what is a stem cell essay

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• Published: 26 February 2019

Stem cells: past, present, and future

• Wojciech Zakrzewski 1 ,
• Maciej Dobrzyński 2 ,
• Maria Szymonowicz 1 &
• Zbigniew Rybak 1  

Stem Cell Research & Therapy volume  10 , Article number:  68 ( 2019 ) Cite this article

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In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Stem cell classification

Stem cells are unspecialized cells of the human body. They are able to differentiate into any cell of an organism and have the ability of self-renewal. Stem cells exist both in embryos and adult cells. There are several steps of specialization. Developmental potency is reduced with each step, which means that a unipotent stem cell is not able to differentiate into as many types of cells as a pluripotent one. This chapter will focus on stem cell classification to make it easier for the reader to comprehend the following chapters.

Totipotent stem cells are able to divide and differentiate into cells of the whole organism. Totipotency has the highest differentiation potential and allows cells to form both embryo and extra-embryonic structures. One example of a totipotent cell is a zygote, which is formed after a sperm fertilizes an egg. These cells can later develop either into any of the three germ layers or form a placenta. After approximately 4 days, the blastocyst’s inner cell mass becomes pluripotent. This structure is the source of pluripotent cells.

Pluripotent stem cells (PSCs) form cells of all germ layers but not extraembryonic structures, such as the placenta. Embryonic stem cells (ESCs) are an example. ESCs are derived from the inner cell mass of preimplantation embryos. Another example is induced pluripotent stem cells (iPSCs) derived from the epiblast layer of implanted embryos. Their pluripotency is a continuum, starting from completely pluripotent cells such as ESCs and iPSCs and ending on representatives with less potency—multi-, oligo- or unipotent cells. One of the methods to assess their activity and spectrum is the teratoma formation assay. iPSCs are artificially generated from somatic cells, and they function similarly to PSCs. Their culturing and utilization are very promising for present and future regenerative medicine.

Multipotent stem cells have a narrower spectrum of differentiation than PSCs, but they can specialize in discrete cells of specific cell lineages. One example is a haematopoietic stem cell, which can develop into several types of blood cells. After differentiation, a haematopoietic stem cell becomes an oligopotent cell. Its differentiation abilities are then restricted to cells of its lineage. However, some multipotent cells are capable of conversion into unrelated cell types, which suggests naming them pluripotent cells.

Oligopotent stem cells can differentiate into several cell types. A myeloid stem cell is an example that can divide into white blood cells but not red blood cells.

Unipotent stem cells are characterized by the narrowest differentiation capabilities and a special property of dividing repeatedly. Their latter feature makes them a promising candidate for therapeutic use in regenerative medicine. These cells are only able to form one cell type, e.g. dermatocytes.

Stem cell biology

A blastocyst is formed after the fusion of sperm and ovum fertilization. Its inner wall is lined with short-lived stem cells, namely, embryonic stem cells. Blastocysts are composed of two distinct cell types: the inner cell mass (ICM), which develops into epiblasts and induces the development of a foetus, and the trophectoderm (TE). Blastocysts are responsible for the regulation of the ICM microenvironment. The TE continues to develop and forms the extraembryonic support structures needed for the successful origin of the embryo, such as the placenta. As the TE begins to form a specialized support structure, the ICM cells remain undifferentiated, fully pluripotent and proliferative [ 1 ]. The pluripotency of stem cells allows them to form any cell of the organism. Human embryonic stem cells (hESCs) are derived from the ICM. During the process of embryogenesis, cells form aggregations called germ layers: endoderm, mesoderm and ectoderm (Fig.  1 ), each eventually giving rise to differentiated cells and tissues of the foetus and, later on, the adult organism [ 2 ]. After hESCs differentiate into one of the germ layers, they become multipotent stem cells, whose potency is limited to only the cells of the germ layer. This process is short in human development. After that, pluripotent stem cells occur all over the organism as undifferentiated cells, and their key abilities are proliferation by the formation of the next generation of stem cells and differentiation into specialized cells under certain physiological conditions.

Oocyte development and formation of stem cells: the blastocoel, which is formed from oocytes, consists of embryonic stem cells that later differentiate into mesodermal, ectodermal, or endodermal cells. Blastocoel develops into the gastrula

Signals that influence the stem cell specialization process can be divided into external, such as physical contact between cells or chemical secretion by surrounding tissue, and internal, which are signals controlled by genes in DNA.

Stem cells also act as internal repair systems of the body. The replenishment and formation of new cells are unlimited as long as an organism is alive. Stem cell activity depends on the organ in which they are in; for example, in bone marrow, their division is constant, although in organs such as the pancreas, division only occurs under special physiological conditions.

Stem cell functional division

Whole-body development.

During division, the presence of different stem cells depends on organism development. Somatic stem cell ESCs can be distinguished. Although the derivation of ESCs without separation from the TE is possible, such a combination has growth limits. Because proliferating actions are limited, co-culture of these is usually avoided.

ESCs are derived from the inner cell mass of the blastocyst, which is a stage of pre-implantation embryo ca. 4 days after fertilization. After that, these cells are placed in a culture dish filled with culture medium. Passage is an inefficient but popular process of sub-culturing cells to other dishes. These cells can be described as pluripotent because they are able to eventually differentiate into every cell type in the organism. Since the beginning of their studies, there have been ethical restrictions connected to the medical use of ESCs in therapies. Most embryonic stem cells are developed from eggs that have been fertilized in an in vitro clinic, not from eggs fertilized in vivo.

Somatic or adult stem cells are undifferentiated and found among differentiated cells in the whole body after development. The function of these cells is to enable the healing, growth, and replacement of cells that are lost each day. These cells have a restricted range of differentiation options. Among many types, there are the following:

Mesenchymal stem cells are present in many tissues. In bone marrow, these cells differentiate mainly into the bone, cartilage, and fat cells. As stem cells, they are an exception because they act pluripotently and can specialize in the cells of any germ layer.

Neural cells give rise to nerve cells and their supporting cells—oligodendrocytes and astrocytes.

Haematopoietic stem cells form all kinds of blood cells: red, white, and platelets.

Skin stem cells form, for example, keratinocytes, which form a protective layer of skin.

The proliferation time of somatic stem cells is longer than that of ESCs. It is possible to reprogram adult stem cells back to their pluripotent state. This can be performed by transferring the adult nucleus into the cytoplasm of an oocyte or by fusion with the pluripotent cell. The same technique was used during cloning of the famous Dolly sheep.

hESCs are involved in whole-body development. They can differentiate into pluripotent, totipotent, multipotent, and unipotent cells (Fig.  2 ) [ 2 ].

Changes in the potency of stem cells in human body development. Potency ranges from pluripotent cells of the blastocyst to unipotent cells of a specific tissue in a human body such as the skin, CNS, or bone marrow. Reversed pluripotency can be achieved by the formation of induced pluripotent stem cells using either octamer-binding transcription factor (Oct4), sex-determining region Y (Sox2), Kruppel-like factor 4 (Klf4), or the Myc gene

Pluripotent cells can be named totipotent if they can additionally form extraembryonic tissues of the embryo. Multipotent cells are restricted in differentiating to each cell type of given tissue. When tissue contains only one lineage of cells, stem cells that form them are called either called oligo- or unipotent.

iPSC quality control and recognition by morphological differences

The comparability of stem cell lines from different individuals is needed for iPSC lines to be used in therapeutics [ 3 ]. Among critical quality procedures, the following can be distinguished:

Short tandem repeat analysis—This is the comparison of specific loci on the DNA of the samples. It is used in measuring an exact number of repeating units. One unit consists of 2 to 13 nucleotides repeating many times on the DNA strand. A polymerase chain reaction is used to check the lengths of short tandem repeats. The genotyping procedure of source tissue, cells, and iPSC seed and master cell banks is recommended.

Identity analysis—The unintentional switching of lines, resulting in other stem cell line contamination, requires rigorous assay for cell line identification.

Residual vector testing—An appearance of reprogramming vectors integrated into the host genome is hazardous, and testing their presence is a mandatory procedure. It is a commonly used procedure for generating high-quality iPSC lines. An acceptable threshold in high-quality research-grade iPSC line collections is ≤ 1 plasmid copies per 100 cells. During the procedure, 2 different regions, common to all plasmids, should be used as specific targets, such as EBNA and CAG sequences [ 3 ]. To accurately represent the test reactions, a standard curve needs to be prepared in a carrier of gDNA from a well-characterized hPSC line. For calculations of plasmid copies per cell, it is crucial to incorporate internal reference gDNA sequences to allow the quantification of, for example, ribonuclease P (RNaseP) or human telomerase reverse transcriptase (hTERT).

Karyotype—A long-term culture of hESCs can accumulate culture-driven mutations [ 4 ]. Because of that, it is crucial to pay additional attention to genomic integrity. Karyotype tests can be performed by resuscitating representative aliquots and culturing them for 48–72 h before harvesting cells for karyotypic analysis. If abnormalities are found within the first 20 karyotypes, the analysis must be repeated on a fresh sample. When this situation is repeated, the line is evaluated as abnormal. Repeated abnormalities must be recorded. Although karyology is a crucial procedure in stem cell quality control, the single nucleotide polymorphism (SNP) array, discussed later, has approximately 50 times higher resolution.

Viral testing—When assessing the quality of stem cells, all tests for harmful human adventitious agents must be performed (e.g. hepatitis C or human immunodeficiency virus). This procedure must be performed in the case of non-xeno-free culture agents.

Bacteriology—Bacterial or fungal sterility tests can be divided into culture- or broth-based tests. All the procedures must be recommended by pharmacopoeia for the jurisdiction in which the work is performed.

Single nucleotide polymorphism arrays—This procedure is a type of DNA microarray that detects population polymorphisms by enabling the detection of subchromosomal changes and the copy-neutral loss of heterozygosity, as well as an indication of cellular transformation. The SNP assay consists of three components. The first is labelling fragmented nucleic acid sequences with fluorescent dyes. The second is an array that contains immobilized allele-specific oligonucleotide (ASO) probes. The last component detects, records, and eventually interprets the signal.

Flow cytometry—This is a technique that utilizes light to count and profile cells in a heterogeneous fluid mixture. It allows researchers to accurately and rapidly collect data from heterogeneous fluid mixtures with live cells. Cells are passed through a narrow channel one by one. During light illumination, sensors detect light emitted or refracted from the cells. The last step is data analysis, compilation and integration into a comprehensive picture of the sample.

Phenotypic pluripotency assays—Recognizing undifferentiated cells is crucial in successful stem cell therapy. Among other characteristics, stem cells appear to have a distinct morphology with a high nucleus to cytoplasm ratio and a prominent nucleolus. Cells appear to be flat with defined borders, in contrast to differentiating colonies, which appear as loosely located cells with rough borders [ 5 ]. It is important that images of ideal and poor quality colonies for each cell line are kept in laboratories, so whenever there is doubt about the quality of culture, it can always be checked according to the representative image. Embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers must be performed. It is important to note that colonies cultured under different conditions may have different morphologies [ 6 ].

Histone modification and DNA methylation—Quality control can be achieved by using epigenetic analysis tools such as histone modification or DNA methylation. When stem cells differentiate, the methylation process silences pluripotency genes, which reduces differentiation potential, although other genes may undergo demethylation to become expressed [ 7 ]. It is important to emphasize that stem cell identity, together with its morphological characteristics, is also related to its epigenetic profile [ 8 , 9 ]. According to Brindley [ 10 ], there is a relationship between epigenetic changes, pluripotency, and cell expansion conditions, which emphasizes that unmethylated regions appear to be serum-dependent.

hESC derivation and media

hESCs can be derived using a variety of methods, from classic culturing to laser-assisted methodologies or microsurgery [ 11 ]. hESC differentiation must be specified to avoid teratoma formation (see Fig.  3 ).

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There is a different result, however, when commitment signals (in forms of soluble factors and culture conditions) are applied and enable the selection of progenitor cells

hESCs spontaneously differentiate into embryonic bodies (EBs) [ 12 ]. EBs can be studied instead of embryos or animals to predict their effects on early human development. There are many different methods for acquiring EBs, such as bioreactor culture [ 13 ], hanging drop culture [ 12 ], or microwell technology [ 14 , 15 ]. These methods allow specific precursors to form in vitro [ 16 ].

The essential part of these culturing procedures is a separation of inner cell mass to culture future hESCs (Fig.  4 ) [ 17 ]. Rosowski et al. [ 18 ] emphasizes that particular attention must be taken in controlling spontaneous differentiation. When the colony reaches the appropriate size, cells must be separated. The occurrence of pluripotent cells lasts for 1–2 days. Because the classical utilization of hESCs caused ethical concerns about gastrulas used during procedures, Chung et al. [ 19 ] found out that it is also possible to obtain hESCs from four cell embryos, leaving a higher probability of embryo survival. Additionally, Zhang et al. [ 20 ] used only in vitro fertilization growth-arrested cells.

Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells are formed. Blastocysts with ICM are formed on the sixth day after fertilization. Pluripotent stem cells from ICM can then be successfully transmitted on a dish

Cell passaging is used to form smaller clusters of cells on a new culture surface [ 21 ]. There are four important passaging procedures.

Enzymatic dissociation is a cutting action of enzymes on proteins and adhesion domains that bind the colony. It is a gentler method than the manual passage. It is crucial to not leave hESCs alone after passaging. Solitary cells are more sensitive and can easily undergo cell death; collagenase type IV is an example [ 22 , 23 ].

Manual passage , on the other hand, focuses on using cell scratchers. The selection of certain cells is not necessary. This should be done in the early stages of cell line derivation [ 24 ].

Trypsin utilization allows a healthy, automated hESC passage. Good Manufacturing Practice (GMP)-grade recombinant trypsin is widely available in this procedure [ 24 ]. However, there is a risk of decreasing the pluripotency and viability of stem cells [ 25 ]. Trypsin utilization can be halted with an inhibitor of the protein rho-associated protein kinase (ROCK) [ 26 ].

Ethylenediaminetetraacetic acid ( EDTA ) indirectly suppresses cell-to-cell connections by chelating divalent cations. Their suppression promotes cell dissociation [ 27 ].

Stem cells require a mixture of growth factors and nutrients to differentiate and develop. The medium should be changed each day.

Traditional culture methods used for hESCs are mouse embryonic fibroblasts (MEFs) as a feeder layer and bovine serum [ 28 ] as a medium. Martin et al. [ 29 ] demonstrated that hESCs cultured in the presence of animal products express the non-human sialic acid, N -glycolylneuraminic acid (NeuGc). Feeder layers prevent uncontrolled proliferation with factors such as leukaemia inhibitory factor (LIF) [ 30 ].

First feeder layer-free culture can be supplemented with serum replacement, combined with laminin [ 31 ]. This causes stable karyotypes of stem cells and pluripotency lasting for over a year.

Initial culturing media can be serum (e.g. foetal calf serum FCS), artificial replacement such as synthetic serum substitute (SSS), knockout serum replacement (KOSR), or StemPro [ 32 ]. The simplest culture medium contains only eight essential elements: DMEM/F12 medium, selenium, NaHCO 3, l -ascorbic acid, transferrin, insulin, TGFβ1, and FGF2 [ 33 ]. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.

Turning point in stem cell therapy

The turning point in stem cell therapy appeared in 2006, when scientists Shinya Yamanaka, together with Kazutoshi Takahashi, discovered that it is possible to reprogram multipotent adult stem cells to the pluripotent state. This process avoided endangering the foetus’ life in the process. Retrovirus-mediated transduction of mouse fibroblasts with four transcription factors (Oct-3/4, Sox2, KLF4, and c-Myc) [ 34 ] that are mainly expressed in embryonic stem cells could induce the fibroblasts to become pluripotent (Fig.  5 ) [ 35 ]. This new form of stem cells was named iPSCs. One year later, the experiment also succeeded with human cells [ 36 ]. After this success, the method opened a new field in stem cell research with a generation of iPSC lines that can be customized and biocompatible with the patient. Recently, studies have focused on reducing carcinogenesis and improving the conduction system.

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their role as somatic cells and, once again, become pluripotent and can differentiate into any cell type of human body

The turning point was influenced by former discoveries that happened in 1962 and 1987.

The former discovery was about scientist John Gurdon successfully cloning frogs by transferring a nucleus from a frog’s somatic cells into an oocyte. This caused a complete reversion of somatic cell development [ 37 ]. The results of his experiment became an immense discovery since it was previously believed that cell differentiation is a one-way street only, but his experiment suggested the opposite and demonstrated that it is even possible for a somatic cell to again acquire pluripotency [ 38 ].

The latter was a discovery made by Davis R.L. that focused on fibroblast DNA subtraction. Three genes were found that originally appeared in myoblasts. The enforced expression of only one of the genes, named myogenic differentiation 1 (Myod1), caused the conversion of fibroblasts into myoblasts, showing that reprogramming cells is possible, and it can even be used to transform cells from one lineage to another [ 39 ].

Although pluripotency can occur naturally only in embryonic stem cells, it is possible to induce terminally differentiated cells to become pluripotent again. The process of direct reprogramming converts differentiated somatic cells into iPSC lines that can form all cell types of an organism. Reprogramming focuses on the expression of oncogenes such as Myc and Klf4 (Kruppel-like factor 4). This process is enhanced by a downregulation of genes promoting genome stability, such as p53. Additionally, cell reprogramming involves histone alteration. All these processes can cause potential mutagenic risk and later lead to an increased number of mutations. Quinlan et al. [ 40 ] checked fully pluripotent mouse iPSCs using whole genome DNA sequencing and structural variation (SV) detection algorithms. Based on those studies, it was confirmed that although there were single mutations in the non-genetic region, there were non-retrotransposon insertions. This led to the conclusion that current reprogramming methods can produce fully pluripotent iPSCs without severe genomic alterations.

During the course of development from pluripotent hESCs to differentiated somatic cells, crucial changes appear in the epigenetic structure of these cells. There is a restriction or permission of the transcription of genes relevant to each cell type. When somatic cells are being reprogrammed using transcription factors, all the epigenetic architecture has to be reconditioned to achieve iPSCs with pluripotency [ 41 ]. However, cells of each tissue undergo specific somatic genomic methylation. This influences transcription, which can further cause alterations in induced pluripotency [ 42 ].

Source of iPSCs

Because pluripotent cells can propagate indefinitely and differentiate into any kind of cell, they can be an unlimited source, either for replacing lost or diseased tissues. iPSCs bypass the need for embryos in stem cell therapy. Because they are made from the patient’s own cells, they are autologous and no longer generate any risk of immune rejection.

At first, fibroblasts were used as a source of iPSCs. Because a biopsy was needed to achieve these types of cells, the technique underwent further research. Researchers investigated whether more accessible cells could be used in the method. Further, other cells were used in the process: peripheral blood cells, keratinocytes, and renal epithelial cells found in urine. An alternative strategy to stem cell transplantation can be stimulating a patient’s endogenous stem cells to divide or differentiate, occurring naturally when skin wounds are healing. In 2008, pancreatic exocrine cells were shown to be reprogrammed to functional, insulin-producing beta cells [ 43 ].

The best stem cell source appears to be the fibroblasts, which is more tempting in the case of logistics since its stimulation can be fast and better controlled [ 44 ].

• Teratoma formation assay

The self-renewal and differentiation capabilities of iPSCs have gained significant interest and attention in regenerative medicine sciences. To study their abilities, a quality-control assay is needed, of which one of the most important is the teratoma formation assay. Teratomas are benign tumours. Teratomas are capable of rapid growth in vivo and are characteristic because of their ability to develop into tissues of all three germ layers simultaneously. Because of the high pluripotency of teratomas, this formation assay is considered an assessment of iPSC’s abilities [ 45 ].

Teratoma formation rate, for instance, was observed to be elevated in human iPSCs compared to that in hESCs [ 46 ]. This difference may be connected to different differentiation methods and cell origins. Most commonly, the teratoma assay involves an injection of examined iPSCs subcutaneously or under the testis or kidney capsule in mice, which are immune-deficient [ 47 ]. After injection, an immature but recognizable tissue can be observed, such as the kidney tubules, bone, cartilage, or neuroepithelium [ 30 ]. The injection site may have an impact on the efficiency of teratoma formation [ 48 ].

There are three groups of markers used in this assay to differentiate the cells of germ layers. For endodermal tissue, there is insulin/C-peptide and alpha-1 antitrypsin [ 49 ]. For the mesoderm, derivatives can be used, e.g. cartilage matrix protein for the bone and alcian blue for the cartilage. As ectodermal markers, class III B botulin or keratin can be used for keratinocytes.

Teratoma formation assays are considered the gold standard for demonstrating the pluripotency of human iPSCs, demonstrating their possibilities under physiological conditions. Due to their actual tissue formation, they could be used for the characterization of many cell lineages [ 50 ].

Directed differentiation

To be useful in therapy, stem cells must be converted into desired cell types as necessary or else the whole regenerative medicine process will be pointless. Differentiation of ESCs is crucial because undifferentiated ESCs can cause teratoma formation in vivo. Understanding and using signalling pathways for differentiation is an important method in successful regenerative medicine. In directed differentiation, it is likely to mimic signals that are received by cells when they undergo successive stages of development [ 51 ]. The extracellular microenvironment plays a significant role in controlling cell behaviour. By manipulating the culture conditions, it is possible to restrict specific differentiation pathways and generate cultures that are enriched in certain precursors in vitro. However, achieving a similar effect in vivo is challenging. It is crucial to develop culture conditions that will allow the promotion of homogenous and enhanced differentiation of ESCs into functional and desired tissues.

Regarding the self-renewal of embryonic stem cells, Hwang et al. [ 52 ] noted that the ideal culture method for hESC-based cell and tissue therapy would be a defined culture free of either the feeder layer or animal components. This is because cell and tissue therapy requires the maintenance of large quantities of undifferentiated hESCs, which does not make feeder cells suitable for such tasks.

Most directed differentiation protocols are formed to mimic the development of an inner cell mass during gastrulation. During this process, pluripotent stem cells differentiate into ectodermal, mesodermal, or endodermal progenitors. Mall molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. There is a variety of signal intensities and molecular families that may affect the establishment of germ layers in vivo, such as fibroblast growth factors (FGFs) [ 53 ]; the Wnt family [ 54 ] or superfamily of transforming growth factors—β(TGFβ); and bone morphogenic proteins (BMP) [ 55 ]. Each candidate factor must be tested on various concentrations and additionally applied to various durations because the precise concentrations and times during which developing cells in embryos are influenced during differentiation are unknown. For instance, molecular antagonists of endogenous BMP and Wnt signalling can be used for ESC formation of ectoderm [ 56 ]. However, transient Wnt and lower concentrations of the TGFβ family trigger mesodermal differentiation [ 57 ]. Regarding endoderm formation, a higher activin A concentration may be required [ 58 , 59 ].

There are numerous protocols about the methods of forming progenitors of cells of each of germ layers, such as cardiomyocytes [ 60 ], hepatocytes [ 61 ], renal cells [ 62 ], lung cells [ 63 , 64 ], motor neurons [ 65 ], intestinal cells [ 66 ], or chondrocytes [ 67 ].

Directed differentiation of either iPSCs or ESCs into, e.g. hepatocytes, could influence and develop the study of the molecular mechanisms in human liver development. In addition, it could also provide the possibility to form exogenous hepatocytes for drug toxicity testing [ 68 ].

Levels of concentration and duration of action with a specific signalling molecule can cause a variety of factors. Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These can be used for either activating or deactivating specific signalling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method.

One of the successful examples of small-molecule cell therapies is antagonists and agonists of the Hedgehog pathway. They show to be very useful in motor neuron regeneration [ 69 ]. Endogenous small molecules with their function in embryonic development can also be used in in vitro methods to induce the differentiation of cells; for example, retinoic acid, which is responsible for patterning the nervous system in vivo [ 70 ], surprisingly induced retinal cell formation when the laboratory procedure involved hESCs [ 71 ].

The efficacy of differentiation factors depends on functional maturity, efficiency, and, finally, introducing produced cells to their in vivo equivalent. Topography, shear stress, and substrate rigidity are factors influencing the phenotype of future cells [ 72 ].

The control of biophysical and biochemical signals, the biophysical environment, and a proper guide of hESC differentiation are important factors in appropriately cultured stem cells.

Stem cell utilization and their manufacturing standards and culture systems

The European Medicines Agency and the Food and Drug Administration have set Good Manufacturing Practice (GMP) guidelines for safe and appropriate stem cell transplantation. In the past, protocols used for stem cell transplantation required animal-derived products [ 73 ].

The risk of introducing animal antigens or pathogens caused a restriction in their use. Due to such limitations, the technique required an obvious update [ 74 ]. Now, it is essential to use xeno-free equivalents when establishing cell lines that are derived from fresh embryos and cultured from human feeder cell lines [ 75 ]. In this method, it is crucial to replace any non-human materials with xeno-free equivalents [ 76 ].

NutriStem with LN-511, TeSR2 with human recombinant laminin (LN-511), and RegES with human foreskin fibroblasts (HFFs) are commonly used xeno-free culture systems [ 33 ]. There are many organizations and international initiatives, such as the National Stem Cell Bank, that provide stem cell lines for treatment or medical research [ 77 ].

Stem cell use in medicine

Stem cells have great potential to become one of the most important aspects of medicine. In addition to the fact that they play a large role in developing restorative medicine, their study reveals much information about the complex events that happen during human development.

The difference between a stem cell and a differentiated cell is reflected in the cells’ DNA. In the former cell, DNA is arranged loosely with working genes. When signals enter the cell and the differentiation process begins, genes that are no longer needed are shut down, but genes required for the specialized function will remain active. This process can be reversed, and it is known that such pluripotency can be achieved by interaction in gene sequences. Takahashi and Yamanaka [ 78 ] and Loh et al. [ 79 ] discovered that octamer-binding transcription factor 3 and 4 (Oct3/4), sex determining region Y (SRY)-box 2 and Nanog genes function as core transcription factors in maintaining pluripotency. Among them, Oct3/4 and Sox2 are essential for the generation of iPSCs.

Many serious medical conditions, such as birth defects or cancer, are caused by improper differentiation or cell division. Currently, several stem cell therapies are possible, among which are treatments for spinal cord injury, heart failure [ 80 ], retinal and macular degeneration [ 81 ], tendon ruptures, and diabetes type 1 [ 82 ]. Stem cell research can further help in better understanding stem cell physiology. This may result in finding new ways of treating currently incurable diseases.

Haematopoietic stem cell transplantation

Haematopoietic stem cells are important because they are by far the most thoroughly characterized tissue-specific stem cell; after all, they have been experimentally studied for more than 50 years. These stem cells appear to provide an accurate paradigm model system to study tissue-specific stem cells, and they have potential in regenerative medicine.

Multipotent haematopoietic stem cell (HSC) transplantation is currently the most popular stem cell therapy. Target cells are usually derived from the bone marrow, peripheral blood, or umbilical cord blood [ 83 ]. The procedure can be autologous (when the patient’s own cells are used), allogenic (when the stem cell comes from a donor), or syngeneic (from an identical twin). HSCs are responsible for the generation of all functional haematopoietic lineages in blood, including erythrocytes, leukocytes, and platelets. HSC transplantation solves problems that are caused by inappropriate functioning of the haematopoietic system, which includes diseases such as leukaemia and anaemia. However, when conventional sources of HSC are taken into consideration, there are some important limitations. First, there is a limited number of transplantable cells, and an efficient way of gathering them has not yet been found. There is also a problem with finding a fitting antigen-matched donor for transplantation, and viral contamination or any immunoreactions also cause a reduction in efficiency in conventional HSC transplantations. Haematopoietic transplantation should be reserved for patients with life-threatening diseases because it has a multifactorial character and can be a dangerous procedure. iPSC use is crucial in this procedure. The use of a patient’s own unspecialized somatic cells as stem cells provides the greatest immunological compatibility and significantly increases the success of the procedure.

Stem cells as a target for pharmacological testing

Stem cells can be used in new drug tests. Each experiment on living tissue can be performed safely on specific differentiated cells from pluripotent cells. If any undesirable effect appears, drug formulas can be changed until they reach a sufficient level of effectiveness. The drug can enter the pharmacological market without harming any live testers. However, to test the drugs properly, the conditions must be equal when comparing the effects of two drugs. To achieve this goal, researchers need to gain full control of the differentiation process to generate pure populations of differentiated cells.

Stem cells as an alternative for arthroplasty

One of the biggest fears of professional sportsmen is getting an injury, which most often signifies the end of their professional career. This applies especially to tendon injuries, which, due to current treatment options focusing either on conservative or surgical treatment, often do not provide acceptable outcomes. Problems with the tendons start with their regeneration capabilities. Instead of functionally regenerating after an injury, tendons merely heal by forming scar tissues that lack the functionality of healthy tissues. Factors that may cause this failed healing response include hypervascularization, deposition of calcific materials, pain, or swelling [ 84 ].

Additionally, in addition to problems with tendons, there is a high probability of acquiring a pathological condition of joints called osteoarthritis (OA) [ 85 ]. OA is common due to the avascular nature of articular cartilage and its low regenerative capabilities [ 86 ]. Although arthroplasty is currently a common procedure in treating OA, it is not ideal for younger patients because they can outlive the implant and will require several surgical procedures in the future. These are situations where stem cell therapy can help by stopping the onset of OA [ 87 ]. However, these procedures are not well developed, and the long-term maintenance of hyaline cartilage requires further research.

Osteonecrosis of the femoral hip (ONFH) is a refractory disease associated with the collapse of the femoral head and risk of hip arthroplasty in younger populations [ 88 ]. Although total hip arthroplasty (THA) is clinically successful, it is not ideal for young patients, mostly due to the limited lifetime of the prosthesis. An increasing number of clinical studies have evaluated the therapeutic effect of stem cells on ONFH. Most of the authors demonstrated positive outcomes, with reduced pain, improved function, or avoidance of THA [ 89 , 90 , 91 ].

Rejuvenation by cell programming

Ageing is a reversible epigenetic process. The first cell rejuvenation study was published in 2011 [ 92 ]. Cells from aged individuals have different transcriptional signatures, high levels of oxidative stress, dysfunctional mitochondria, and shorter telomeres than in young cells [ 93 ]. There is a hypothesis that when human or mouse adult somatic cells are reprogrammed to iPSCs, their epigenetic age is virtually reset to zero [ 94 ]. This was based on an epigenetic model, which explains that at the time of fertilization, all marks of parenteral ageing are erased from the zygote’s genome and its ageing clock is reset to zero [ 95 ].

In their study, Ocampo et al. [ 96 ] used Oct4, Sox2, Klf4, and C-myc genes (OSKM genes) and affected pancreas and skeletal muscle cells, which have poor regenerative capacity. Their procedure revealed that these genes can also be used for effective regenerative treatment [ 97 ]. The main challenge of their method was the need to employ an approach that does not use transgenic animals and does not require an indefinitely long application. The first clinical approach would be preventive, focused on stopping or slowing the ageing rate. Later, progressive rejuvenation of old individuals can be attempted. In the future, this method may raise some ethical issues, such as overpopulation, leading to lower availability of food and energy.

For now, it is important to learn how to implement cell reprogramming technology in non-transgenic elder animals and humans to erase marks of ageing without removing the epigenetic marks of cell identity.

Cell-based therapies

Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues (Fig.  6 ). Currently, when the need for transplantable tissues and organs outweighs the possible supply, stem cells appear to be a perfect solution for the problem. The most common conditions that benefit from such therapy are macular degenerations [ 98 ], strokes [ 99 ], osteoarthritis [ 89 , 90 ], neurodegenerative diseases, and diabetes [ 100 ]. Due to this technique, it can become possible to generate healthy heart muscle cells and later transplant them to patients with heart disease.

Stem cell experiments on animals. These experiments are one of the many procedures that proved stem cells to be a crucial factor in future regenerative medicine

In the case of type 1 diabetes, insulin-producing cells in the pancreas are destroyed due to an autoimmunological reaction. As an alternative to transplantation therapy, it can be possible to induce stem cells to differentiate into insulin-producing cells [ 101 ].

Stem cells and tissue banks

iPS cells with their theoretically unlimited propagation and differentiation abilities are attractive for the present and future sciences. They can be stored in a tissue bank to be an essential source of human tissue used for medical examination. The problem with conventional differentiated tissue cells held in the laboratory is that their propagation features diminish after time. This does not occur in iPSCs.

The umbilical cord is known to be rich in mesenchymal stem cells. Due to its cryopreservation immediately after birth, its stem cells can be successfully stored and used in therapies to prevent the future life-threatening diseases of a given patient.

Stem cells of human exfoliated deciduous teeth (SHED) found in exfoliated deciduous teeth has the ability to develop into more types of body tissues than other stem cells [ 102 ] (Table  1 ). Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:

Guaranteed donor-match autologous transplant that causes no immune reaction and rejection of cells [ 103 ]

Simple and painless for both child and parent

Less than one third of the cost of cord blood storage

Not subject to the same ethical concerns as embryonic stem cells [ 104 ]

In contrast to cord blood stem cells, SHED cells are able to regenerate into solid tissues such as connective, neural, dental, or bone tissue [ 105 , 106 ]

SHED can be useful for close relatives of the donor

Fertility diseases

In 2011, two researchers, Katsuhiko Hayashi et al. [ 107 ], showed in an experiment on mice that it is possible to form sperm from iPSCs. They succeeded in delivering healthy and fertile pups in infertile mice. The experiment was also successful for female mice, where iPSCs formed fully functional eggs .

Young adults at risk of losing their spermatogonial stem cells (SSC), mostly cancer patients, are the main target group that can benefit from testicular tissue cryopreservation and autotransplantation. Effective freezing methods for adult and pre-pubertal testicular tissue are available [ 108 ].

Qiuwan et al. [ 109 ] provided important evidence that human amniotic epithelial cell (hAEC) transplantation could effectively improve ovarian function by inhibiting cell apoptosis and reducing inflammation in injured ovarian tissue of mice, and it could be a promising strategy for the management of premature ovarian failure or insufficiency in female cancer survivors.

For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced. The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure.

Therapy for incurable neurodegenerative diseases

Thanks to stem cell therapy, it is possible not only to delay the progression of incurable neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease (AD), and Huntington disease, but also, most importantly, to remove the source of the problem. In neuroscience, the discovery of neural stem cells (NSCs) has nullified the previous idea that adult CNS were not capable of neurogenesis [ 110 , 111 ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ 112 , 113 , 114 ]. Awe et al. [ 115 ] clinically derived relevant human iPSCs from skin punch biopsies to develop a neural stem cell-based approach for treating AD. Neuronal degeneration in Parkinson’s disease (PD) is focal, and dopaminergic neurons can be efficiently generated from hESCs. PD is an ideal disease for iPSC-based cell therapy [ 116 ]. However, this therapy is still in an experimental phase ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539501 /). Brain tissue from aborted foetuses was used on patients with Parkinson’s disease [ 117 ]. Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy.

Stem cell use in dentistry

Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure. Currently, there is a chance for stem cells to become more widely used than synthetic materials. Teeth have a large advantage of being the most natural and non-invasive source of stem cells.

For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery. For example, there are stem cells in periodontal ligament [ 118 , 119 ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ 120 ]. Tissue engineering is a successful method for treating periodontal diseases. Stem cells of the root apical areas are able to recreate periodontal ligament. One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ 121 ].

As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ 122 ].

Enamel is more difficult to regenerate than dentin. After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ 123 ].

Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ 124 ]. There are several dental stem cell groups that can be isolated (Fig.  7 ).

Localization of stem cells in dental tissues. Dental pulp stem cells (DPSCs) and human deciduous teeth stem cells (SHED) are located in the dental pulp. Periodontal ligaments stem cells are located in the periodontal ligament. Apical papilla consists of stem cells from the apical papilla (SCAP)

Dental pulp stem cell (DPSC)

These were the first dental stem cells isolated from the human dental pulp, which were [ 125 ] located inside dental pulp (Table  2 ). They have osteogenic and chondrogenic potential. Mesenchymal stem cells (MSCs) of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue (e.g. bone marrow, adipose tissue) and foetal (e.g. umbilical cord) [ 126 ] tissue, and they are able to differentiate densely [ 127 ]. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone. Their best source locations are the third molars [ 125 ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities. These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity. DPSCs are able to generate all structures of the developed tooth [ 128 ]. In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation (laser stimulation), which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ 129 ]. DPSCs can be induced to form neural cells to help treat neurological deficits.

Stem cells of human exfoliated deciduous teeth (SHED) have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e.g. other mesenchymal and non-mesenchymal stem cell derivatives, such as neural cells [ 130 ]. These cells possess one major disadvantage: they form a non-complete dentin/pulp-like complex in vivo. SHED do not undergo the same ethical concerns as embryonic stem cells. Both DPSCs and SHED are able to form bone-like tissues in vivo [ 131 ] and can be used for periodontal, dentin, or pulp regeneration. DPSCs and SHED can be used in treating, for example, neural deficits [ 132 ]. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ 133 ].

Periodontal ligament stem cells (PDLSCs)

These cells are used in periodontal ligament or cementum tissue regeneration. They can differentiate into mesenchymal cell lineages to produce collagen-forming cells, adipocytes, cementum tissue, Sharpey’s fibres, and osteoblast-like cells in vitro. PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ 134 ]. PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ 135 , 136 ].

Stem cells from apical papilla (SCAP)

These cells are mesenchymal structures located within immature roots. They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes. SCAP have a higher capacity of proliferation than DPSCs, which makes them a better choice for tissue regeneration [ 137 , 138 ].

Dental follicle stem cells (DFCs)

These cells are loose connective tissues surrounding the developing tooth germ. DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ 139 , 140 ]. Additionally, these cells proliferate after even more than 30 passages [ 141 ]. DFCs are most commonly extracted from the sac of a third molar. When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ 141 ]. When DFC sheets are induced by Hertwig’s epithelial root sheath cells, they can produce periodontal tissue; thus, DFCs represent a very promising material for tooth regeneration [ 142 ].

Pulp regeneration in endodontics

Dental pulp stem cells can differentiate into odontoblasts. There are few methods that enable the regeneration of the pulp.

The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ 143 ].

The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex. Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues. For now, only pulp-like structures have been created successfully.

Methods of placing stem cells into the root channel constitute are either soft scaffolding [ 144 ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ 145 ]. Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy.

The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth. Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address.

Acquiring non-dental tissue cells by dental stem cell differentiation

In 2013, it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e.g. from urine [ 146 ]. Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ 127 ]. Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells. More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ 147 ].

Use of graphene in stem cell therapy

Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ 148 ]. Both graphene and graphene oxide (GO) represent high in-plane stiffness [ 149 ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry. Graphene exhibits biocompatibility with cells and their proper adhesion. It also tested positively for enhancing the proliferation or differentiation of stem cells [ 148 ]. After positive experiments, graphene revealed great potential as a scaffold and guide for specific lineages of stem cell differentiation [ 150 ]. Graphene has been successfully used in the transplantation of hMSCs and their guided differentiation to specific cells. The acceleration skills of graphene differentiation and division were also investigated. It was discovered that graphene can serve as a platform with increased adhesion for both growth factors and differentiation chemicals. It was also discovered that π-π binding was responsible for increased adhesion and played a crucial role in inducing hMSC differentiation [ 150 ].

Therapeutic potential of extracellular vesicle-based therapies

Extracellular vesicles (EVs) can be released by virtually every cell of an organism, including stem cells [ 151 ], and are involved in intercellular communication through the delivery of their mRNAs, lipids, and proteins. As Oh et al. [ 152 ] prove, stem cells, together with their paracrine factors—exosomes—can become potential therapeutics in the treatment of, e.g. skin ageing. Exosomes are small membrane vesicles secreted by most cells (30–120 nm in diameter) [ 153 ]. When endosomes fuse with the plasma membrane, they become exosomes that have messenger RNAs (mRNAs) and microRNAs (miRNAs), some classes of non-coding RNAs (IncRNAs) and several proteins that originate from the host cell [ 154 ]. IncRNAs can bind to specific loci and create epigenetic regulators, which leads to the formation of epigenetic modifications in recipient cells. Because of this feature, exosomes are believed to be implicated in cell-to-cell communication and the progression of diseases such as cancer [ 155 ]. Recently, many studies have also shown the therapeutic use of exosomes derived from stem cells, e.g. skin damage and renal or lung injuries [ 156 ].

In skin ageing, the most important factor is exposure to UV light, called “photoageing” [ 157 ], which causes extrinsic skin damage, characterized by dryness, roughness, irregular pigmentation, lesions, and skin cancers. In intrinsic skin ageing, on the other hand, the loss of elasticity is a characteristic feature. The skin dermis consists of fibroblasts, which are responsible for the synthesis of crucial skin elements, such as procollagen or elastic fibres. These elements form either basic framework extracellular matrix constituents of the skin dermis or play a major role in tissue elasticity. Fibroblast efficiency and abundance decrease with ageing [ 158 ]. Stem cells can promote the proliferation of dermal fibroblasts by secreting cytokines such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), and basic fibroblast growth factor. Huh et al. [ 159 ] mentioned that a medium of human amniotic fluid-derived stem cells (hAFSC) positively affected skin regeneration after longwave UV-induced (UVA, 315–400 nm) photoageing by increasing the proliferation and migration of dermal fibroblasts. It was discovered that, in addition to the induction of fibroblast physiology, hAFSC transplantation also improved diseases in cases of renal pathology, various cancers, or stroke [ 160 , 161 ].

Oh [ 162 ] also presented another option for the treatment of skin wounds, either caused by physical damage or due to diabetic ulcers. Induced pluripotent stem cell-conditioned medium (iPSC-CM) without any animal-derived components induced dermal fibroblast proliferation and migration.

Natural cutaneous wound healing is divided into three steps: haemostasis/inflammation, proliferation, and remodelling. During the crucial step of proliferation, fibroblasts migrate and increase in number, indicating that it is a critical step in skin repair, and factors such as iPSC-CM that impact it can improve the whole cutaneous wound healing process. Paracrine actions performed by iPSCs are also important for this therapeutic effect [ 163 ]. These actions result in the secretion of cytokines such as TGF-β, interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and basic fibroblast growth factor (bFGF). Bae et al. [ 164 ] mentioned that TGF-β induced the migration of keratinocytes. It was also demonstrated that iPSC factors can enhance skin wound healing in vivo and in vitro when Zhou et al. [ 165 ] enhanced wound healing, even after carbon dioxide laser resurfacing in an in vivo study.

Peng et al. [ 166 ] investigated the effects of EVs derived from hESCs on in vitro cultured retinal glial, progenitor Müller cells, which are known to differentiate into retinal neurons. EVs appear heterogeneous in size and can be internalized by cultured Müller cells, and their proteins are involved in the induction and maintenance of stem cell pluripotency. These stem cell-derived vesicles were responsible for the neuronal trans-differentiation of cultured Müller cells exposed to them. However, the research article points out that the procedure was accomplished only on in vitro acquired retina.

Challenges concerning stem cell therapy

Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome in the future. One of the first problems is ethical concern.

The most common pluripotent stem cells are ESCs. Therapies concerning their use at the beginning were, and still are, the source of ethical conflicts. The reason behind it started when, in 1998, scientists discovered the possibility of removing ESCs from human embryos. Stem cell therapy appeared to be very effective in treating many, even previously incurable, diseases. The problem was that when scientists isolated ESCs in the lab, the embryo, which had potential for becoming a human, was destroyed (Fig.  8 ). Because of this, scientists, seeing a large potential in this treatment method, focused their efforts on making it possible to isolate stem cells without endangering their source—the embryo.

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate into desired cell types

For now, while hESCs still remain an ethically debatable source of cells, they are potentially powerful tools to be used for therapeutic applications of tissue regeneration. Because of the complexity of stem cell control systems, there is still much to be learned through observations in vitro. For stem cells to become a popular and widely accessible procedure, tumour risk must be assessed. The second problem is to achieve successful immunological tolerance between stem cells and the patient’s body. For now, one of the best ideas is to use the patient’s own cells and devolve them into their pluripotent stage of development.

New cells need to have the ability to fully replace lost or malfunctioning natural cells. Additionally, there is a concern about the possibility of obtaining stem cells without the risk of morbidity or pain for either the patient or the donor. Uncontrolled proliferation and differentiation of cells after implementation must also be assessed before its use in a wide variety of regenerative procedures on living patients [ 167 ].

One of the arguments that limit the use of iPSCs is their infamous role in tumourigenicity. There is a risk that the expression of oncogenes may increase when cells are being reprogrammed. In 2008, a technique was discovered that allowed scientists to remove oncogenes after a cell achieved pluripotency, although it is not efficient yet and takes a longer amount of time. The process of reprogramming may be enhanced by deletion of the tumour suppressor gene p53, but this gene also acts as a key regulator of cancer, which makes it impossible to remove in order to avoid more mutations in the reprogrammed cell. The low efficiency of the process is another problem, which is progressively becoming reduced with each year. At first, the rate of somatic cell reprogramming in Yamanaka’s study was up to 0.1%. The use of transcription factors creates a risk of genomic insertion and further mutation of the target cell genome. For now, the only ethically acceptable operation is an injection of hESCs into mouse embryos in the case of pluripotency evaluation [ 168 ].

Stem cell obstacles in the future

Pioneering scientific and medical advances always have to be carefully policed in order to make sure they are both ethical and safe. Because stem cell therapy already has a large impact on many aspects of life, it should not be treated differently.

Currently, there are several challenges concerning stem cells. First, the most important one is about fully understanding the mechanism by which stem cells function first in animal models. This step cannot be avoided. For the widespread, global acceptance of the procedure, fear of the unknown is the greatest challenge to overcome.

The efficiency of stem cell-directed differentiation must be improved to make stem cells more reliable and trustworthy for a regular patient. The scale of the procedure is another challenge. Future stem cell therapies may be a significant obstacle. Transplanting new, fully functional organs made by stem cell therapy would require the creation of millions of working and biologically accurate cooperating cells. Bringing such complicated procedures into general, widespread regenerative medicine will require interdisciplinary and international collaboration.

The identification and proper isolation of stem cells from a patient’s tissues is another challenge. Immunological rejection is a major barrier to successful stem cell transplantation. With certain types of stem cells and procedures, the immune system may recognize transplanted cells as foreign bodies, triggering an immune reaction resulting in transplant or cell rejection.

One of the ideas that can make stem cells a “failsafe” is about implementing a self-destruct option if they become dangerous. Further development and versatility of stem cells may cause reduction of treatment costs for people suffering from currently incurable diseases. When facing certain organ failure, instead of undergoing extraordinarily expensive drug treatment, the patient would be able to utilize stem cell therapy. The effect of a successful operation would be immediate, and the patient would avoid chronic pharmacological treatment and its inevitable side effects.

Although these challenges facing stem cell science can be overwhelming, the field is making great advances each day. Stem cell therapy is already available for treating several diseases and conditions. Their impact on future medicine appears to be significant.

After several decades of experiments, stem cell therapy is becoming a magnificent game changer for medicine. With each experiment, the capabilities of stem cells are growing, although there are still many obstacles to overcome. Regardless, the influence of stem cells in regenerative medicine and transplantology is immense. Currently, untreatable neurodegenerative diseases have the possibility of becoming treatable with stem cell therapy. Induced pluripotency enables the use of a patient’s own cells. Tissue banks are becoming increasingly popular, as they gather cells that are the source of regenerative medicine in a struggle against present and future diseases. With stem cell therapy and all its regenerative benefits, we are better able to prolong human life than at any time in history.

Abbreviations

Basic fibroblast growth factor

Bone morphogenic proteins

Dental follicle stem cells

Dental pulp stem cells

Embryonic bodies

Embryonic stem cells

Fibroblast growth factors

Good Manufacturing Practice

Graphene oxide

Human amniotic fluid-derived stem cells

Human embryonic stem cells

Human foreskin fibroblasts

Inner cell mass

Non-coding RNA

Induced pluripotent stem cells

In vitro fertilization

Knockout serum replacement

Leukaemia inhibitory factor

Monocyte chemotactic protein-1

Fibroblasts

Messenger RNA

Mesenchymal stem cells of dental pulp

Myogenic differentiation

Osteoarthritis

Octamer-binding transcription factor 3 and 4

Platelet-derived growth factor

Platelet-derived growth factor-AA

Periodontal ligament stem cells

Rho-associated protein kinase

Stem cells from apical papilla

Stem cells of human exfoliated deciduous teeth

Synthetic Serum Substitute

Trophectoderm

Vascular endothelial growth factor

Transforming growth factors

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Zakrzewski, W., Dobrzyński, M., Szymonowicz, M. et al. Stem cells: past, present, and future. Stem Cell Res Ther 10 , 68 (2019). https://doi.org/10.1186/s13287-019-1165-5

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• Differentiation
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What is a stem cell?

A stem cell has the unique ability to develop into other specialised cell types in the body.

• Stem cells are special cells that can turn into different types of cells.
• In a developing embryo, they can develop into any type of cell. Once the body is grown, they can develop into specific cell types, to replace old or damaged cells.
• In medicine, stem cells may be used to replace cells and tissues that have been damaged or lost due to disease.
• Our body is made up of many different types of cells.
• Most cells are ‘specialised’, meaning they perform different functions. For example, red blood cells are specialised to carry oxygen around the body in the blood, while some gut cells are specialised to absorb nutrients from food.
• All specialised cells start out as stem cells – the foundation for every organ and tissue in the body. They provide new cells for the body as it grows and replace specialised cells as they get older or damaged.
• They can divide over and over again to produce new stem cells.
• As they divide, they can change into the other types of cell that make up the body.

There are three main types of stem cell:

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Introduction and Basic Concepts in Stem Cell Research and Therapy: The Facts and the Hype

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• Mohamed Essawy 2   na1 ,
• Shaimaa Shouman 2   na1 ,
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• Nagwa El-Badri 2   na1  

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Stem cells play critical roles in biological processes, such as tissue development and homeostasis; they also present great promise toward promoting breakthroughs in regenerative medicine. Stem cells may be used to explore disease modeling, for screening of new drugs, and for the treatment of intractable diseases. The transition of stem cell biology from basic research to clinical applications has involved both hope and hype. Indeed, premature application of stem cell therapy as a clinical “cure-all” without sufficient experimental, preclinical, or clinical research has led to shady practices and false promises. While this is, understandably, fueled by patients in need of cures for unmanageable chronic and degenerative diseases, hype-based practices have promoted the spread of clinically unproven therapies. These therapies may have no impact on the disease process or may result in devastating outcomes. Stem cells may ultimately have the capacity to treat intractable diseases, including diabetes, cardiovascular disorders, metabolic disorders, hematopoietic disorders, and immunodeficiency disorders. However, and despite significant promise, there remains a need to elucidate numerous misunderstandings associated with stem cell therapy and to define the current barriers and obstacles faced by those involved in stem cell research and its therapeutic applications. As such, the main goal of this chapter was to provide the reader with an overview of basic concepts in stem cell research and review the facts and the unfortunate hype with respect to current clinical applications and disease treatments.

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Abbreviations

Autologous Chondrocyte Implantation

Adipose-derived stem cells

Acute Lymphoblastic Leukemia

Age-related Macular Degeneration

Acute Myeloid Leukemia

Bone Marrow

Bone Marrow Hematopoietic Stem Cells

Bone Marrow Mesenchymal Stem Cells

Chimeric Antigen Receptor

Cord Blood Transplantation

Colony Forming-Unit Fibroblast

Chronic Lymphoblastic Leukemia

Common Lymphoid Progenitor

Chronic Myeloid Leukemia

Donor Leukocyte Infusion

Diabetes Mellitus

Type 1 Diabetes Mellitus

Type 2 Diabetes Mellitus

Extracellular Matrix

Embryonic stem cells

Full-thickness Skin Graft

Granulocyte Colony-stimulating Factor

Graft versus Host Disease

Graft Versus Leukemia

Hematopoietic Stem Cells

Hematopoietic Stem Cell Transplantation

Hematopoietic Stem/Progenitor Cells

Induced Pluripotent Stem Cells

International Society for Stem Cell Research

Multiple Sclerosis

Mesenchymal Stem Cells

Neural Stem Cells

Osteoarthritis

Peripheral Blood

Parkinson’s Disease

Platelet-rich Plasma

Reduced-intensity Conditioning

Retinal Pigment Epithelial

Somatic Cell Nuclear Transfer

Split-thickness Skin Graft

Umbilical Cord Blood

Umbilical Cord Hematopoietic Stem Cells

Umbilical Cord Mesenchymal Stem Cells

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Acknowledgments

This work was supported by grant # 5300 from the Egyptian Science and Technology Development Fund (STDF), and by internal funding from Zewail City of Science and Technology (ZC 003-2019).

Take Home Message

The biology of stem cells in tissue homeostasis and development has made it the prospect for the field of regenerative medicine.

Stem cell potency is more pronounced in embryonic tissues compared to adult cells. In the adult tissues, stem cells are widely distributed throughout the body including, but not limited to, the bone marrow, adipose tissue, intestine, skin, synovial membrane, and dental pulp.

Reprogramming somatic cells by induced pluripotent stem cell (iPSC) technology, gene editing, and applying modern techniques of nanotechnology and bioprinting have all made it possible for extensive applications of adult stem cells in regenerative medicine.

Hematopoietic stem cells transplantation (HSCT) is already a routine practice, and has secured FDA approval for its cellular products to treat hematological diseases.

Research is still in progress for wound healing and osteoarthritis treatment using stem cells.

Preclinical and clinical studies showed new hope in treating incurable chronic diseases like multiple sclerosis, macular degeneration, Parkinson’s Disease, and diabetes mellitus with stem cells.

FDA, CDC, ISSCR and other stem cell societies and institutes are regularly warning about the misused stem cell therapy away from their approved applications to minimize patients’ risks.

Various types of stem cells need more clinical investigations to test their safety and efficacy before being clinically translated.

Patients have to be cautious about the credibility of any cell-based medical application; and especially before undergoing stem cell therapy.

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Mohamed Essawy, Shaimaa Shouman, Shireen Magdy, and Ahmed Abdelfattah-Hassan contributed equally.

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Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Helmy Institute of Biomedical Sciences, Zewail City of Science and Technology, Giza, Egypt

Mohamed Essawy, Shaimaa Shouman, Shireen Magdy & Nagwa El-Badri

Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt

Ahmed Abdelfattah-Hassan

Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt

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Correspondence to Nagwa El-Badri .

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Essawy, M., Shouman, S., Magdy, S., Abdelfattah-Hassan, A., El-Badri, N. (2020). Introduction and Basic Concepts in Stem Cell Research and Therapy: The Facts and the Hype. In: El-Badri, N. (eds) Regenerative Medicine and Stem Cell Biology . Learning Materials in Biosciences. Springer, Cham. https://doi.org/10.1007/978-3-030-55359-3_1

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Stem cells: past, present, and future

Affiliations.

• 1 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland. [email protected].
• 2 Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425, Poland.
• 3 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland.
• PMID: 30808416
• PMCID: PMC6390367
• DOI: 10.1186/s13287-019-1165-5

In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Keywords: Differentiation; Growth media; Induced pluripotent stem cell (iPSC); Pluripotency; Stem cell derivation; Stem cells; Teratoma formation assay; Tissue banks; Tissue transplantation.

Publication types

• Research Support, Non-U.S. Gov't
• Cell Differentiation / genetics*
• Cell- and Tissue-Based Therapy / trends*
• Graphite / chemistry
• Graphite / therapeutic use
• Induced Pluripotent Stem Cells / transplantation*
• Stem Cell Transplantation / classification
• Stem Cells / classification
• Stem Cells / cytology*
• Tissue Scaffolds / chemistry

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Stem-cell research is the area of research that studies the properties of stem cells and their potential use in medicine. As stem cells are the source of all tissues, understanding their properties helps in our understanding of the healthy and diseased body's development and homeostasis.

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•   Types of Stem Cell
•   History of Stem Cell Use
•   Importance of Stem Cells
•   Pros and Cons
•   Stem Cell FAQs
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Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lung, skin, sperm, eggs and other tissues. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.

Given their unique regenerative abilities, stem cells offer new potentials for treating diseases such as diabetes, and heart disease. However, much work remains to be done in the laboratory and the clinic to understand how to use these cells for cell-based therapies to treat disease, which is also referred to as regenerative or reparative medicine.

Laboratory studies of stem cells enable scientists to learn about the cells’ essential properties and what makes them different from specialized cell types. Scientists are already using stem cells in the laboratory to screen new drugs and to develop model systems to study normal growth and identify the causes of birth defects.

Research on stem cells continues to advance knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. Stem cell research is one of the most fascinating areas of contemporary biology, but, as with many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

Can doctors use stem cells to treat patients? 

Some stem cells, such as the adult bone marrow or peripheral blood stem cells, have been used in clinical therapies for over 40 years.  Other therapies utilizing stem cells include skin replacement from adult stem cells harvested from hair follicles that have been grown in culture to produce skin grafts.  Other clinical trials for neuronal damage/disease have also been conducted using neural stem cells.  There were side effects accompanying these studies and further investigation is warranted.  Although there is much research to be conducted in the future, these studies give us hope for the future of therapeutics with stem cell research.

Potential Therapies using Stem Cells

Adult Stem Cell Therapies

Bone marrow and peripheral blood stem cell transplants have been utilized for over 40 years as therapy for blood disorders such as leukemia and lymphoma, amongst many others.  Scientists have also shown that stem cells reside in most tissues of the body and research continues to learn how to identify, extract, and proliferate these cells for further use in therapy.  Scientists hope to yield therapies for diseases such as type I diabetes and repair of heart muscle following heart attack.

Scientists have also shown that there is potential in reprogramming ASCs to cause them to transdifferentiate (turn back into a different cell type than the resident tissue it was replenishing). 

Embryonic Stem Cell (ESC) Therapies

There is potential with ESCs to treat certain diseases in the future.  Scientists continue to learn how ESCs differentiate and once this method is better understood, the hope is to apply the knowledge to get ESCs to differentiate into the cell of choice that is needed for patient therapy.  Diseases that are being targeted with ESC therapy include diabetes, spinal cord injury, muscular dystrophy, heart disease, and vision/hearing loss.

Induced Pluripotent Stem Cell Therapies

Therapies using iPSCs are exciting because somatic cells of the recipient can be reprogrammed to en “ESC like” state.  Then mechanisms to differentiate these cells may be applied to generate the cells in need.  This is appealing to clinicians because this avoids the issue of histocompatibility and lifelong immunosuppression, which is needed if transplants use donor stem cells. 

iPS cells mimic most ESC properties in that they are pluripotent cells, but do not currently carry the ethical baggage of ESC research and use because iPS cells have not been able to be manipulated to grow the outer layer of an embryonic cell required for the development of the cell into a human being.

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Essays on Stem Cell

Brief description of stem cell.

Stem cells are undifferentiated cells with the potential to develop into many different cell types in the body. They are a critical part of the body's repair system and have the potential to treat a wide range of diseases and medical conditions. Stem cell research holds great promise for the future of medicine and has the potential to revolutionize the way we treat various health issues.

Importance of Writing Essays on This Topic

Essays on stem cells are significant for academic and personal exploration because they allow students to delve into the ethical, scientific, and medical implications of this cutting-edge field. By researching and writing about stem cells, students can develop a deeper understanding of the complex issues surrounding this topic and contribute to the ongoing conversation about the potential uses and limitations of stem cell research.

Tips on Choosing a Good Topic

• Consider the ethical implications of stem cell research and its impact on society.
• Explore the latest advancements in stem cell technology and their potential applications in medicine.
• Examine the controversies and debates surrounding the use of embryonic stem cells in research and treatment.

Essay Topics

• The ethical considerations of using embryonic stem cells for medical research.
• The potential applications of stem cell therapy in treating neurodegenerative diseases.
• The role of stem cells in regenerative medicine and tissue engineering.
• The impact of government regulations on stem cell research and its implications for medical advancements.
• The use of induced pluripotent stem cells in disease modeling and drug discovery.
• The controversies surrounding the use of adult stem cells versus embryonic stem cells.
• The potential role of stem cells in personalized medicine and targeted therapies.
• The legal and ethical implications of stem cell banking and its impact on future medical treatments.
• The challenges and opportunities in translating stem cell research into clinical practice.
• The ethical considerations of using stem cells to create human-animal chimeras.

Concluding Thought

Exploring the world of stem cells through essay writing can provide valuable insights into the potential and challenges of this groundbreaking field. By choosing engaging and meaningful topics, students can contribute to the ongoing dialogue about the ethical, scientific, and medical implications of stem cell research.

Stem Cell Research: Persuasive Speech

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Stem Cells – The Ideal of Medicine

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Stem Cells and Their Types

Human embryonic stem cells (hescs), hematopoietic stem cell transplantation for lupus nephritis, why stem cell research should be sustained by the u.s government, get a personalized essay in under 3 hours.

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Stem Cell Transplantation

Controversial views on stem cell research in america, research on correlation of notch signaling pathway in the prognosis of breast cancer, hematopoietic stem cells specification, mesenchymal stem cells and it's usage in treatment, tissue engineering and stem cells, current research on the ovarian stem cells: a brief review, juvenile diabetes or type 1 diabetes: stem cell therapy.

Stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell.

The term stem cell was coined by Theodor Boveri and Valentin Haecker in late 19th century. Pioneering works in theory of blood stem cell were conducted in the beginning of 20th century by Artur Pappenheim, Alexander Maximow, Franz Ernst Christian Neumann. The first therapy using stem cells was a bone marrow transplant performed by French oncologist Georges Mathé in 1958 on five workers at the Vinča Nuclear Institute in Yugoslavia who had been affected by a criticality accident. The workers all survived.

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• Biology Article

“Stem cells are special human cells that can develop into many different types of cells, from muscle cells to brain cells.”

What are Stem Cells?

Stem cells also have the ability to repair damaged cells. These cells have strong healing power. They can evolve into any type of cell.

Research on stem cells is going on, and it is believed that stem cell therapies can cure ailments like paralysis and Alzheimer’s as well. Let us have a detailed look at stem cells, their types and their functions.

Also Read: Gene Therapy

Types of cells

Stem cells are of the following different types:

Embryonic Stem Cells

Adult stem cells, induced pluripotent stem cells.

• Mesenchymal stem cells

The fertilized egg begins to divide immediately. All the cells in the young embryo are totipotent cells. These cells form a hollow structure within a few days. Cells in one region group together to form the inner cell mass. This contains pluripotent cells that make up the developing foetus.

The embryonic stem cells can be further classified as:

• Totipotent Stem Cells:  These can differentiate into all possible types of stem cells.
• Pluripotent Stem Cells:  These are the cells from an early embryo and can differentiate into any cell type.
• Multipotent Stem Cells:  These differentiate into a closely related cell type. E.g., the hematopoietic stem cells differentiate into red blood cells and white blood cells.
• Oligopotent Stem Cells:  Adult lymphoid or myeloid cells are oligopotent. They can differentiate into a few different types of cells.
• Unipotent Stem Cells:  They can produce cells only of their own type. Since they have the ability to renew themselves, they are known as unipotent stem cells. E.g., Muscle stem cells.

These stem cells are obtained from developed organs and tissues. They can repair and replace the damaged tissues in the region where they are located. For eg., hematopoietic stem cells are found in the bone marrow. These stem cells are used in bone marrow transplants to treat specific types of cancers.

These cells have been tested and arranged by converting tissue-specific cells into embryonic cells in the lab. These cells are accepted as an important tool to learn about the normal development, onset and progression of the disease and are also helpful in testing various drugs. These stem cells share the same characteristics as embryonic cells do. They also have the potential to give rise to all the different types of cells in the human body.

Mesenchymal Stem Cells

These cells are mainly formed from the connective tissues surrounding other tissues and organs, known as the stroma. These mesenchymal stem cells are accurately called stromal cells. The first mesenchymal stem cells were found in the bone marrow that is capable of developing bones, fat cells, and cartilage.

There are different mesenchymal stem cells that are used to treat various diseases as they have been developed from different tissues of the human body. The characteristics of mesenchymal stem cells depend on the organ from where they originate.

Applications of Stem Cells

Following are the important applications of stem cells:

Tissue Regeneration

This is the most important application of stem cells. The stem cells can be used to grow a specific type of tissue or organ. This can be helpful in kidney and liver transplants. The doctors have already used the stem cells from beneath the epidermis to develop skin tissue that can repair severe burns or other injuries by tissue grafting.

Treatment of Cardiovascular Disease

A team of researchers have developed blood vessels in mice using human stem cells. Within two weeks of implantation, the blood vessels formed their network and were as efficient as the natural vessels.

Treatment of Brain Diseases

Stem cells can also treat diseases such as Parkinson’s disease and Alzheimer’s. These can help to replenish the damaged brain cells. Researchers have tried to differentiate embryonic stem cells into these types of cells and make it possible to treat diseases.

Blood Disease Treatment

The adult hematopoietic stem cells are used to treat cancers, sickle cell anaemia, and other immunodeficiency diseases. These stem cells can be used to produce red blood cells and white blood cells in the body.

Sources of Stem Cells

Stem Cells originate from different parts of the body. Adult stem cells can be found in specific tissues in the human body. Matured cells are specialized to conduct various functions. Generally, these cells can develop the kind of cells found in tissues where they reside.

Embryonic Stem Cells are derived from 5-day-old blastocysts that develop into embryos and are pluripotent in nature. These cells can develop any type of cell and tissue in the body. These cells have the potential to regenerate all the cells and tissues that have been lost because of any kind of injury or disease.

To know more about stem cells, their types, applications and sources, keep visiting BYJU’S website.

Frequently Asked Questions

What is stem cell therapy.

Stem-cell therapy is the use of stem cells to cure or prevent a disease or condition. The damaged cells are repaired by the generated stem cells, which can also hasten the healing process in the injured tissue. These cells are essential for the regeneration and transplanting of tissue.

What are totipotent stem cells?

Stem cells have the capacity to self-renew and differentiate into specialized cell types. Totipotent stem cells come from an early embryo and can differentiate into all possible types of stem cells.

What are the four types of stem cells?

The four types of stem cells are the embryonic stem cells, adult stem cells, induced pluripotent stem cells and mesenchymal stem cells

What are adult stem cells?

Adult stem cells are undifferentiated cells taken from tissues and developing organs. They can replace and restore damaged tissues. Example – hematopoietic stem cells in the bone marrow.

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Stem Cell Research and Health Education

Stem cells are being touted as the greatest discovery for the potential treatment of a myriad of diseases in the new millennium, but there is still much research to be done before it will be known whether they can live up to this description. There is also an ethical debate over the production of one of the most valuable types of stem cell: the embryonic form. Consequently, there is public confusion over the benefits currently being derived from the use of stem cells and what can potentially be expected from their use in the future. The health educator’s role is to give an unbiased account of the current state of stem cell research. This paper provides the groundwork by discussing the types of cells currently identified, their potential use, and some of the political and ethical pitfalls resulting from such use.

INTRODUCTION

Stem cells are believed to be one of the greatest untapped resources currently available for the prevention and treatment of many diseases. Inasmuch as current knowledge of stem cells is a combination of scientific reality and cautious speculation, considerable research is required to identify the true, long-term potential for medical advances from these cells. As health resources professionals, communicators, and advocates, 1 health educators are in a position to advance the public dialogue about this promising technology. This article offers a general overview of stem cells, their potential for extending life and improving its overall quality, and some thoughts on the role of health educators with regard to professional and lay audiences.

WHAT ARE STEM CELLS?

Stem cells are template cells found throughout the body that can grow to become cells with specialized functions. 2 – 6 These cells replicate to generate “offspring” cells that can be either stem cells (and hence, self-renewing) or specialized cells (i.e., differentiated cells) that play a specific role—becoming blood, bone, brain, or skin cells, among others. 7 Stem cells, therefore, have the potential to act as repair systems for replacement of damaged cells. 2 – 6 The field in which a great deal of research is currently underway to determine the use of stems cells in the treatment of diseases and injuries is called “regenerative medicine.” Under “normal” conditions stem cells continue to replicate until they receive a signal to differentiate into a specific cell type. 8 When stem cells receive such a signal they first become progenitor cells, and later, the final mature cell type. Determination of the different signals that cause the stem cell to become a specific type rather than just continue to replicate is important (and, in some cases, it is the absence rather than the presence of a signal that is the important factor). 8 The ability of stem cells from one area to differentiate into another completely different type is known as plasticity, and embryonic stem cells appear to be the “most plastic” of the four types discussed below. 2 – 6

Stem cells are described as being of a specific cell line, dependent on the characteristics and location of the original template cells from which all future offspring cells have grown (reflecting the self-renewing capability of the cells). Assuming that no contamination of the cell line occurs as a result of mutations or infections, and no differentiating triggers occur, the cell lines could potentially grow ad infinitum. 2

DIFFERENT TYPES OF STEM CELLS

There are several types of stem cells: embryonic stem cells, fetal stem cells, adult stem cells, embryonic germ cells, and amniotic and umbilical cord stem cells. These stem cell varieties and their distinct properties are discussed below.

Embryonic and Fetal Stem Cells

The development of an organism can be compartmentalized into several stages. 9 Following the union of the egg and sperm, the initial four to five days from conception are characterized by a period of rapid cell division. A “ball” of 50 to 150 cells known as a blastocyst is created, so named because it is a hollow sphere. The blastocyst is composed of three parts: the trophoblast or outer surface, the blastocoel or inner cavity, and the inner cell mass found inside the blastocoel which is composed of stem cells. 9 These inner-lying cells are said to be “embryonic” even though the term embryo does not technically apply until after this initial two-week stage.

The next eight-week stage is characterized by cell growth and multiplication. Following this eight-week stage, the organism has recognizable structures and is classified as a fetus. At this time, embryonic stem cells continue to proliferate and are said to be pluripotent or plastic, meaning that they can differentiate into almost any type of cell that makes up the body. 10 The embryonic stem cell is believed by many scientists to be the most useful for potential medical treatments, but its use is restricted by federal legislation (described later in this article). Existing stem cells for medical research can come from four primary sources: existing stem cell lines, aborted or miscarried fetuses, discarded embryos from fertilization treatments, or cloned embryos. Only the first source can be used in federally funded research programs, however. 11 , 12

The cloning of embryos is another controversial area of research. The cloning of humans to full term is banned almost worldwide. 13 , 14 In some cases, short-term cloning has been performed to allow for the generation and extraction of stem cells, followed by the termination of the cloned embryo by the sixth day after fertilization. Cloning of some animals has been allowed to proceed to full term; the first and most famous example was the work of Scottish scientists resulting in the creation of a sheep known as “Dolly.” 15 That achievement became the driving force for new regulations to prevent a similar event occurring with human cells. The latest evidence suggests that cloned cells do not “reset their longevity clocks,” thus resulting in reduced lifespan. Furthermore, not only is the success rate of cloning low, but the cloned organism is beset with problems, some of which may not become apparent until adulthood, assuming life extends to that age. 16 , 17

For research to occur with embryonic stem cells, the inner cell mass of the blastocyst is extracted (thus destroying the embryo) and grown in cell culture. 18 , 19 This process enables cells to grow on plates coated with a feeder layer that provides anchorage and nutrients. The stem cells become attached to the plate and grow in the nutrient broth (i.e., cell culture media tailored to the specific needs of the cell line being grown). 18 , 19 As the cells proliferate they fill the plate until a point is reached where they would be forced to compete for space and nutrients. Shortly before such competition breaks out, the cultures are replated at the original cell density (meaning that one starting plate could be divided across two or more plates) and the process is repeated. This procedure is known as “passaging.” 20 After several months, the cells will number in the billions without differentiating or changing in any detectable way. They can either be frozen for storage or continue replicating. However, there is some evidence that with continued passaging, a point may be reached in which the cells become less stable with respect to their ability to replicate, differentiate, or avoid mutations. 21 This instability seems to be particularly true when adult and embryonic stem cells are compared (see below).

Fetal stem cells, typically obtained following abortion or miscarriage, are believed to be as pluripotent as their embryonic counterparts, though they occur at a later stage than the true embryonic stem cell. 22 Several biotechnological companies are experimenting with these cells as treatments for a myriad of diseases. For instance, ReNeuron, Inc. (UK) has several cell lines derived from the fetal brain that they are testing for the treatment of neurodegenerative disorders, including stroke, Parkinson’s disease, and Alzheimer’s disease. 23 , 24

Adult Stem Cells

A small number of stem cells can be found in adult humans at specific locations, such as in the bone marrow or the subventricular zone of the brain. 25 , 26 Until the discovery of these and other cells in the central nervous system, it was believed that the brain was the only organ that could not replicate. However, it is now clear that certain regions of the brain may have some limited capability to replace damaged or dead cells as a consequence of endogenous stem cells. 27 , 28

Whereas embryonic stem cells are derived from the inner cell mass of the blastocyst, knowledge of the origin of the adult stem cell is less certain. Its source could potentially be the same, with the adult stem cell being many generations removed from the original source. If this speculation is true, then one would expect the body to have large numbers of these cells, which it does not. It has therefore been suggested that halting of replication is the means by which the number of stem cells found in the organs of the body is limited. 29 The stem cells are said to have entered a state of quiescence, until they receive an activation signal due to cell damage. Determination of the signal that triggers adult stem cells to “wake up” is critical to maximizing their benefit. In addition, identification of what makes the cells quiescent is of considerable merit. One study revealed the presence of a “master switch” that can trigger the change from embryonic to adult stem cell characteristics, suggesting that this signal may originate from the same source. 30

There is considerable debate as to how pluripotent adult stem cells are. The original belief was that they were not as versatile, healthy, or durable as embryonic stem cells because they appeared to be limited to forming only cells of a similar origin (e.g., bone marrow stem cells could only produce blood cells). Consequently, these cells became known as multipotent cells. These characteristics meant that adult stem cells would be harder to manipulate or control compared with embryonic cells. Also, due to their presence in adults, it is likely that the cells could have accumulated abnormalities through continuous exposure of the organism to environmental hazards (such as viruses) or to replication errors. 31 , 32 The latter problems are normally corrected, but with the aging organism, the ability to correct replication errors is believed to diminish. 32 , 33 In the majority of cases, the ability of adult stem cells to replicate also appears to be limited compared with embryonic stem cells, thus reducing their usefulness. 34 However, these cells do have an advantage over embryonic stem cells: theoretically, they can be removed from a patient, grown in culture, and then returned to the patient. 35 Therefore, they would not induce an immunological rejection response that may be seen with embryonic stem cells. 35 , 36 In addition, there is more flexibility in using these cells than human embryonic stem cells, especially with regard to federal funding.

Some research shows that certain adult stem cells can differentiate into a number of varied cell types, including neurons 37 – 39 of the peripheral and central nervous system. However, this observation may not be true of all adult stem cells, and more research is required to determine how useful these cells might be for use in treating human disease and injury.

Most research on adult stem cells is based on mesenchymal cells, i.e., cells from regions originally derived from the mesodermal layer of the embryo. These cells include connective tissue and, in particular, bone marrow and muscles. They are multipotent cells and are a relatively homogeneous population of mononuclear progenitor cells that can be made to differentiate into specific cell lines following environmental cues. Additionally, there are stromal stem cells found in the bone marrow, which are a more heterogeneous population of different cell types with varying degrees of proliferation and differentiation potential. 40 Adult stem cells also can be found in children, in the placenta, and in blood from the umbilical cord. These specialized cells are discussed below.

Embryonic Germ Cells

Germ cells are the precursors to the gametes (egg and sperm) and are therefore found in adult testes and ovaries, and in the areas of the embryo that ultimately differentiate into testes or ovaries. 41 These cells appear to be as pluripotent as other embryonic stem cells. However, they have been found to differentiate spontaneously, which would suggest that there is less control over their development than with other stem cells. 42

Two studies 43 , 44 suggest that adult stem cells can be easily derived from germ cells of both sexes. Further research is needed to explore the validity of this hypothesis, though the findings are certainly intriguing and potentially useful.

Amniotic Fluid (or Placental) and Umbilical Cord Blood Stem Cells

The amniotic fluid that surrounds and protects a developing fetus in its mother’s uterus, as well as the placenta, have also been shown to contain stem cells. 45 An amniocentesis procedure—where amniotic fluid is collected through the insertion of a long, thin needle into a pregnant woman’s abdomen to check for abnormalities, including Down syndrome—is generally considered safe for both the mother and embryo. 46 The collected amniotic fluid is normally discarded once testing is complete, but now that it has been found to contain stem cells, there is potential for further research and storage of such fluid. The current belief is that amniotic fluid contains a mixture of embryonic and adult stem cells. 47 , 48 Testing of these cells has been limited to date. It is believed that they are able to differentiate into a variety of cell types, but it is not known whether they are as pluripotent as other types of stem cells. Some authorities have suggested they could be used as a potential treatment for diabetes. 49

Umbilical cord blood contains low levels of stem cells as well as a number of hematopoietic (blood forming) cells, including lymphocytes and monocytes. There is a considerable amount of research focusing on umbilical cord blood for the treatment of stroke, myocardial infarction, and a variety of blood-related disorders, with some degree of success. 50 – 53 The benefits of such blood have already been demonstrated in the treatment of hematopoietic disorders, with over 6,000 transplants being performed worldwide since it was first used to treat a five-year-old child afflicted with Fanconi anemia in 1988. 50 And there is good experimental evidence that it can help with other disorders as well. 53 , 54 However, it is unclear precisely how these benefits are obtained. Current evidence suggests that in many cases it is not the stem cells per se that provide the benefit, but rather the growth factors these cells release. Some research shows that umbilical cord blood cells do seem to have the ability to become neuronal-like cells in vitro, but do not appear to produce neurons of any significant number in animal models of stroke. 53 , 54

The current research interest in umbilical cord blood cells 53 , 54 has resulted in the formation of many companies worldwide that allow public and private storage of these cells. As a result, at least 18 states have proposed legislation to encourage and inform the public about this potential resource, and in several cases to provide funding for the setting up and/or running of umbilical cord cell banks (see http://www.ncsl.org/programs/health/genetics/geneticsDB.cfm for a searchable database of such legislation). Additionally, official Japanese, European, and Australian banks exist, as well as the many private companies that are currently “getting in on the act.” 55 – 57 This resource could prove to be valuable. Although the potential benefit of these cells still remains relatively unexplored, the practice of banking them already has at least one undeniable benefit: providing donors with a source of their own cells, which considerably reduces the chance of rejection if they ever do need them for medical reasons.

Two other recent papers have demonstrated an additional potential source of adult multipotent stem cells: menstrual blood. 58 , 59

POTENTIAL USES OF STEM CELLS

Adult stem cells derived from bone marrow (i.e., the hematopoietic system) have been used frequently over the past 30 years for successful treatment of numerous blood-based disorders. Current treatments include nuclear radiation exposure and transplantation for the treatment of genetic diseases or cell cancers of the blood and the blood-forming system. 40 , 60 – 63

According to a White House report, there are currently more than 1,200 non-embryonic stem cell clinical trials under way, while none are being performed using embryonic cells. 64 The freeze on federal funding to support embryonic studies, rather than a lack of efficacy, is most likely a major factor behind this statistic. It is important to remember, however, that embryonic stem cell research has never been illegal in the United States; it just cannot be funded from federal sources other than those lines that were approved in August 2001. It is also noteworthy that adult stem cells have been researched for three decades, whereas embryonic stem cell research is considerably more recent, with the first human embryonic stem cell being isolated in 1998 at the University of Wisconsin–Madison by James Thomson. 18 That discovery led to several patents/licenses by the Wisconsin Alumni Research Foundation (WARF), further restricting the use and research of such cells, given the expense of purchasing them. These patents were revoked in April 2007 by the U.S. Patent and Trademark Office, 65 but WARF appealed the decision. In March 2008, WARF’s appeal was upheld. 66 To provide cells to researchers, the National Institutes of Health has established a subsidy that allows the purchase of cell lines approved in August 2001, at much reduced rates, thus resolving some of the previous issues related to their use.

Many of the adult stem cell trials are also oncology studies rather than regenerative medicine studies. 67 , 68 Ongoing clinical studies include phase II trials in which patients suffering from myocardial ischemia have their own adult bone marrow stem cells transplanted into their heart, theoretically increasing revascularization of the affected areas. 69 , 70 Additional cardiac therapies are summarized in a review by Ramos and Hare. 71

A myriad of basic research is underway worldwide on both embryonic and non-embryonic stem cells derived from a number of sources. This research encompasses treatment of various disorders including organ regeneration, cardiovascular improvements, diabetes, and neurodegenerative conditions. They comprise the complete continuum of research from preliminary explorative studies through preclinical and clinical trails. Promising results include the promotion of liver regeneration by bone marrow stem cells in patients with hepatic malignancies, 72 the formation of blood vessels in mice from human embryonic stem cells that have been made to differentiate into endothelial precursor cells, 73 the treatment of stroke and heart ischemia animal models by human umbilical cord blood transplants in rats, 51 , 53 , 54 and the ability of embryonic stem cells to differentiate into functioning heart tissue (myocytes). 74 Adult stem cells also have been used for the latter purpose, but the differentiated cells appear to impair heart function. However, preliminary data from a clinical phase I trial of an intravenous formulation (Provacel) of adult bone marrow–derived mesenchymal stem cells appears to demonstrate some benefit in decreasing subsequent problems among heart attack patients (Schaer, American College of Cardiology’s Innovation in Intervention, March 25, 2007). Also, Yacoub 75 announced that his team has been able to grow a heart valve from bone marrow stem cells using a collagen scaffold. This procedure has yet to be tested to determine if the valve is functional in vivo , but it clearly represents a promising discovery. Similarly, preliminary testing of the recently discovered stem cells in amniotic fluid for treating heart disease has demonstrated some encouraging results that require further study and verification. 76 Unfortunately, transplantation of these cells has been accompanied by a strong immunological response.

Elsewhere, a study using embryonic stem cells has shown considerable improvement in mice specially bred to exhibit symptoms of Sandhoff disease, a childhood disorder. 77 The implanted cells appear to function by replacing the neurons killed by the disease, as well as restoring normal levels of the enzyme hexosaminidase (low levels cause the disease). The disease was found to eventually return, but Lee et al. 78 believe that additional treatments could inhibit recurrence and are conducting further research in this area.

Preliminary findings from other studies involving fetal neural stem cells in culture and in animals have shown rescue of retinal cells after injury or disease. 79 This observation appears to demonstrate a restorative rather than a replacement action by these cells.

In general, considerable research is underway to ensure that the development of treatments involves only those cell types being sought, and that it includes ways of ensuring desired outcomes—i.e., controlling the stem cells so that they form the desired cells and do not proliferate indefinitely, which could lead to malignancy once transplanted. Achieving such outcomes may constitute one of the biggest stumbling blocks to stem cell research. One possible method would be to differentiate the cells before transplantation; Keller 79 has summarized various attempts at this method. Yet, a study involving transplantation of stem cells obtained from the human central nervous system into a primate Parkinsonian model resulted in behavioral improvements and integration of cells without tumor formation. 80 Therefore, predifferentiation of cells before transplant may not be necessary, though further research is required to be sure that this is the case. This avenue of research is likely to see many initiatives, given the anticipated dividends.

Additionally, study of the body’s ability to reject “foreign” tissue is also important because certain embryonic tissue is likely to have the ability to induce a significant immunologic response. Some studies are now suggesting that immature embryonic stem cells and umbilical cord blood cells are not as likely to cause an immunological reaction as differentiated adult stem cells. 81 – 83 With adult stem cells, harvesting from the same patient undergoing the transplant generally eliminates this problem.

A few studies have found that co-transplantation of two or more different types of cells has resulted in a synergistic effect that maintained their survival and execution of beneficial effects. For instance, the co-culture of amniotic epithelial and neural stem cells promoted neuronal differentiation of the latter. 84 Both trophic support and direct contact between the two cell types appeared to have important but independent effects on the neuronal survival and differentiation.

One caveat to consider in stem cell treatment of disease is that the replacement of dying cells by new ones is only a temporary solution because whatever resulted in the death of the cells initially—unless purely intrinsic to the dying cells themselves or only a onetime event—will eventually prove lethal to the new cells, too. This phenomenon has been demonstrated in a paper on fetal tissue grafts for the treatment of Parkinson’s disease. 85 Consequently, calling stem cells a “cure” for diseases is really a misnomer; instead, calling them the “best available treatment” may be more accurate at present. This caveat makes the assumption that stem cell transplants are replacing the dying cells. Studies on stroke models using umbilical cord blood–derived stem cells do not support the idea of replacement, but do show an improvement in the size of the stroke lesion and behavioral markers. 53 , 54 Some of their benefit may be more related to controlling the inflammatory response that causes cell death or to promoting more rapid healing. A study by Capone et al. 86 demonstrated that stem cells do act in this fashion, modifying the microenvironment following stroke to afford neuroprotection, rather than replacing “sick” cells. Similar findings have been observed in other studies, including the eye experiments mentioned previously. Thus, stem cells may help to support the cells that are already present and protect them from further injury or death due to the factors that cause or perpetuate the initial disease or injury. This support in turn leads to another consideration: are pluripotent cells necessarily better than multipotent ones? Assuming that adult stem cells from a specific source (e.g., adult stem cells from the brain) can differentiate into the required replacement cell (e.g., neural cells) or provide the required supporting factors, they do not need to be pluripotent. Therefore, pluripotent (embryonic stem) cells would only be required when adult stem cells are not present or cannot differentiate into the cell of interest or produce the necessary factors to give the desired result. Consequently, research on both pluripotent and multipotent cells would seem to still be necessary. 87

Not only does stem cell research provide direct cell replacement benefits or improve the survivability of “sick” or “injured” cells, it also offers considerable insight on what causes cells to proliferate and differentiate—an important phenomenon to understand in the fight against cancers and in general research dedicated to the development and normal life cycle of cells. 88 – 92 Studies of stem cells could, therefore, have far-reaching implications that are not limited to just disease treatment. 88 – 94 Finally, stem cells could also be used to model organs for the testing of drugs or new surgical techniques—another potentially powerful benefit of stem cell research. 95 , 96

PREDOMINANT CONTROVERSIES ABOUT STEM CELL RESEARCH

There are four main controversies currently surrounding stem cells. Perhaps the most significant involves moral arguments regarding the use of embryonic material to harvest stem cells. The focus of this controversy is on when life begins—which some consider to be at conception—and whether any individual has the right to terminate a life. Strong spiritual and religious beliefs are frequently central to this controversy, and the practice is considered unacceptable by many. One study 97 suggested the possibility of removing one or a few stem cells without harming an in vitro–fertilized embryo prior to implantation, thus maintaining its viability. As of yet, however, it is unclear exactly what impact this action has on the growing organism and whether such studies can be confirmed. Consequently, because of the controversy over when life begins, many countries either ban embryonic stem cell research or severely restrict it. As indicated previously, only those embryonic stem cell lines approved for study in August 2001 can receive federal funding and support in the United States.

Three connected groups of scientists reported success in transforming normal mouse skin cells into embryonic stem cell–like cells via genetic manipulation. 98 – 100 Further research is required to confirm these findings and those of other studies 101 , 102 have translated this technique to human cells. Additionally, the transformed cells are prone to tumorigenesis, and therefore, would not be useful for transplantation in humans in their current form. This technique would not necessarily replace the use of embryo-derived stem cells, as further characterization is necessary to confirm that the cells do possess all of the same characteristics—including the same receptors and response to treatments. Nevertheless, it is a small step in the right direction for those opposed to embryonic sources.

A second controversy surrounding stem cell research is the apparent groundbreaking outcome of studies performed by a research team in South Korea. In 2004, this team reported in Science that they had obtained human embryonic stem cells from the nuclear transfer of oocytes (i.e., the replacement of the nucleus of an egg with that of an already differentiated cell). The following year, this team again reported in Science that they were able to generate patient-specific immune-matched embryonic stem cells for the treatment of diseases. In the end, the data were found to be fraudulent, and some of the female researchers had apparently been coerced to donate their own eggs for the process of obtaining stem cells, a significant ethical breach in the field. 103 As a result of these findings, both papers were retracted in 2005, and significant penalties were imposed on the researchers. This scandal cast a large shadow over the competitiveness in the field and the possible unethical means of obtaining stem cells for research purposes.

A third controversy has to do with stem cells’ alleged potential to produce malignancies once implanted due to their theoretically immortal nature (viewed as such because stem cells can reproduce ad infinitum ). Some research suggests that certain kinds of stem cells could cause cancer because a small number of defective stem cells have been found in tumors, where they may have acted as a seed. 104 Given their ability to proliferate continuously, these cells carry an increased likelihood of mutations, which in turn increases the probability that they will grow out of control and become cancerous. Therefore, their use in treatments could be fraught with problems, at least until a clearer understanding emerges regarding the signals that turn them on and off in their growth cycles. Adult stem cells are normally quiescent, meaning that identification of the process by which mutations occur could prove to be vitally important in preventing transplant tumorigenicity or in preventing cancers altogether.

Interestingly, studies using embryonic carcinoma cells—which are malignant, similar to stem cells, and generally derived from germinal cells—have provided some neurodegenerative improvement in animal models. 105 These cells can be made to differentiate into human neurons under retinoic acid treatment. When this conversion occurs, the cells appear to lose their malignant properties. 105 Once the mechanism for this process has been determined, it could be tested in stem cells, perhaps creating the ability to turn off the malignant characteristics of these cells.

At the same time, another recent study suggested that although stem cells—specifically, those obtained from bone marrow—may look like malignant cells, they do not necessarily function like them. In other words, stem cells may not be cancerous and may not be able to seed tumors. 106 Further research is required to determine whether this is true for all stem cells found in tumors, and whether they are acting as “developmental mimics” or seed tumors.

The fourth main controversy concerns whether adult stem cells are as beneficial as embryonic stem cells. A seminal paper from a group led by Catherine Verfaillie (see Jiang et al. 107 ) reported that adult stem cells from the bone marrow of rats, which they called “multipotent adult progenitor cells” (MAPCs), had the potential to differentiate into almost every type of cell in the body, a claim that previously applied only to embryonic stem cells. Unfortunately, little success has been made in replicating these results. More recent evidence suggests that the paper was flawed, adding further consternation to this area of investigation. 108 , 109 Subsequent research from a number of teams reported that when MAPCs could be successfully isolated from bone marrow using a different technique than that originally proposed, they did have the ability to become any type of blood cell but not other cells. But overall, it is still unclear whether this and other types of adult stem cells are as efficacious as originally proposed. 110 – 112 Criteria that stem cells have to meet to be classified as pluripotent have been proposed, 113 , 114 and few studies have actually met these criteria, with the majority being explained by cell fusion 115 and incorrect interpretation. 111 , 116 Thus, many researchers still believe that embryonic stem cells may provide more benefit due to their hypothetical ability to differentiate into all cell types, though most would prefer both avenues to be explored, acknowledging that adult stem cells could be useful in some circumstances.

Two independent studies by the groups of Yamanaka 101 and Thomson 102 may make this controversy a moot point. Expanding on the mouse studies 98 – 100 mentioned in an earlier section, they reported two similar methods of converting adult human skin cells into embryonic-like stem cells. This was achieved by the insertion of 4 genes that led to the reprogramming of the cells (interestingly, two of the genes differed between the research groups but had similar functions). This research has great potential but requires considerable additional testing to ensure that the embryonic-like stem cells behave in a similar fashion to embryonic stem cells obtained in the “normal” fashion. Additionally, there is the concern that one of the genes the researchers inserted was a cancer gene, which could increase the likelihood for tumorigen-esis using this approach. There is also concern over the retroviruses used to insert the genes, which can have potentially carcinogenic and other detrimental effects due to their ability to randomly insert the gene of interest into the genome. A major bonus of this approach is the ability to take the cells from the patients themselves and therefore reduce the likelihood of transplant rejection. There is also the potential to model a disease more directly by removing the affected cells from a patient and growing them in culture so that they can be characterized and compared with healthy cells. Research by Jaenisch’s group 117 has demonstrated that reprogrammed skin cells can treat the sickle cell anemia mouse model, thus confirming the potentially beneficial effects of such cells.

STATUS OF LEGISLATION ON STEM CELL USE

In the United States, federal funding for embryonic stem cell research from sources such as the National Institutes of Health is restricted by congressional legislation, which mandates that only cell lines approved in August 2001 be used in funded research. At that time, there were more than 60 lines, but only 20 have proven to be viable and available for general use. All of these cell lines have been grown on a mouse fibroblast feeder layer to restrict differentiation and only allow replication. Unfortunately, it has been found that these stem cells are likely contaminated with mouse proteins and sugars that could generate severe immunological responses following transplantation into humans to treat diseases. 118 However, some studies suggest that the proteins and sugars can be removed or cultured out to make the cells safer for human transplantation. 119 Newer procedures that use completely human components have been developed, so any future cell lines are unlikely to have this problem. Research involving adult stem cells is not limited under the current federal restrictions.

The 20 embryonic cell lines that are federally permissible represent only a small fraction of the genetically and immunologically heterogenous population of the world. 120 , 121 This limitation casts doubt over whether any treatments derived from these cell lines will be suitable for treating all of the ethnically diverse populations that exist in the United States and abroad. This limitation is both an incentive for developing additional cell lines and an important factor that should be considered with respect to all types of stem cells. The genetic diversity inherent in the world’s different ethnic groups implies that different ethnicities may respond in different ways to these cell lines. Therefore, any success found with these cells would need to be replicated using cell lines derived from other ethnic groups to determine their general use among the world’s population. 122

In 2006, a congressional bill was proposed to allow research on stem cells derived from embryos discarded after in vitro fertilization treatments. This bill was vetoed by the president based on ethical, moral, and religious concerns. The bill resurfaced following the 2006 midterm elections in which Democrats regained control of the House and Senate, but no change to the veto is likely under the current administration. 123

The restriction on federal funding for embryonic stem cell research led New Jersey to appropriate state funding for research on both embryonic and adult stem cells in early 2004. Ohio had previously proposed funding dedicated to adult stem cell research. The most well known example of funding at the state level is California, which proposed its own legislation in 2004 (Proposition 71) involving the sale of $3 billion in bonds to provide $295 million annually for 10 years to the funding of stem cell research. 124

Since then, several other states have sought endorsement of similar propositions ( Table 1 and Table 2 ). Currently, at least 33 states have specific guidelines with respect to the use of embryos in research, which in several cases (e.g., Arizona, South Dakota, Texas) conform to federal legislation. However, there is considerable variation among these states regarding their support of separate initiatives for stem cell research.

States That Are Encouraging Stem Cell Research

Sources: Compiled from various online reports, including www.ncsl.org/programs/health/genetics/embfet.htm , http://isscr.org/public/regions , and “Yahoo! Alerts Health News: Stem Cells” (all last accessed December 7, 2007).

States with Legislation Relating to Embryonic Stem Cell Use

The International Society for Stem Cell Research recently proposed international guidelines for the use of embryonic tissue to ensure uniform research and experimental practice worldwide. 125 At the core of these guidelines is that embryonic research should be rigorously overseen by sponsoring organizations or regulatory bodies with specific policies and procedures that conform to the recommendations of the scientific community. In all policies, no cloning is to be undertaken to create humans. The society’s policies also recommend the establishment of an institutional oversight committee to review and determine approval of all stem cell research. The use of “chimeras” (i.e., animals created with human cells) is allowed with approval from this committee. Further, the use of any cells donated for research purposes should require consent from those donating them. Regulations pertaining to stem cell use by state and country are kept reasonably up to date at the following websites:

• http://www.ncsl.org/programs/health/genetics/embfet.htm
• http://isscr.org/public/regions

Initially, the federal funding restriction was seen as detrimental to stem cell research. However, some scientists are now suggesting that the restriction has actually opened other funding opportunities that may be more helpful to the research community. As Table 1 shows, federal restrictions have created unprecedented state funding far exceeding any that the National Institutes of Health would likely provide. This alternative funding source has also piqued the interest of pharmaceutical companies. Such companies may be able to position themselves for a larger share of patents and licenses from state-funded research—they already have a near monopoly on drug therapies derived from this research. This apparent paradox was discussed in an opinion piece in The Scientist by Dr. Paul Sanberg. 126

STEM CELL RESEARCH AND HEALTH EDUCATION PRACTICE

Health educators are charged with numerous roles and responsibilities in the public sector. 1 These essential tasks intersect with current and anticipated research involving stem cells. What follows is an iteration of ways in which health educators might be expected to address relevant stem cell knowledge and research issues. Although not exhaustive, the points below highlight the importance of keeping public dialogue about this topic both vibrant and accurate.

Assessing Individual and Community Needs

Health education competencies and subcompetencies in this area include, but are not limited to, selecting valid sources of information about health needs and interests. The debate over stem cell research inevitably becomes enmeshed in moral arguments and political posturing, so it is important that scientifically accurate information and data be made prominent in the public eye. Health educators are positioned to translate technical information and make it accessible to the lay public and other interested consumers. Presently, although there are many avenues of availability for this information in the scientific and medical communities, it is far less available to the general public. What is needed are accurate sources of relevant stem cell data and other information that neither refute scientific discovery nor escalate optimism inappropriately or prematurely.

Planning, Implementing, and Administering Strategies and Programs

The highly diverse nature of the health information consumer includes different levels of health literacy, disparate ethical and moral belief systems, and widely varying learning styles. Health educators are professionally prepared as a group to respond to the needs of these different audiences by identifying individuals and groups who can best benefit from knowledge about stem cell research, incorporating appropriate organizational frameworks, establishing specific learning objectives based on assessment of baseline knowledge, assigning audience-specific modes of education delivery, and developing a program delivery method that includes optimal use of learning technologies.

Health educators are able to assess both knowledge and attitude shifts through the use of well chosen surveys and other assessment instruments. Moreover, health educators can infer needed future activities and programs that build either in a linear or a spiraling fashion on past activities. Stem cell research is a pioneering endeavor, and the knowledge shifts can, therefore, be rapid; the need for recurring data and information sources suitable for general and specific audience consumption is as dynamic as the shifting sands. Health educators are prime candidates for interpreting these changes, putting them in context, and making the necessary and relevant adjustments to the public’s informational needs.

Serving as an Education Resource Person

Health educators should be masters at retrieval of information that can be translated from technical to more audience-friendly language. As with their other resource functions, health educators should be able to match information needs with the appropriate retrieval systems; to select data and data systems commensurate with program needs; and to determine the relevance of various computerized health information resources, access those resources, and employ electronic technology for retrieving references. To enhance the match between information and audience, health educators should be positioned to perform readability assessments using such tools as the SMOG Test, 127 the Flesch Reading Ease Formula, 128 and other indices, 129 thereby increasing the likelihood that relevant information about stem cells will be understood.

Advocating for Education about Stem Cell Research

Health educators are expected to analyze and respond to current and future needs in health education. Particularly pertinent to stem cell research is the analysis of factors (e.g., social, demographic, political) that influence individuals who make decisions about the direction of, and restrictions on, stem cell research. Currently, the wise course may be for health educators to be as politically neutral as possible in organizing and communicating information about stem cell research—standing neither for nor against liberalization of current research postures by the federal government and other entities. Health educators, like any other professional group, are subject to their own biases, including those emanating from personal moral philosophy, ethical principles, or other convictions. Nevertheless, they are obligated to report on stem cell matters factually. They can also serve as advocates for promoting discussions in the public sector, at professional conferences, and in their own scientific literature. Finally, practice standards support health educators’ participation in continuing education on stem cell issues and their development of plans for ongoing professional development.

Stem cell research is a major area in biomedical research, one that could have a far-reaching impact on the overall health of the human race. Many people, professional and lay alike, obtain their knowledge from sources that present personal agendas or dubious interpretations of facts. In this article, we have endeavored to give a fair, balanced, and unbiased view—as much as our personal limits as scientists and individuals permit—of the potential of stem cells. We have also argued that health educators can position themselves to bring some orderliness to the debate about the merits of stem cell research and support a healthy dialogue among lay audiences as well as their own professional peers.

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Examining the ethics of embryonic stem cell research

Following the recent passage by both houses of Congress of the Stem Cell Research Enhancement Act of 2007, which would permit federal funding of research using donated surplus embryonic stem cells from fertility clinics, the president has once again threatened a veto.

Because neither the House nor the Senate had sufficient votes to override a presidential veto, it appears unlikely this new bill will be enacted into law, further stalling the pace of this research. “This bill crosses a moral line that I and others find troubling,” stated Bush, following the Senate’s vote.

SCL : What are th e main arguments for and against embryonic stem cell research? MS : Proponents argue that embryonic stem cell research holds great promise for understanding and curing diabetes, Parkinson’s disease, spinal cord injury, and other debilitating conditions. Opponents argue that the research is unethical, because deriving the stem cells destroys the blastocyst, an unimplanted human embryo at the sixth to eighth day of development. As Bush declared when he vetoed last year’s stem cell bill, the federal government should not support “the taking of innocent human life.”

It is surprising that, despite the extensive public debate—in Congress, during the 2004 and 2006 election campaigns, and on the Sunday morning talk shows—relatively little attention has been paid to the moral issue at the heart of the controversy: Are the opponents of stem cell research correct in their claim that the unimplanted human embryo is already a human being, morally equivalent to a person?

“It is important to be clear about the embryo from which stem cells are extracted. It is not implanted and growing in a woman’s uterus. It is not a fetus. It has no recognizable human features or form. It is, rather, a blastocyst, a cluster of 180 to 200 cells, growing in a petri dish, barely visible to the naked eye.”

SCL : What are the contradictions in Bush’s stance? MS : Before we address that, it is important to be clear about the embryo from which stem cells are extracted. It is not implanted and growing in a woman’s uterus. It is not a fetus. It has no recognizable human features or form.

It is, rather, a blastocyst, a cluster of 180 to 200 cells, growing in a petri dish, barely visible to the naked eye. Such blastocysts are either cloned in the lab or created in fertility clinics. The bill recently passed by Congress would fund stem cell research only on excess blastocysts left over from infertility treatments.

The blastocyst represents such an early stage of embryonic development that the cells it contains have not yet differentiated, or taken on the properties of particular organs or tissues—kidneys, muscles, spinal cord, and so on. This is why the stem cells that are extracted from the blastocyst hold the promise of developing, with proper coaxing in the lab, into any kind of cell the researcher wants to study or repair.

The moral and political controversy arises from the fact that extracting the stem cells destroys the blastocyst. It is important to grasp the full force of the claim that the embryo is morally equivalent to a person, a fully developed human being.

For those who hold this view, extracting stem cells from a blastocyst is as morally abhorrent as harvesting organs from a baby to save other people’s lives. This is the position of Senator Sam Brownback, Republican of Kansas, a leading advocate of the right-to-life position. In Brownback’s view, “a human embryo . . . is a human being just like you and me; and it deserves the same respect that our laws give to us all.

If Brownback is right, then embryonic stem cell research is immoral because it amounts to killing a person to treat other people’s diseases.

SCL : What is the basis for the belief that personhood begins at conception? MS : Some base this belief on the religious conviction that the soul enters the body at the moment of conception. Others defend it without recourse to religion, by the following line of reasoning: Human beings are not things. Their lives must not be sacrificed against their will, even for the sake of good ends, like saving other people’s lives. The reason human beings must not be treated as things is that they are inviolable. At what point do humans acquire this inviolability? The answer cannot depend on the age or developmental stage of a particular human life. Infants are inviolable, and few people would countenance harvesting organs for transplantation even from a fetus.

Every human being—each one of us—began life as an embryo. Unless we can point to a definitive moment in the passage from conception to birth that marks the emergence of the human person, we must regard embryos as possessing the same inviolability as fully developed human beings.

SCL : By this line of reasoning, human embryos are inviolable and should not be used for research, even if that research might save many lives. MS : Yes, but this argument can be challenged on a number of grounds. First, it is undeniable that a human embryo is “human life” in the biological sense that it is living rather than dead, and human rather than, say, bovine.

But this biological fact does not establish that the blastocyst is a human being, or a person. Any living human cell (a skin cell, for example) is “human life” in the sense of being human rather than bovine and living rather than dead. But no one would consider a skin cell a person, or deem it inviolable. Showing that a blastocyst is a human being, or a person, requires further argument.

Some try to base such an argument on the fact that human beings develop from embryo to fetus to child. Every person was once an embryo, the argument goes, and there is no clear, non-arbitrary line between conception and adulthood that can tell us when personhood begins. Given the lack of such a line, we should regard the blastocyst as a person, as morally equivalent to a fully developed human being.

SCL : What is the flaw in this argument? MS : Consider an analogy: although every oak tree was once an acorn, it does not follow that acorns are oak trees, or that I should treat the loss of an acorn eaten by a squirrel in my front yard as the same kind of loss as the death of an oak tree felled by a storm. Despite their developmental continuity, acorns and oak trees differ. So do human embryos and human beings, and in the same way. Just as acorns are potential oaks, human embryos are potential human beings.

The distinction between a potential person and an actual one makes a moral difference. Sentient creatures make claims on us that nonsentient ones do not; beings capable of experience and consciousness make higher claims still. Human life develops by degrees.

SCL : Yet there are people who disagree that life develops by degrees, and believe that a blastocyst is a person and, therefore, morally equivalent to a fully developed human being. MS : Certainly some people hold this belief. But a reason to be skeptical of the notion that blastocysts are persons is to notice that many who invoke it do not embrace its full implications.

President Bush is a case in point. In 2001, he announced a policy that restricted federal funding to already existing stem cell lines, so that no taxpayer funds would encourage or support the destruction of embryos. And in 2006, he vetoed a bill that would have funded new embryonic stem cell research, saying that he did not want to support “the taking of innocent human life.”

“The distinction between a potential person and an actual one makes a moral difference. Sentient creatures make claims on us that nonsentient ones do not; beings capable of experience and consciousness make higher claims still. Human life develops by degrees.”

But it is a striking feature of the president’s position that, while restricting the funding of embryonic stem cell research, he has made no effort to ban it. To adapt a slogan from the Clinton administration, the Bush policy might be summarized as “don’t fund, don’t ban.” But this policy is at odds with the notion that embryos are human beings.

SCL : If Bush’s policy were consistent with his stated beliefs, how, in your opinion, would it differ from his current “don’t fund, don’t ban” policy? MS : If harvesting stem cells from a blastocyst were truly on a par with harvesting organs from a baby, then the morally responsible policy would be to ban it, not merely deny it federal funding.

If some doctors made a practice of killing children to get organs for transplantation, no one would take the position that the infanticide should be ineligible for federal funding but allowed to continue in the private sector. In fact, if we were persuaded that embryonic stem cell research were tantamount to infanticide, we would not only ban it but treat it as a grisly form of murder and subject scientists who performed it to criminal punishment.

SCL : Couldn’t it be argued, in defense of the president’s policy, that Congress would be unlikely to enact an outright ban on embryonic stem cell research? MS : Perhaps. But this does not explain why, if the president really considers embryos to be human beings, he has not at least called for such a ban, nor even called upon scientists to stop doing stem cell research that involves the destruction of embryos. In fact, Bush has cited the fact that “there is no ban on embryonic stem cell research” in touting the virtues of his “balanced approach.”

The moral oddness of the Bush “don’t fund, don’t ban” position confused even his spokesman, Tony Snow. Last year, Snow told the White House press corps that the president vetoed the stem cell bill because he considered embryonic stem cell research to be “murder,” something the federal government should not support. When the comment drew a flurry of critical press attention, the White House retreated. No, the president did not believe that destroying an embryo was murder. The press secretary retracted his statement, and apologized for having “overstated the president’s position.”

How exactly the spokesman had overstated the president’s position is unclear. If embryonic stem cell research does constitute the deliberate taking of innocent human life, it is hard to see how it differs from murder. The chastened press secretary made no attempt to parse the distinction. His errant statement that the president considered embryo destruction to be “murder” simply followed the moral logic of the notion that embryos are human beings. It was a gaffe only because the Bush policy does not follow that logic.

SCL : You have stated that the president’s refusal to ban privately funded embryonic stem cell research is not the only way in which his policies betray the principle that embryos are persons. How so? MS : In the course of treating infertility, American fertility clinics routinely discard thousands of human embryos. The bill that recently passed in the Senate would fund stem cell research only on these excess embryos, which are already bound for destruction. (This is also the position taken by former governor Mitt Romney, who supports stem cell research on embryos left over from fertility clinics.) Although Bush would ban the use of such embryos in federally funded research, he has not called for legislation to ban the creation and destruction of embryos by fertility clinics.

SCL : If embryos are morally equivalent to fully developed human beings, doesn’t it then follow that allowing fertility clinics to discard thousands of embryos is condoning mass murder? MS : It does. If embryos are human beings, to allow fertility clinics to discard them is to countenance, in effect, the widespread creation and destruction of surplus children. Those who believe that a blastocyst is morally equivalent to a baby must believe that the 400,000 excess embryos languishing in freezers in U.S. fertility clinics are like newborns left to die by exposure on a mountainside. But those who view embryos in this way should not only be opposing embryonic stem cell research; they should also be leading a campaign to shut down what they must regard as rampant infanticide in fertility clinics.

Some principled right-to-life opponents of stem cell research meet this test of moral consistency. Bush’s “don’t fund, don’t ban” policy does not. Those who fail to take seriously the belief that embryos are persons miss this point. Rather than simply complain that the president’s stem cell policy allows religion to trump science, critics should ask why the president does not pursue the full implications of the principle he invokes.

If he does not want to ban embryonic stem cell research, or prosecute stem cell scientists for murder, or ban fertility clinics from creating and discarding excess embryos, this must mean that he does not really consider human embryos as morally equivalent to fully developed human beings after all.

But if he doesn’t believe that embryos are persons, then why ban federally funded embryonic stem cell research that holds promise for curing diseases and saving lives? 

Stem cells provide new insight into genetic pathway of childhood cancer

Scientists have discovered a new insight into the genetic pathway of childhood cancer, offering new hope for tailored treatments.

Researchers from the University of Sheffield have created a stem cell model designed to investigate the origins of neuroblastoma, a cancer primarily affecting babies and young children.

Neuroblastoma is the most common childhood tumour occurring outside the brain, affecting the lives of approximately 600 children in the European Union and the United Kingdom each year.

Until now, studying genetic changes and their role in neuroblastoma initiation has been challenging due to the lack of suitable laboratory methods. A new model developed by researchers at the University of Sheffield, in collaboration with the St Anna Children's Cancer Research Institute in Vienna, replicates the emergence of early neuroblastoma cancer-like cells, giving an insight into the genetic pathway of the disease.

The research, published in Nature Communications , sheds light on the intricate genetic pathways which initiate neuroblastoma. The international research team found that specific mutations in chromosomes 17 and 1, combined with overactivation of the MYCN gene, play a pivotal role in the development of aggressive neuroblastoma tumours.

Childhood cancer is often diagnosed and detected late, leaving researchers with very little idea of the conditions that led to tumour initiation, which occurs very early during fetal development. In order to understand tumour initiation, models which recreate the conditions that lead to the appearance of a tumour are vital.

The formation of neuroblastoma usually starts in the womb when a group of normal embryonic cells called 'trunk neural crest (NC)' become mutated and cancerous.

In an interdisciplinary effort spearheaded by stem cell expert Dr Ingrid Saldana from the University of Sheffield's School of Biosciences and computational biologist Dr Luis Montano from the St Anna Children's Cancer Research Institute in Vienna, the new study found a way in which to use human stem cells to grow trunk NC cells in a petri dish.

These cells carried genetic changes often seen in aggressive neuroblastoma tumours. Using genomics analysis and advanced imaging techniques, the researchers found that the altered cells started behaving like cancer cells and looked very similar to the neuroblastoma cells found in sick children.

The findings offer new hope for the creation of tailored treatments that specifically target the cancer while minimising the adverse effects experienced by patients from existing therapies.

Dr Anestis Tsakiridis, from the University of Sheffield's School of Biosciences and lead author of the study, said: "Our stem cell-based model mimics the early stages of aggressive neuroblastoma formation, providing invaluable insights into the genetic drivers of this devastating childhood cancer. By recreating the conditions that lead to tumour initiation, we will be able to understand better the mechanisms underpinning this process and thus design improved treatment strategies in the longer term.

"This is very important as survival rates for children with aggressive neuroblastoma are poor and most survivors suffer from side effects linked to the harsh treatments currently used, which include potential hearing, fertility and lung problems."

Dr. Florian Halbritter, from St. Anna Children's Cancer Research Institute and second lead author of the study, said: "This was an impressive team effort, breaching geographic and disciplinary boundaries to enable new discoveries in childhood cancer research."

This research supports the University of Sheffield's cancer research strategy. Through the strategy, the University aims to prevent cancer-related deaths by undertaking high quality research, leading to more effective treatments, as well as methods to better prevent and detect cancer and improve quality of life.

• Lung Cancer
• Breast Cancer
• Skin Cancer
• Brain Tumor
• Prostate Cancer
• Colon Cancer
• Stem cell treatments
• Cervical cancer
• Colorectal cancer
• Breast cancer
• Prostate cancer

Story Source:

Materials provided by University of Sheffield . Note: Content may be edited for style and length.

Journal Reference :

• Ingrid M. Saldana-Guerrero, Luis F. Montano-Gutierrez, Katy Boswell, Christoph Hafemeister, Evon Poon, Lisa E. Shaw, Dylan Stavish, Rebecca A. Lea, Sara Wernig-Zorc, Eva Bozsaky, Irfete S. Fetahu, Peter Zoescher, Ulrike Pötschger, Marie Bernkopf, Andrea Wenninger-Weinzierl, Caterina Sturtzel, Celine Souilhol, Sophia Tarelli, Mohamed R. Shoeb, Polyxeni Bozatzi, Magdalena Rados, Maria Guarini, Michelle C. Buri, Wolfgang Weninger, Eva M. Putz, Miller Huang, Ruth Ladenstein, Peter W. Andrews, Ivana Barbaric, George D. Cresswell, Helen E. Bryant, Martin Distel, Louis Chesler, Sabine Taschner-Mandl, Matthias Farlik, Anestis Tsakiridis, Florian Halbritter. A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations . Nature Communications , 2024; 15 (1) DOI: 10.1038/s41467-024-47945-7

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Journal of Materials Chemistry A

High-efficiency ultrathin flexible organic solar cells with a bilayer hole transport layer.

Abstracts: The storage stability and mechanical durability are two key parameters for the application of flexible organic solar cells (OSCs), which are considered a promising power source for wearable electronics. However, most of the high-efficiency flexible OSCs are fabricated based on the poly(3,4-ethylenedioxythiophene):poly(styrene-sulfonate) (PEDOT:PSS) hole transport layer, which hinders the long-term operation, especially under cyclic bending or stretching. Herein, we develop an ultrathin flexible OSC (with a total thickness of less than 2 μm) based on the bilayer hole transport layer, incorporating a MoO3 interlayer between the PEDOT:PSS and ITO, which can simultaneously improve the efficiency, storage stability and mechanical stability of ultrathin flexible OSCs. The ultrathin OSC based on the bilayer HTL achieves a power conversion efficiency (PCE) of 17.0% and a power-per-weight ratio of 39.3 W/g, compared to single-layer HTL devices with a PCE of 16.4%. To the best of our knowledge, it is the highest efficiency among all ITO-based ultrathin OSCs. Furthermore, the best-performed ultrathin OSCs show PCE retentions of 89% and 84% after 1000 cycles of bending (with a bending radius of 1 mm) and 1000 cycles of stretching/compression tests, respectively.

• This article is part of the themed collection: Journal of Materials Chemistry A HOT Papers

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D. Zhang, Y. Ji, Y. Cheng, X. Liu, Z. Xia, X. Liu, X. Liu, X. Yang and W. Huang, J. Mater. Chem. A , 2024, Accepted Manuscript , DOI: 10.1039/D4TA01679C

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