditions resulting amputations or heart issues.

“Tet1 plays a crucial role in this process by altering gene expression in the stem cells,” said Dr. Messina. “Restoring Tet1 expression in the stem cells of hypercholesterolemic mice improved artery enlargement and blood flow recovery.”

Currently, there is no highly effective drug or cell therapy available to boost blood flow in these vessels. The study's results offer a new direction for developing treatments that could help improve blood flow by targeting specific genes in stem cells.

“Our findings suggest that therapies targeting this specific mechanism could be developed to treat PAD and other conditions affected by poor collateral artery growth,” said Dr. Messina.

Understanding the genetic and cellular factors that contribute to vascular diseases can help in developing treatments for people with high cholesterol, aiming to improve their blood flow and overall health by targeting how these blood cells behave.

More Diabetes Center of Excellence News