stem cell research resource paper

Articles will undergo the journal’s standard peer-review process  and are subject to all of the journal’s standard  policies . Articles will be added to the Collection as they are published.

The Editors have no competing interests with the submissions which they handle through the peer review process. The peer review of any submissions for which the Editors have competing interests is handled by another Editorial Board Member who has no competing interests.

NIH Stem Cell Information

Nih guidelines for human stem cell research.

SUMMARY: The National Institutes of Health (NIH) is hereby publishing final "National Institutes of Health Guidelines for Human Stem Cell Research" (Guidelines).

On March 9, 2009, President Barack H. Obama issued Executive Order 13505: Removing Barriers to Responsible Scientific Research Involving Human Stem Cells. The Executive Order states that the Secretary of Health and Human Services, through the Director of NIH, may support and conduct responsible, scientifically worthy human stem cell research, including human embryonic stem cell (hESC) research, to the extent permitted by law.

These Guidelines implement Executive Order 13505, as it pertains to extramural NIH-funded stem cell research, establish policy and procedures under which the NIH will fund such research, and helps ensure that NIH-funded research in this area is ethically responsible, scientifically worthy, and conducted in accordance with applicable law. Internal NIH policies and procedures, consistent with Executive Order 13505 and these Guidelines, will govern the conduct of intramural NIH stem cell research.

EFFECTIVE DATE: These Guidelines are effective on July 7, 2009.

SUMMARY OF PUBLIC COMMENTS ON DRAFT GUIDELINES: On April 23, 2009 the NIH published draft Guidelines for research involving hESCs in the Federal Register for public comment, 74 Fed. Reg. 18578 (April 23, 2009). The comment period ended on May 26, 2009.

The NIH received approximately 49,000 comments from patient advocacy groups, scientists and scientific societies, academic institutions, medical organizations, religious organizations, and private citizens. The NIH also received comments from members of Congress. This Notice presents the final Guidelines together with the NIH response to public comments that addressed provisions of the Guidelines.

Title of the Guidelines, Terminology, and Background :

Respondents felt the title of the NIH draft guidelines was misleading, in that it is entitled "National Institutes of Health Guidelines for Human Stem Cell Research," yet addresses only one type of human stem cell. The NIH notes that although the Guidelines pertain primarily to the donation of embryos for the derivation of hESCs, one Section also applies to certain uses of both hESCs and human induced pluripotent stem cells. Also, the Guidelines discuss applicable regulatory standards when research involving human adult stem cells or induced pluripotent stem cells constitutes human subject research. Therefore, the title of the Guidelines was not changed.

Respondents also disagreed with the definition of human embryonic stem cells in the draft Guidelines, and asked that the NIH define them as originating from the inner cell mass of the blastocyst. The NIH modified the definition to say that human embryonic stem cells "are cells that are derived from the inner cell mass of blastocyst stage human embryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers."

Financial Gain

Respondents expressed concern that derivers of stem cells might profit from the development of hESCs. Others noted that because the stem cells eligible for use in research using NIH funding under the draft Guidelines are those cells that are subject to existing patents, there will be insufficient competition in the licensing of such rights. These respondents suggested that this could inhibit research, as well as increase the cost of any future clinical benefits. The Guidelines do not address the distribution of stem cell research material. It is, however, the NIH's expectation that stem cell research materials developed with NIH funds, as well as associated intellectual property and data, will be distributed in accordance with the NIH’s existing policies and guidance, including "Sharing Biomedical Research Resources, Principles and Guidelines for Recipients of NIH Grants and Contracts" and "Best Practices for the Licensing of Genomic Inventions." http://www.ott.nih.gov/policy/policies_and_guidelines.aspx Even where such policies are not directly applicable, the NIH encourages others to refrain from imposing on the transfer of research tools, such as stem cells, any conditions that hinder further biomedical research. In addition, the Guidelines were revised to state that there should be documentation that "no payments, cash or in kind, were offered for the donated embryos."

Respondents were concerned that donor(s) be clearly "apprised up front by any researchers that financial gain may come from the donation and that the donor(s) should know up front if he/she will share in the financial gain." The Guidelines address this concern by asking that donor(s) was/were informed during the consent process that the donation was made without any restriction or direction regarding the individual(s) who may receive medical benefit from the use of the stem cells, such as who may be the recipients of cell transplants. The Guidelines also require that the donor(s) receive(s) information that the research was not intended to provide direct medical benefit to the donor(s); that the results of research using the hESCs may have commercial potential, and that the donor(s) would not receive financial or any other benefits from any such commercial development.

IRB Review under the Common Rule

Respondents suggested that the current regulatory structure of IRB review under the Common Rule (45 C.F.R. Part 46, Subpart A) addresses the core ethical principles needed for appropriate oversight of hESC derivation. They noted that IRB review includes a full review of the informed consent process, as well as a determination of whether individuals were coerced to participate in the research and whether any undue inducements were offered to secure their participation. These respondents urged the NIH to replace the specific standards to assure voluntary and informed consent in the draft Guidelines with a requirement that hESC research be reviewed and approved by an IRB, in conformance with 45 C.F.R. Part 46, Subpart A, as a prerequisite to NIH funding. Respondents also requested that the NIH create a registry of eligible hESC lines to avoid burdensome and repetitive assurances from multiple funding applicants. The NIH agrees that the IRB system of review under the Common Rule provides a comprehensive framework for the review of the donation of identifiable human biological materials for research. However, in the last several years, guidelines on hESC research have been issued by a number of different organizations and governments, and different practices have arisen around the country and worldwide, resulting in a patchwork of standards. The NIH concluded that employing the IRB review system for the donation of embryos would not ameliorate stated concerns about variations in standards for hESC research and would preclude the establishment of an NIH registry of hESCs eligible for NIH funding, because there would be no NIH approval of particular hESCs. To this end and response to comments, these Guidelines articulate policies and procedures that will allow the NIH to create a Registry. These Guidelines also provide scientists who apply for NIH funding with a specific set of standards reflecting currently recognized ethical principles and practices specific to embryo donation that took place on or after the issuance of the Guidelines, while also establishing procedures for the review of donations that took place before the effective date of the Guidelines.

Federal Funding Eligibility of Human Pluripotent Cells from Other Sources

Respondents suggested that the allowable sources of hESCs potentially available for federal funding be expanded to include hESC lines from embryos created expressly for research purposes, and lines created, or pluripotent cells derived, following parthenogenesis or somatic cell nuclear transfer (SCNT). The Guidelines allow for funding of research using hESCs derived from embryos created using in vitro fertilization (IVF) for reproductive purposes and no longer needed for these purposes, assuming the research has scientific merit and the embryos were donated after proper informed consent was obtained from the donor(s). The Guidelines reflect the broad public support for federal funding of research using hESCs created from such embryos based on wide and diverse debate on the topic in Congress and elsewhere. The use of additional sources of human pluripotent stem cells proposed by the respondents involve complex ethical and scientific issues on which a similar consensus has not emerged. For example, the embryo-like entities created by parthenogenesis and SCNT require women to donate oocytes, a procedure that has health and ethical implications, including the health risk to the donor from the course of hormonal treatments needed to induce oocyte production.

Respondents noted that many embryos undergo Pre-implantation Genetic Diagnosis (PGD). This may result in the identification of chromosomal abnormalities that would make the embryos medically unsuitable for clinical use. In addition, the IVF process may also produce embryos that are not transferred into the uterus of a woman because they are determined to be not appropriate for clinical use. Respondents suggested that hESCs derived from such embryos may be extremely valuable for scientific study, and should be considered embryos that were created for reproductive purposes and were no longer needed for this purpose . The NIH agrees with these comments. As in the draft, the final Guidelines allow for the donation of embryos that have undergone PGD.

Donation and Informed Consent

Respondents commented in numerous ways that the draft Guidelines are too procedurally proscriptive in articulating the elements of appropriate informed consent documentation. This over-reliance on the specific details and format of the informed consent document, respondents argued, coupled with the retroactive application of the Guidelines to embryos already donated for research, would result in a framework that fails to appreciate the full range of factors contributing to the complexity of the informed consent process. For example, respondents pointed to several factors that were precluded from consideration by the proposed Guidelines, such as contextual evidence of the consent process, other established governmental frameworks (representing local and community influences), and the changing standards for informed consent in this area of research over time. Respondents argued that the Guidelines should be revised to allow for a fuller array of factors to be considered in determining whether the underlying ethical principle of voluntary informed consent had been met. In addition to these general issues, many respondents made the specific recommendation that all hESCs derived before the final Guidelines were issued be automatically eligible for Federal funding without further review, especially those eligible under prior Presidential policy, i.e., "grandfathered." The final Guidelines seek to implement the Executive Order by issuing clear guidance to assist this field of science to advance and reach its full potential while ensuring adherence to strict ethical standards. To this end, the NIH is establishing a set of conditions that will maximize ethical oversight, while ensuring that the greatest number of ethically derived hESCs are eligible for federal funding. Specifically, for embryos donated in the U.S. on or after the effective date of the Guidelines, the only way to establish eligibility will be to either use hESCs listed on the NIH Registry, or demonstrate compliance with the specific procedural requirements of the Guidelines by submitting an assurance with supporting information for administrative review by the NIH. Thus, for future embryo donations in the United States, the Guidelines articulate one set of procedural requirements. This responds to concerns regarding the patchwork of requirements and guidelines that currently exist.

However, the NIH is also cognizant that in the more than a decade between the discovery of hESCs and today, many lines were derived consistent with ethical standards and/or guidelines developed by various states, countries, and other entities such as the International Society for Stem Cell Research (ISSCR) and the National Academy of Sciences (NAS). These various policies have many common features, rely on a consistent ethical base, and require an informed consent process, but they differ in details of implementation. For example, some require specific wording in a written informed consent document, while others do not. It is important to recognize that the principles of ethical research, e.g., voluntary informed consent to participation, have not varied in this time period, but the requirements for implementation and procedural safeguards employed to demonstrate compliance have evolved. In response to these concerns, the Guidelines state that applicant institutions wishing to use hESCs derived from embryos donated prior to the effective date of the Guidelines may either comply with Section II (A) of the Guidelines or undergo review by a Working Group of the Advisory Committee to the Director (ACD). The ACD, which is a chartered Federal Advisory Committee Act (FACA) committee, will advise NIH on whether the core ethical principles and procedures used in the process for obtaining informed consent for the donation of the embryo were such that the cell line should be eligible for NIH funding. This Working Group will not undertake a de novo evaluation of ethical standards, but will consider the materials submitted in light of the principles and points to consider in the Guidelines, as well as 45 C.F.R. Part 46 Subpart A. Rather than “grandfathering,” ACD Working Group review will enable pre-existing hESCs derived in a responsible manner to be eligible for use in NIH funded research.

In addition, for embryos donated outside the United States prior to the effective date of these Guidelines, applicants may comply with either Section II (A) or (B). For embryos donated outside of the United States on or after the effective date of the Guidelines, applicants seeking to determine eligibility for NIH research funding may submit an assurance that the hESCs fully comply with Section II (A) or submit an assurance along with supporting information, that the alternative procedural standards of the foreign country where the embryo was donated provide protections at least equivalent to those provided by Section II (A) of these Guidelines. These materials will be reviewed by the NIH ACD Working Group, which will recommend to the ACD whether such equivalence exists. Final decisions will be made by the NIH Director. This special consideration for embryos donated outside the United States is needed because donation of embryos in foreign countries is governed by the laws and policies of the respective governments of those nations. Although such donations may be responsibly conducted, such governments may not or cannot change their national donation requirements to precisely comply with the NIH Guidelines. The NIH believes it is reasonable to provide a means for reviewing such hESCs because ethically derived foreign hESCs constitute an important scientific asset for the U.S.

Respondents expressed concern that it might be difficult in some cases to provide assurance that there was a "clear separation" between the prospective donor(s)’ decision to create embryos for reproductive purposes and the donor(s)’ decision to donate the embryos for research purposes. These respondents noted that policies vary at IVF clinics, especially with respect to the degree to which connections with researchers exist. Respondents noted that a particular clinic’s role may be limited to the provision of contact information for researchers. A clinic that does not have any particular connection with research would not necessarily have in place a written policy articulating the separation contemplated by the Guidelines. Other respondents noted that embryos that are determined not to be suitable for medical purposes, either because of genetic defects or other concerns, may be donated prior to being frozen. In these cases, it is possible that the informed consent process for the donation might be concurrent with the consent process for IVF treatment. Respondents also noted that the initial consent for IVF may contain a general authorization for donating embryos in excess of clinical need, even though a more detailed consent is provided at the actual time of donation. The NIH notes that the Guidelines specifically state that consent should have been obtained at the time of donation, even if the potential donor(s) had given prior indication of a general intent to donate embryos in excess of clinical need for the purposes of research. Accordingly, a general authorization for research donation when consenting for reproductive treatment would comply with the Guidelines, so long as specific consent for the donation is obtained at the time of donation. In response to comments regarding documentation necessary to establish a separation between clinical and research decisions, the NIH has changed the language of the Guidelines to permit applicant institutions to submit consent forms, written policies or other documentation to demonstrate compliance with the provisions of the Guidelines. This change should provide the flexibility to accommodate a range of practices, while adhering to the ethical principles intended.

Some respondents want to require that the IVF physician and the hESC researcher should be different individuals, to prevent conflict of interest. Others say they should be the same person, because people in both roles need to have detailed knowledge of both areas (IVF treatment and hESC research). There is also a concern that the IVF doctor will create extra embryos if he/she is also the researcher. As a general matter, the NIH believes that the doctor and the researcher seeking donation should be different individuals. However, this is not always possible, nor is it required, in the NIH's view, for ethical donation.

Some respondents want explicit language (in the Guidelines and/or in the consent) stating that the embryo will be destroyed when the inner cell mass is removed. In the process of developing guidelines, the NIH reviewed a variety of consent forms that have been used in responsible derivations. Several had extensive descriptions of the process and the research to be done, going well beyond the minimum expected, yet they did not use these exact words. Given the wide variety and diversity of forms, as well as the various policy, statutory and regulatory obligations individual institutions face, the NIH declines to provide exact wording for consent forms, and instead endorses a robust informed consent process where all necessary details are explained and understood in an ongoing, trusting relationship between the clinic and the donor(s).

Respondents asked for clarification regarding the people who must give informed consent for the donation of embryos for research. Some commenters suggested that NIH should require consent from the gamete donors, in cases where those individuals may be different than the individuals seeking reproductive treatment. The NIH requests consent from “the individual(s) who sought reproductive treatment” because this/these individual(s) is/are responsible for the creation of the embryo(s) and, therefore, its/their disposition. With regard to gamete donation, the risks are associated with privacy and, as such, are governed by requirements of the Common Rule, where applicable.

Respondents also requested clarification on the statement in the draft Guidelines noting that "although human embryonic stem cells are derived from embryos, such stem cells are not themselves human embryos." For the purpose of NIH funding, an embryo is defined by Section 509, Omnibus Appropriations Act, 2009, Pub. L. 111-8, 3/11/09, otherwise known as the Dickey Amendment, as any organism not protected as a human subject under 45 C.F.R. Part 46 that is derived by fertilization, parthenogenesis, cloning or any other means from one or more human gametes or human diploid cells. Since 1999, the Department of Health and Human Services (HHS) has consistently interpreted this provision as not applicable to research using hESCs, because hESCs are not embryos as defined by Section 509. This long-standing interpretation has been left unchanged by Congress, which has annually reenacted the Dickey Amendment with full knowledge that HHS has been funding hESC research since 2001. These guidelines therefore recognize the distinction, accepted by Congress, between the derivation of stem cells from an embryo that results in the embryo’s destruction, for which federal funding is prohibited, and research involving hESCs that does not involve an embryo nor result in an embryo’s destruction, for which federal funding is permitted.

Some respondents wanted to ensure that potential donor(s) are either required to put their "extra" embryos up for adoption before donating them for research, or are at least offered this option. The Guidelines require that all the options available in the health care facility where treatment was sought pertaining to the use of embryos no longer needed for reproductive purposes were explained to the potential donor(s). Since not all IVF clinics offer the same services, the healthcare facility is only required to explain the options available to the donor(s) at that particular facility.

Commenters asked that donor(s) be made aware of the point at which their donation decision becomes irrevocable. This is necessary because if the embryo is de-identified, it may be impossible to stop its use beyond a certain point. The NIH agrees with these comments and revised the Guidelines to require that donor(s) should have been informed that they retained the right to withdraw consent for the donation of the embryo until the embryos were actually used to derive embryonic stem cells or until information which could link the identity of the donor(s) with the embryo was no longer retained, if applicable.

Medical Benefits of Donation

Regarding medical benefit, respondents were concerned that the language of the Guidelines should not somehow eliminate a donor's chances of benefitting from results of stem cell research. Respondents noted that although hESCs are not currently being used clinically, it is possible that in the future such cells might be used for the medical benefit of the person donating them. The Guidelines are meant to preclude individuals from donating embryos strictly for use in treating themselves only or from donating but identifying individuals or groups they do or do not want to potentially benefit from medical intervention using their donated cells. While treatment with hESCs is one of the goals of this research, in practice, years of experimental work must still be done before such treatment might become routinely available. The Guidelines are designed to make it clear that immediate medical benefit from a donation is highly unlikely at this time. Importantly, it is critical to note that the Guidelines in no way disqualify a donor from benefitting from the medical outcomes of stem cell research and treatments that may be developed in the future.

Monitoring and Enforcement Actions

Respondents have expressed concern about the monitoring of funded research and the invocation of possible penalties for researchers who do not follow the Guidelines. A grantee's failure to comply with the terms and conditions of award, including confirmed instances of research misconduct, may cause the NIH to take one or more enforcement actions, depending on the severity and duration of the non-compliance. For example, the following actions may be taken by the NIH when there is a failure to comply with the terms and conditions of any award: (1) Under 45 CFR 74.14, the NIH can impose special conditions on an award, including but not limited to increased oversight/monitoring/reporting requirements for an institution, project, or investigator; and (2) under 45 CFR 74.62 the NIH may impose enforcement actions, including but not limited to withholding funds pending correction of the problem, disallowing all or part of the costs of the activity that was not in compliance, withholding further awards for the project, or suspending or terminating all or part of the funding for the project. Individuals and institutions may be debarred from eligibility for all Federal financial assistance and contracts under 2 CFR Part 376 and 48 CFR Subpart 9.4, respectively. The NIH will undertake all enforcement actions in accordance with applicable statutes, regulations, and policies.

National Institutes of Health Guidelines for Research Using Human Stem Cells

These Guidelines apply to the expenditure of National Institutes of Health (NIH) funds for research using human embryonic stem cells (hESCs) and certain uses of induced pluripotent stem cells (See Section IV). The Guidelines implement Executive Order 13505.

Long-standing HHS regulations for Protection of Human Subjects, 45 C.F.R. 46, Subpart A establish safeguards for individuals who are the sources of many human tissues used in research, including non-embryonic human adult stem cells and human induced pluripotent stem cells. When research involving human adult stem cells or induced pluripotent stem cells constitutes human subject research, Institutional Review Board review may be required and informed consent may need to be obtained per the requirements detailed in 45 C.F.R. 46, Subpart A. Applicants should consult http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html .

It is also important to note that the HHS regulation, Protection of Human Subjects , 45 C.F.R. Part 46, Subpart A, may apply to certain research using hESCs. This regulation applies, among other things, to research involving individually identifiable private information about a living individual, 45 C.F.R. § 46.102(f). The HHS Office for Human Research Protections (OHRP) considers biological material, such as cells derived from human embryos, to be individually identifiable when they can be linked to specific living individuals by the investigators either directly or indirectly through coding systems. Thus, in certain circumstances, IRB review may be required, in addition to compliance with these Guidelines. Applicant institutions are urged to consult OHRP guidances at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

To ensure that the greatest number of responsibly derived hESCs are eligible for research using NIH funding, these Guidelines are divided into several sections, which apply specifically to embryos donated in the U.S. and foreign countries, both before and on or after the effective date of these Guidelines. Section II (A) and (B) describe the conditions and review processes for determining hESC eligibility for NIH funds. Further information on these review processes may be found at www.NIH.gov . Sections IV and V describe research that is not eligible for NIH funding.

These guidelines are based on the following principles:

• Responsible research with hESCs has the potential to improve our understanding of human health and illness and discover new ways to prevent and/or treat illness.
• Individuals donating embryos for research purposes should do so freely, with voluntary and informed consent.

As directed by Executive Order 13505, the NIH shall review and update these Guidelines periodically, as appropriate.

For the purpose of these Guidelines, "human embryonic stem cells (hESCs)" are cells that are derived from the inner cell mass of blastocyst stage human embryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers. Although hESCs are derived from embryos, such stem cells are not themselves human embryos. All of the processes and procedures for review of the eligibility of hESCs will be centralized at the NIH as follows:

• that were created using in vitro fertilization for reproductive purposes and were no longer needed for this purpose;
• that were donated by individuals who sought reproductive treatment (hereafter referred to as "donor(s)") and who gave voluntary written consent for the human embryos to be used for research purposes; and
• All options available in the health care facility where treatment was sought pertaining to the embryos no longer needed for reproductive purposes were explained to the individual(s) who sought reproductive treatment.
• No payments, cash or in kind, were offered for the donated embryos.
• Policies and/or procedures were in place at the health care facility where the embryos were donated that neither consenting nor refusing to donate embryos for research would affect the quality of care provided to potential donor(s).
• Decisions related to the creation of human embryos for reproductive purposes should have been made free from the influence of researchers proposing to derive or utilize hESCs in research. The attending physician responsible for reproductive clinical care and the researcher deriving and/or proposing to utilize hESCs should not have been the same person unless separation was not practicable.
• At the time of donation, consent for that donation should have been obtained from the individual(s) who had sought reproductive treatment. That is, even if potential donor(s) had given prior indication of their intent to donate to research any embryos that remained after reproductive treatment, consent for the donation for research purposes should have been given at the time of the donation.
• Donor(s) should have been informed that they retained the right to withdraw consent for the donation of the embryo until the embryos were actually used to derive embryonic stem cells or until information which could link the identity of the donor(s) with the embryo was no longer retained, if applicable.
• that the embryos would be used to derive hESCs for research;
• what would happen to the embryos in the derivation of hESCs for research;
• that hESCs derived from the embryos might be kept for many years;
• that the donation was made without any restriction or direction regarding the individual(s) who may receive medical benefit from the use of the hESCs, such as who may be the recipients of cell transplants.;
• that the research was not intended to provide direct medical benefit to the donor(s);
• that the results of research using the hESCs may have commercial potential, and that the donor(s) would not receive financial or any other benefits from any such commercial development;
• whether information that could identify the donor(s) would be available to researchers.
• By complying with Section II (A) of the Guidelines; or

The materials submitted must demonstrate that the hESCs were derived from human embryos: 1) that were created using in vitro fertilization for reproductive purposes and were no longer needed for this purpose; and 2) that were donated by donor(s) who gave voluntary written consent for the human embryos to be used for research purposes.

The Working Group will review submitted materials, e.g., consent forms, written policies or other documentation, taking into account the principles articulated in Section II (A), 45 C.F.R. Part 46, Subpart A, and the following additional points to consider. That is, during the informed consent process, including written or oral communications, whether the donor(s) were: (1) informed of other available options pertaining to the use of the embryos; (2) offered any inducements for the donation of the embryos; and (3) informed about what would happen to the embryos after the donation for research.

• For embryos donated outside the United States before the effective date of these Guidelines, applicants may comply with either Section II (A) or (B). For embryos donated outside of the United States on or after the effective date of the Guidelines, applicants seeking to determine eligibility for NIH research funding may submit an assurance that the hESCs fully comply with Section II (A) or submit an assurance along with supporting information, that the alternative procedural standards of the foreign country where the embryo was donated provide protections at least equivalent to those provided by Section II (A) of these Guidelines. These materials will be reviewed by the NIH ACD Working Group , which will recommend to the ACD whether such equivalence exists. Final decisions will be made by the NIH Director.
• NIH will establish a new Registry listing hESCs eligible for use in NIH funded research. All hESCs that have been reviewed and deemed eligible by the NIH in accordance with these Guidelines will be posted on the new NIH Registry.

Prior to the use of NIH funds, funding recipients should provide assurances, when endorsing applications and progress reports submitted to NIH for projects using hESCs, that the hESCs are listed on the NIH registry.

This section governs research using hESCs and human induced pluripotent stem cells, i.e., human cells that are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers. Although the cells may come from eligible sources, the following uses of these cells are nevertheless ineligible for NIH funding, as follows:

• Research in which hESCs (even if derived from embryos donated in accordance with these Guidelines) or human induced pluripotent stem cells are introduced into non-human primate blastocysts.
• Research involving the breeding of animals where the introduction of hESCs (even if derived from embryos donated in accordance with these Guidelines) or human induced pluripotent stem cells may contribute to the germ line.
• NIH funding of the derivation of stem cells from human embryos is prohibited by the annual appropriations ban on funding of human embryo research (Section 509, Omnibus Appropriations Act, 2009, Pub. L. 111-8, 3/11/09), otherwise known as the Dickey Amendment.
• Research using hESCs derived from other sources, including somatic cell nuclear transfer, parthenogenesis, and/or IVF embryos created for research purposes, is not eligible for NIH funding.

Raynard S Kington, M.D., Ph.D. Acting Director, NIH

Stem Cell Research

Lab resource: stem cell line, last update 5 february 2020.

This Special Issue collates Lab Resource articles published in Stem Cell Research. Lab Resource articles detail the establishment of new pluripotent stem cell lines derived from embryos, generated by SCNT and reprogramming or the establishment of genetically modified stem cell sub-lines. For more information on requirements and submission of this article type please go to https://www.journals.elsevier.com/stem-cell-research/lab-resources

Actions for selected articles

Select all / Deselect all

Derivation of the human embryonic stem cell line RCe006-A (RC-2)

Generation of spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cell line sca3.a11, derivation of the human embryonic stem cell line rce007-a (rc-3), generation of spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cell line sca3.b11, derivation of hybrid es cell lines from two different strains of mice, genomic imprinting defect in zfp57 mutant ips cell lines, generation of induced pluripotent stem cells (ipscs) from an alzheimer's disease patient carrying a m146i mutation in psen1, generation of induced pluripotent stem cells (ipscs) from an alzheimer's disease patient carrying an a79v mutation in psen1, induced pluripotent stem cells derived from bernard-soulier syndrome patient's peripheral blood cells with a p.phe55ser mutation in the gpix gene, a feeder- and xeno-free human induced pluripotent stem cell line obtained from primary human dermal fibroblasts with epigenetic repression of reprogramming factors expression: gpcci001-a, generation of sibling-matched induced pluripotent stem cell lines from spinal and bulbar muscular atrophy patients, generation of an induced pluripotent stem cell line that mimics the disease phenotypes from a patient with fanconi anemia by conditional complementation, generation and characterization of two ipsc lines from human epicardium-derived cells, reporting on methods to generate and purify rodent and human oligodendrocytes from different sources, generation of human induced pluripotent stem cell lines from human dermal fibroblasts using a modified rna system, generation of an ipsc line from a patient with gtp cyclohydrolase 1 ( gch1 ) deficiency: hdmc0061i-gch1, generation of ipsc line epihuvec from human umbilical vein endothelial cells, generation of poikiloderma with neutropenia (pn) induced pluripotent stem cells (ipscs), reprogramming of mouse amniotic fluid cells using a piggybac transposon system, generation and characterization of the human ipsc line pbmc1-ips4f1 from adult peripheral blood mononuclear cells, derivation of genea015 human embryonic stem cell line, derivation of genea016 human embryonic stem cell line, derivation of genea043 human embryonic stem cell line, derivation of genea042 human embryonic stem cell line, derivation of genea047 human embryonic stem cell line, derivation of genea057 human embryonic stem cell line, derivation of genea052 human embryonic stem cell line, episomal plasmid-based generation of induced pluripotent stem cells from fetal femur-derived human mesenchymal stromal cells, generation and characterization of human ipsc lines derived from a primary hyperoxaluria type i patient with p.i244t mutation, generation of induced pluripotent stem cells (ipscs) from an alzheimer's disease patient carrying a l150p mutation in psen-1, generation of a human ipsc line from a patient with a defect of intergenomic communication, lymphoblast-derived integration-free ips cell line from a 65-year-old alzheimer's disease patient expressing the trem2 p.r47h variant, generation of a human induced pluripotent stem cell line from urinary cells of a healthy donor using an integration free vector, generation of a human ipsc line from a patient with a mitochondrial encephalopathy due to mutations in the gfm1 gene, derivation of the human embryonic stem cell line rcm1, withdrawn: generation of a human induced pluripotent stem cell line from urinary cells of a healthy donor using integration free sendai technology, generation of human embryonic stem cell line expressing green fluorescent protein, generation of kcl037 clinical grade human embryonic stem cell line, generation of kcl038 clinical grade human embryonic stem cell line, generation of human ipsc line grx-mcips4f-a2 from adult peripheral blood mononuclear cells (pbmcs) with spanish genetic background, induced pluripotent stem cells (ipscs) derived from frontotemporal dementia patient's peripheral blood mononuclear cells, human amniotic epithelial cells as feeder layer to derive and maintain human embryonic stem cells from poor-quality embryos, derivation of lif-independent mouse ips cells with modified oct4, derivation of genea002 human embryonic stem cell line, generation of an ips cell line from bone marrow derived mesenchymal stromal cells from an elderly patient, development of buffalo ( bubalus bubalis ) embryonic stem cell lines from somatic cell nuclear transferred blastocysts, generation of ipsc lines from primary human chorionic villi cells, human embryonic stem cells derived from abnormal blastocyst donated by marfan syndrome patient, generation of ipsc lines from a nijmegen breakage syndrome patient, generation of ipsc lines from primary human amniotic fluid cells, generation of human control ips cell line chopwt9 from healthy adult peripheral blood mononuclear cells, transgene-free human induced pluripotent stem cell line (hs5-sv.hips) generated from cesarean scar-derived fibroblasts, generation of kcl032 clinical grade human embryonic stem cell line, lymphoblast-derived integration-free ips cell line from a 69-year-old male, generation of integration free induced pluripotent stem cells from fibrodysplasia ossificans progressiva (fop) patients from urine samples, human embryonic stem cells derived from abnormal blastocyst donated by glucose-6-phosphate dehydrogenase deficiency patient, generation of a human ipsc line from a patient with leigh syndrome, induced pluripotent stem cells (ipscs) derived from a patient with frontotemporal dementia caused by a r406w mutation in microtubule-associated protein tau (mapt), induced pluripotent stem cells (ipscs) derived from a pre-symptomatic carrier of a r406w mutation in microtubule-associated protein tau (mapt) causing frontotemporal dementia, generation of ipsc line ipsc-fh2.1 in hypoxic conditions from human foreskin fibroblasts, generation of spinocerebellar ataxia type 2 patient-derived ipsc line h271, generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived ipsc line h271, generation of spinocerebellar ataxia type 2 patient-derived ipsc line h266, derivation of human embryonic stem cell from spinal muscular atrophy patient, generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived ipsc line h196, generation of transgenic human embryonic stem cell line bjnhem20–ociad1-ov, generation of kcl031 clinical grade human embryonic stem cell line, generation of kcl034 clinical grade human embryonic stem cell line, generation of kcl040 clinical grade human embryonic stem cell line, generation of kcl039 clinical grade human embryonic stem cell line, generation of a heterozygous knockout human embryonic stem cell line for the ociad1 locus using crispr/cas9 mediated targeting: bjnhem20-ociad1-crispr-39, induced pluripotent stem cells (ipscs) derived from a patient with frontotemporal dementia caused by a p301l mutation in microtubule-associated protein tau (mapt), generation of ipsc line hel24.3 from human neonatal foreskin fibroblasts, generation of ipsc line hel47.2 from healthy human adult fibroblasts, derivation of human induced pluripotent stem cells through continued exposure of oct4-induced plastic human fibroblasts to reprogramming media, generation and characterization of human ipsc line generated from mesenchymal stem cells derived from adipose tissue, generation of kcl016 research grade human embryonic stem cell line carrying a mutation in vhl gene, episomal-based generation of an ips cell line from human fetal foreskin fibroblasts, generation of a human control ipsc line with a european mitochondrial haplogroup u background, generation of human ips cell line ihfib3.2 from dermal fibroblasts, generation of ipsc line mu011.a-hips from homozygous α-thalassemia fetal skin fibroblasts, generation of integration-free induced pluripotent stem cells from a patient with familial mediterranean fever (fmf), derivation of huntington disease affected genea090 human embryonic stem cell line, generation of kcl036 research grade human embryonic stem cell line carrying a mutation in the htt gene, generation of an induced pluripotent stem cell line from a patient with hereditary multiple endocrine neoplasia 2a (men2a) syndrome with ret mutation, murine transgenic ips cell line for monitoring and selection of cardiomyocytes, generation of an induced pluripotent stem cell line from a patient with chronic myeloid leukemia (cml) resistant to targeted therapies, generation of a gene-corrected isogenic control cell line from an alzheimer's disease patient ipsc line carrying a a79v mutation in psen1, integration-free erythroblast-derived human induced pluripotent stem cells (ipscs) from an individual with ataxia-telangiectasia (a-t), generation of a human induced pluripotent stem cell (ipsc) line from a patient carrying a p33t mutation in the pdx1 gene, generation of a human induced pluripotent stem cell (ipsc) line from a patient with family history of diabetes carrying a c18r mutation in the pdx1 gene, induced pluripotent stem cells (ipsc) created from skin fibroblasts of patients with prader-willi syndrome (pws) retain the molecular signature of pws, generation of hexa -deficient hipscs from fibroblasts of a tay-sachs disease patient, generation of induced pluripotent stem cells (ipscs) from a retinoblastoma patient carrying a c.2663g > a mutation in rb1 gene, generation of a human induced pluripotent stem cell line from urinary cells of a healthy donor using integration free sendai virus technology, a human ve-cadherin-tdtomato and cd43-green fluorescent protein dual reporter cell line for study endothelial to hematopoietic transition, generation, genome edition and characterization of ipsc lines from a patient with coenzyme q 10 deficiency harboring a heterozygous mutation in coq4 gene, generation of a tle1 homozygous knockout human embryonic stem cell line using crispr-cas9, generation of a tle3 heterozygous knockout human embryonic stem cell line using crispr-cas9, generation of induced pluripotent stem cells (ipscs) from a hereditary spastic paraplegia patient carrying a homozygous y275x mutation in cyp7b1 (spg5).

ISSN: 1873-5061

Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Mice and stem cell research

What are stem cells and why are they important?

Where are they collected from?

Stem cells are found at all stage in life, but for practical purposes are regarded as being from three stages of development: early embryos, fetuses, and adults. Scientists collect embryonic stem cells from the inner layer of early embryos, usually of rodents, when they are about five days old and consist of a double-layered ball of cells. These embryos can be created using test tube (in-vitro) fertilisation. The cells can be implanted into other animals, even of a different species, without being rejected by the body's immune system. Fetal stem cells are collected from blood taken from the placental end of the umbilical cord. There is thus a plentiful supply of cells that are normally discarded. Although each sample is relatively small, it is possible to make the stem cells contained therein multiply. Adult stem cells are harder to find, with the notable exception of bone marrow cells that give rise to the different kinds of blood cells. Bone marrow stem cells can be induced to proliferate by injecting a growth factor. This makes them spill over into the bloodstream, from  where they are easily collected. Skin stem cells have been isolated in mice, and have been used to grow new skin in recipient mice. Embryonic stem cells give rise to any of the 216 kinds of cell in the body, but adult stem cells are more specialised—for example, bone  marrow stem cells normally only form blood cells. However, they seem to 'change direction' (transdifferentiate) when injected into other tissues such as heart and brain, and some research is aimed at growing stem cells in the laboratory and 'taking back' (dedifferentiating) adult stem cells to become more versatile and less able to provoke an immune reaction. We know that stem cells from adult mice, when grown in mouse or chick embryos, revert to an unspecialised state and become identical to the surrounding tissue, depending on which cell layer they are injected into. The extent to which stem cells transdifferentiate is uncertain; some of them also seem to fuse with host cells, forming pluripotent cells, and recent (2004) debate and experiment has aimed at finding out the extent of these two factors. In October 2004 a third quality of stem cells was discovered. Scientists at the University of California in San Diego found, amazingly, that when embryonic stem cells — just 15 cells, taken from normal mice — are injected into the abdomen of mice pregnant with fetuses carrying a genetic heart defect, the pups are born with normal hearts. The stem cells do not cross the placenta into the fetuses, but secrete hormone-like chemicals that play an essential role of normal growth and development. to their chemical action. Two of these chemicals have been identified — they are called IGF1 and WNT5a.

Stem cell transplants today

Following successful animal research, stem cell transplants are now  routine in the treatment of several types of cancer. They enable patients to undergo high-dose chemotherapy despite its toxic effect on bone marrow, as the patient can afterwards be given their own or a donor’s bone marrow stem cells, which engraft back into the bone. A further development, pioneered in animals and now entering clinical practice, is to use donor stem cells to treat certain serious and often fatal inherited blood disorders such as Fanconi anaemia, severe combined immune deficiency, and, potentially, sickle cell disease and thalassaemia. The patient’s own bone marrow, which produces diseased blood cells, is destroyed using high-dose chemotherapy and replaced by donor stem cells.

Bone marrow stem cells for tissues other than blood

Research has aimed to replace various missing tissues using bone marrow stem cells, and there seems to be evidence that this happens at least some of the time. The problem researchers have faced is knowing whether, some months later, any of the cells in the tissue being studied (usually heart or brain) is derived from the injected stem cells. The presence of apparently newly-generated tissue could also be due to the body’s existing capacity to repair itself or to environmental influences, which include oxygen lack and convulsions. Even learning and exercise can stimulate new nerve cell production. One way round this problem is to inject male cells into female bodies, wait a few months, and see if the brain or other organ contains Y-chromosomes, which are only normally found in males. It is also essential to check whether the Y-chromosomes are in new nerve cells and are not —as sometimes happens—merely the product of fusion of the injected stem cells with existing cells. Scientists have developed techniques to do this. A further problem is that a wait of six months between giving the transplant and killing a rodent for study represents a quarter of its lifespan.

The heart, blood vessels, and blood

During heart attacks — myocardial infarction — there is cell death in  the area deprived of oxygen. Early (2001) research in rats and mice  suggested that when bone marrow stem cells were injected into the heart, new heart muscle cells grew. It was then tried in humans, and  clinicians thought that heart muscle was regenerated: the patients' heart seemed stronger and it was presumed that this was due to new muscle formation. In April 2004, two papers in the prestigious science journal Nature challenged these observations and the science underpinning them. Using state-of-the-art genetic tools, they discovered that bone marrow stem cells showed little or no capacity to turn into heart muscle. Instead, they turned into blood cells. Any functional improvement, they said, seems to have been caused by growth of new blood vessels, which has proved an unexpected side effect of treatment. In view of the potential hazards of mistaken cellular identity, reports of bone marrow stem cell versatility are now undergoing rigorous scrutiny. Better, but mixed, results came from research using muscle stem cells. When patients’ hearts were injects with their own muscle stem  cells, there was an over-riding improvement in heart function in most  patients, but some developed an irregular heartbeat, probably because the transplanted cells failed to become electrically linked to the rest of the heart. The best animal results yet (May 2004) came when embryonic stem cells were transplanted within a man-made 3D structure into damaged hearts of rodents which had suffered heart attacks. In the same month there were reports of successful human grafts, where it was shown that new heart cells were derived from injected umbilical cord stem cells. In animals, fetal heart cells graft easily into the heart, adopt the identity of adult heart cells, and become electrically coupled. However, their use in humans is ethically problematic. The search is now on for heart precursor cells and to discover the signals that guide the way they migrate, renew themselves, and become adult heart cells.

Making new muscle

New muscle cells have been formed in mouse muscle in the test-tube, and in living mice. In both cases the cells were reprogrammed by signals from surrounding cells, suggesting that adult tissues may be able to instruct transplanted cells to adopt the fates appropriate to their new location. Muscle regeneration has also resulted from injecting several types of stem cells — from bone marrow, from human knee joints, and from newborn mouse muscles — repairing damage similar to muscular dystrophy. Injured muscle seems to send distress signals around the body that summon the cells. But there are still doubts about whether adult stem cells can be used to provide effective treatments for diseases such as muscular dystrophy.

The brain and nervous system

The brain is immune privileged, which means that it does not reject cells from other animals or even other species, and this makes it a prime target for stem cell therapy. Fetal brain stem cells are relatively easy to collect and grow in the laboratory, and can divide indefinitely with no tendency to tumour growth. Research to date shows similar problems to that of heart research. Stem cells transplants have improved (but not cured) most (but not all) mice with Parkinson's, stroke, EAE (an induced form of multiple sclerosis) spinal cord injury, motor neurone disease and other conditions. Some of the injected stem cells create an environment that protects and aids the survival of the host nerve cells. In the spinal cord, only a tiny proportion of injected cells become new motor nerves that penetrate muscle. In normal brains after injury nerve stem cells cluster round the injury site and generate new stem cells, though it is self-evident that they do not produce sufficient to fully repair the damage done. In the eye, injected stem cells attach to a type of retinal cell called astrocytes. However, unless they are genetically modified, they form new blood vessels, which can obstruct clear vision. In May 2004 it was reported that three cancer patients, all female, who had received stem cell transplants from their brothers formed new brain support cells. The new cells contained Y-chromosomes, which proves they were of male origin, but the findings do not rule out fusion between bone marrow and other stem cells. Purkinje nerve cells in the cerebellum can fuse with bone marrow cells in both mice and humans.

Digestive organ diseases; diabetes

Research in rats and mice shows that pancreatic, liver, and bone marrow stem cells can transform into insulin-producing cells. Stem cell research may also cure Hirschprung disease, a genetic condition wherein a defect stops nerve stem cells forming nerves that control the small intestine. With diabetes, some researchers have found that bone marrow stem cells transdifferentiated into pancreatic beta cells, whereas other research teams have failed to see this. In July 2004 The Lancet commented: "As in every emerging field in biology, early reports seem conflicting and confusing. Embryonic and adult stem cells are potential sources for [pancreatic] beta-cell replacement and merit further scientific investigation. Discrepancies between different results need to be reconciled. Fundamental processes in determining the differentiation pathways of stem cells need to be elucidated, so that rigorous and reliable differentiation protocols can be established. Encouraging studies in rodent models may ultimately set the stage of large-animal studies and translational investigation."

Further information

The Royal Society policy pages on cloning and stem cells , includes official statements, comprehensive information and links. Edinburgh University Institute for Stem Cell Research answers questions such as What are stem cells? and Why are scientists so interested in them? The Cambridge Stem Cell Research Institute opened in June 2004. The Medical Research Council's booklet titled Stem cells focuses on MRC-funded research into stem cells, including the exciting potential these have for repairing damaged body tissues and replacing them with healthy new cells. The National Institute for Medical Research has a 2001 "Mill Hill Essay" on stem cell therapy and research. Use of human stem cells in research raises ethical, legal, religious, and policy questions which were addressed in a 1999 report of the American Association for the Advancement of Science and the Institute for Civil Society . Mice in the world of stem cell biology , Geraldine Guasch & Elaine Fuchs, 2005, Nature Genetics supplement, 37, 1201. Stem Cells. Stem Cell Science in the UK (2008) Human Tissue Authority. Hope and hype, an analysis of stem cells in the media , November 2011, NHS Choices. IMAGE©ISTOCKPHOTO.COM/DRA_SCHWARTZ

Featured news

Inviting protestors to talk

The animal research behind a new device to treat epilepsy

Ten organisations account for half of all animal research in Great Britain in 2023

Subscribe to our newsletter.

Get the latest articles and news from Understanding Animal Research in your email inbox every month. For more information, please see our  privacy policy .

An official website of the United States government

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

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

• Publications
• Account settings

The PMC website is updating on October 15, 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Int J Mol Sci

Stem Cell Therapy: From Idea to Clinical Practice

Regenerative medicine is a new and promising mode of therapy for patients who have limited or no other options for the treatment of their illness. Due to their pleotropic therapeutic potential through the inhibition of inflammation or apoptosis, cell recruitment, stimulation of angiogenesis, and differentiation, stem cells present a novel and effective approach to several challenging human diseases. In recent years, encouraging findings in preclinical studies have paved the way for many clinical trials using stem cells for the treatment of various diseases. The translation of these new therapeutic products from the laboratory to the market is conducted under highly defined regulations and directives provided by competent regulatory authorities. This review seeks to familiarize the reader with the process of translation from an idea to clinical practice, in the context of stem cell products. We address some required guidelines for clinical trial approval, including regulations and directives presented by the Food and Drug Administration (FDA) of the United States, as well as those of the European Medicine Agency (EMA). Moreover, we review, summarize, and discuss regenerative medicine clinical trial studies registered on the Clinicaltrials.gov website.

1. Introduction

Despite the progress in medical science, there still exist various diseases in the world for which there is no suitable treatment. People affected by incurable disorders typically use treatment methods intended to decrease the somatic and psychological symptoms and, in these situations, the physician offers treatment methods only to manage the disease, not treat it. Therefore, researchers are attempting to develop new treatment methods to not only control the symptoms of, but also to treat those diseases for which no cure is available at present.

Regenerative medicine is considered a promising new source of treatment for untreatable diseases in modern science [ 1 ]. Regenerative medicine is a multidisciplinary field including cell biology, genetic, biomechanics, material science, and computer science [ 2 , 3 ], the ultimate target of which is returning normal function to defective cells and tissues [ 4 ]. Since the discovery of stem cells and the spread of awareness regarding their unique properties, they have been defined as therapeutic agents for organ and tissue repair, and so are widely considered good candidates for regenerative medicine, due to their many potential applications [ 5 ]. Regenerative medicine is now regarded as an alternative to traditional drug-based treatments by researchers who study its potential applications in various diseases, including degenerative diseases, among others [ 6 , 7 , 8 , 9 , 10 ]. The main concept of regenerative medicine is implied tissue/organ regeneration using cells and, to reach this target, different kinds of cells have been used. However, various studies have indicated that cell therapy is restricted by a few limitations. In recent years, different alternatives have been introduced for cell therapy in order to resolve these limitations, including the improved application of stem cells for the restoration of tissue, such as the combination of cells with scaffolds, cell cultures with suitable biochemical properties, gene editing, and the immunomodulation of stem cells, as well as the use of stem cell derivatives [ 11 , 12 , 13 , 14 , 15 ]; however, the use of these alternatives clinically may be postponed, as more preclinical studies are required due to their status as newer technologies [ 16 ].

Stem cells are a group of immature cells that have the potential to build and recover every tissue/organ in the body due to their unique proliferative, differentiation, and self-renewal abilities [ 17 ]. Stem cells provide therapeutic effects which improve physical development by regenerating damaged cells to assist in organ recovery. Relying on the natural abilities of stem cells, researchers have used their biological mechanisms for stem-cell-based therapy. The mechanisms of action through which stem cells can promote the regeneration of tissue are diverse, including (1) inhibition of inflammation cascades [ 18 , 19 ], (2) reduction of apoptosis [ 20 , 21 ], (3) cell recruitment [ 22 , 23 ], (4) stimulation of angiogenesis [ 24 , 25 ], and (5) differentiation [ 26 ]. The cause of a disease is a vital consideration in selecting the proper stem cell mechanism and in the regeneration of tissue/organs using stem cells. Many examinations must be carried out to determine the main mechanisms involved in treatment when these cells are to be used in clinical practice, and the convergence of stem cell therapeutic mechanisms and disease mechanisms is expected to increase the chance of developing cures through stem cell applications.

From 1971 to 2021, 40,183 research papers were published regarding stem-cell-based therapies. All of these studies were conducted around discoveries and for the goal of “Stem Cell Therapy” based on the therapeutic efficacy of stem cells [ 27 ]. As basic stem cell research has soared over the past few years, “translation research”, a relatively new field of research, has recently greatly developed, making use of basic research results to develop new treatments. Although many articles on stem-cell-based therapies are published annually and their number increases every year, the number of clinical trial studies has not increased rapidly. Furthermore, among these studies, only a small portion of them can receive full regulatory approval for verification as treatment methods. Although one reason for this difference is due to the need for various prerequisite preclinical studies before carrying out a clinical trial study, the main reason is due to the sharply defined guidelines which prevent the translation of many preclinical studies to clinical trials.

In this review, we provide a general overview regarding the translation of stem cell therapies from idea to clinical service. Understanding the step-by-step knowledge underlying the translation of ideas to medical services is the first step in introducing a new treatment method. In this review, we divide this pathway into four levels, including idea evaluation, preclinical studies, clinical trial studies, and clinical practice. We focus not only on understanding each level’s requirements, but also discuss how an idea is assessed during the transition from one level to the next and, finally, move on to marketing.

2. From Idea to Preclinical Study

If a researcher has an idea regarding regenerative medicine using stem cells that inspires their use in a study, it must first be evaluated. During the evaluation step, it is important to select the target disease and make sure that the mechanism causing the disease is understood. Disease-related mechanisms refer to the cellular and molecular processes by which a particular disorder is caused [ 28 , 29 ], and stem-cell-based therapies are considered a treatment method intended to compensate for the disruption caused by such mechanisms in order to finally restore the defective tissue. Multiple mechanisms cause diseases [ 30 , 31 , 32 ]; however, stem cells, with their tremendous differentiation, self-renewal, angiogenesis, anti-inflammation, anti-apoptotic, and immunomodulatory potentials, as well as their capacity for induction of growth factor secretion and cell signaling, can affect these mechanisms [ 33 , 34 , 35 , 36 , 37 ].

After subject evaluation, preclinical studies should be carried out to determine whether the idea has any potential to treat the disease, and the safety of the final product should be assessed in an animal model of the target disease [ 38 , 39 , 40 ]. Preclinical studies are composed of in vitro and in vivo studies. In vitro experiments are performed with biological molecules and cells based on various hypotheses and, during the in vitro evaluation, a new treatment method is assayed in this controlled environment [ 39 ]. In contrast, during in vivo studies, as controlling all biological entities is impossible, the new product may be affected by various factors and thus present different effects. The general purpose of a preclinical study is to present scientific evidence supporting the performance of a clinical study, and the following are required for a decision to move forward to clinical study: (i) the feasibility and establishment of the rationale (e.g., validation, separation of active ingredients in vitro, and determination of its mechanism in vivo), (ii) establishment of a pharmacologically effective capacity (e.g., secure initial dose verification), (iii) optimization of administration route and usage (e.g., safe administration method, repeated administration, and interval verification), (iv) identification and verification of the potential activity and toxicity (e.g., toxicity analysis according to single and repetitive testing), (v) identification of the potential for special toxicity (e.g., genetic, carcinogenic, immunological, and neurotoxic analyses), and (vi) determination of whether to continue or discontinue development of the treatment [ 41 , 42 ].

3. From Preclinical Study to Clinical Trial

In principle, any idea regarding stem cell therapy should be assessed using comprehensive studies (i.e., in vitro and in vivo) before a clinical trial is considered, and the results of these studies should be proved by competent authorities. It can be easy during an in vitro study to create manipulative biological environments such as through the use of genetic mutation, drug testing, and pharmaceuticals, and it is easy to observe changes through the application of manipulated variables through living cells [ 43 , 44 , 45 ]. However, given the many associated variables, such as molecular transport through circulating blood and organ interactions, it is hard to say whether such a study can completely mimic the in vivo environment [ 43 , 44 , 45 ]. Before application in patients, in vivo experiments are conducted after in vitro experiments in order to overcome these weaknesses.

Many researchers use rodents for in vivo studies, due to their anatomical, physiological, and genetic similarities to humans, as well as their other unique advantages including small size, ease of maintenance, short life cycle, and abundant genetic resources [ 46 ]. The strength of in vivo studies is that they can supplement the limitations of in vitro studies, and the outcomes of their applications can be inferred in humans through the use of human-like biological environments. To establish in vivo experiments for stem cell therapies, the most correlated animal model should be selected depending on the specific safety aspects to be evaluated. Where possible, cell-derived drugs made for humans should be used for proof-of-concept and safety studies [ 47 ]. Homogeneous animal models can also be utilized as the most correlated systems in proof-of-concept studies [ 48 ].

Furthermore, in vivo studies require ethical responsibilities and obligations to be upheld according to experimental animal ethics. In other words, unnecessary and unethical experiments must be avoided. Summing up the above, we can see that both in vitro and in vivo approaches are used in preclinical studies, which should be carried out before clinical trial applications based on various interests.

Several factors must be considered in different in vitro and in vivo studies, including cell type determination, cell dose specification, route of administration, and safety and efficiency.

3.1. Stem Cell Source Determination

As expectations rise for regenerative treatment through the application of stem cell therapies, the number of applications of various types and stem cell sources has increased, and stem cell therapies have diversified from autologous to allogenic to iPSCs. These stem cell treatments can vary in risk, depending on the cell manufacturing process [ 49 ], among other factors, and in clinical experience, such that all types of stem cell treatments must be evaluated on the same basis [ 50 ]. Therefore, the strengths and weaknesses of each type of stem cell should be identified in order to determine the maximum therapeutic effect of stem cells in various diseases. This will enable us to build disease-targeted stem cells by applying the appropriate stem cells to the appropriate diseases. Below, we briefly discuss the characteristics of various stem cells.

3.1.1. Mesenchymal Stem Cells (MSCs)

MSCs are lineage-committed cells that divide into mesenchymal systems, primarily fatty cells, chondrocytes, and osteocytes [ 51 ]. It is well known that MSCs can be differentiated into dry cells, nerve cells, glioma cells, and skeletal muscle cells under proper in vitro culture conditions [ 52 , 53 , 54 , 55 , 56 , 57 ]. MSCs are primarily derived from myeloid and adipose tissues [ 58 , 59 ]. At present, MSCs are also isolated from many other tissues, such as the retina, liver, gastric mucosa, tendon, cartilage, placenta, cord blood, and blood [ 60 , 61 , 62 , 63 ]. The biggest characteristics of MSCs are their immunosuppressive functions, which prevent the proliferation of activated T cells through immunosuppressive cytokine secretion and suppression of programmed cell death signaling [ 64 , 65 ]. Due to this role, they have been spotlighted as a potential treatment for immune-related inflammation and disease. The initial clinical application of MSCs was in a case of patients with severe graft versus host disease (GVHD), and these cells have since been well applied in clinical practice, as evidenced through various studies [ 66 , 67 , 68 ].

MSCs have a variety of characteristics according to their organ of origin [ 69 ]. BM-MSCs, which are isolated from bone marrow, are useable in both autologous and allogenic contexts, and can perform stromal functions. However, the process of cell isolation from bone marrow is not only accompanied by the risk of pain and infection, but also has a lower efficiency of collection than other MSC sources. Furthermore, these cells have a longer doubling time (DT) in comparison to MSCs derived from other sources (approximately 60 h) [ 70 ]. Compared to BM-MSCs, AD-MSCs are not only easy to collect, but are also 100 to 500 times more efficient to harvest and have a shorter DT (approximately 20 h) [ 71 ]. However, these are adipose-derived stem cells that have a strong characteristic of adipogenic differentiation, such that they can be suggested as a valid alternative to BM-MSCs, but their nature must be considered regarding proper culture and body environment. Furthermore, there are concerns that these factors may affect the efficacy of treatment, as the amount of cytokines secreted is significantly lower when compared to BM-MSCs [ 72 ]. MSCs extracted from the umbilical cord (UC-MSCs) have come into the spotlight to compensate for these issues: UC-MSCs not only have the advantage of being easily collected compared to other stem cells, but also avoid ethical or donor age issues. They have superior proliferation and differentiation capabilities compared to BM-MSCs and AD-MSCs, and their DT has been reported as 24 h [ 69 , 73 ]. UC-MSCs are currently a subject of concern, as although they are easy to store frozen for a long time (e.g., in a cord blood bank), the cell survival rate and success rate during extraction are not high, due to exposure to cryogenic protectors during cryogenic storage [ 73 ]. Furthermore, as the cells are isolated from other organs, they have limited self-renewal capacity, and their senescence is faster than in other stem cells in long-term cultivation [ 66 , 74 ].

3.1.2. Hematopoietic Stem Cells (HSCs)

HSCs can be differentiated into cells from all hematopoietic systems present in the bone marrow and chest glands, namely myeloid cells and lymphocytes. HSCs can be obtained at good levels from adult bone marrow, the placenta, and cord blood. They can cause immunological problems such as transplant rejection. Nevertheless, they have been shown to be an effective treatment method in various diseases, including leukemia, malignant lymphoma, and regenerative anemia, as well as congenital metabolism, congenital immunodeficiency, nonresponsive autoimmune disease, and solid cancer to date. Furthermore, HSCs are the only stem cell type approved for stem cell treatment by the Food and Drug Administration (FDA) [ 75 , 76 ].

3.1.3. Embryonic Stem Cells (ESCs)

ESCs have established cell lines that can be maintained through in vitro culture. They are pluripotent cells that can be differentiated into almost any type of cell present in the body, and can be differentiated in vitro by adding external factors to the culture medium or by genetic modification. However, they may form teratomas, which are composed of various forms of cells derived from the endoderm, mesoderm, and exoderm, when transplanted into an acceptable host [ 77 ].

3.1.4. Induced Pluripotent Stem Cells (iPSCs)

iPSCs are artificially created stem cells. These cells are made by reprogramming adult somatic cells such as fibroblast cells. They share many of the characteristics of ESCs, including self-renewability, pluripotent differentiation, and malformed species performance. Unfortunately, these cells have little scientific evidence regarding changes in cell-specific regulatory pathways, gene expression, and epigenetic regulation. These characteristics pose a risk of tissue chimerism or cell dysfunction [ 78 ].

In summary, although the FDA-approved stem cell type is HSCs from healthy donors, a variety of issues have been raised, including a lack of donors and immune rejection. Therefore, we need to understand the characteristics of stem cells in order to handle them accordingly and overcome their disadvantages while maximizing their advantages. As stem cells derived from various sources have different characteristics, capabilities, potential, and efficiency, selecting the right source of stem cells that is appropriate for the target can be effective in assuring treatment efficiency.

3.2. Cell Dose Specification

The effective range of administration (i.e., dosage) of stem cells or stem-cell-derived products used in treatment should be determined through in vivo and in vitro studies. The safe and effective treatment capacity must be identified and, where possible, the minimum effective capacity must also be determined. When administered to vulnerable areas such as the central nervous system and myocardium, it has been reported that conducting normal dosage determination tests is unlikely. Thus, if the results of nonclinical studies can safety demonstrate treatment validity, it may be appropriate to conduct early human clinical trials with doses that may indicate therapeutic effects [ 79 ].

Will a high cell dose have better effects, considering only the effectiveness of stem cells? We answer this question below. An increasing dose of CD34 + cells (0.5 × 10 5 per mouse) has been shown to have positive effects, stimulating multilineage hematopoiesis at early stages and increasing the magnitude of reconstitution at post-transplant stages. Furthermore, improved T-cell reconstitution was correlated with higher cell doses of stem cells, compared to lower cell doses [ 80 ]. However, a few studies related to acute myeloblastic leukemia (AML) have reported that high doses of HSCs were correlated with restored function and rapid hematological and immunological recovery, but these results were not unconditional. In this study, a higher dose of HSCs (≥7 × 10 6 /kg) resulted in poorer outcomes and a higher relapse rate than the lower dose of HSCs (<1 × 10 6 /kg) [ 81 ]. In preclinical studies on heart disease, Golpanian et al. have demonstrated, through comparison of some preclinical studies for optimized cell dose, the therapeutic effects of stem cell types (i.e., allogenic and autologous MSCs), as well as the proper cell dose of stem cells and route of administration (direct epicardial and intravenous) in heart disease. Their results showed that the total number of cells used was different, but were inconsistent with the hypothesis that a higher number of cells would have higher therapeutic efficacy [ 82 ]. Therefore, these conclusions suggest that the currently reported data do not provide a decisive answer, such that sufficient and detailed early-stage studies may be needed before proceeding with clinical trials.

3.3. Route of Administration

Stem cells have been extensively studied under various disease conditions, depending on their type and characteristics. At this time, the route of administration should not be overlooked in favor of the number of stem cells transplanted. Several reports have shown that engraftment ability typically has a lower rate of reaching target organs relative to the number of transplanted cells, and does not have a temporary longer duration [ 83 , 84 ].

The methods of stem cell administration can largely be divided into local and systemic transmission. Local transmission involves specific injections through various manipulations and direct intra-organ injections, such as intraperitoneal (IP), intramuscular, and intracardiac injections. Systemic transmission uses vascular pathways, such as intravenous (IV) and intra-arterial (IA) methods. According to the publications in the literature, IV is the most common method, followed by intrasplenic and IP [ 85 , 86 , 87 ]. In a liver disease model, IV was shown to be not only suitable for targeting the liver, but also showed better liver regeneration effects than other routes of administration [ 85 , 88 ]. Intracardial injection showed better cell retention in heart disease, while intradermal injection showed better treatment in skin diseases [ 89 , 90 ]. Hence, we can determine that, in the context of these various diseases, the routes of administration should be different depending on the target organ. Many researchers have suggested that intravascular injection is a minimally invasive procedure, but it also poses a risk of clogged blood vessels, such that direct intravascular injection increases the risk of requiring open-air operations [ 91 ]. Clinical trials have reported that the number of cells and treatment efficacy under the same conditions, as in preclinical studies, are not significant, but also differ in significance depending on the route of administration [ 92 , 93 ]. Therefore, researchers should continue to study which cells are appropriate for a given route of administration—even within the same disease—based on many precedents [ 82 ]. In addition, researchers should explore the appropriate routes of administration for safer and more effective therapeutic effects.

3.4. Manipulation of Cell Transplantation for Safety and Efficiency Improvement of Administration

All medical treatments have benefits and risks. It is not particularly safe to apply these unproven stem cell treatments to patients. As expectations for regenerative treatment through stem cell therapies increase, the application of various administration pathways, including through the spinal cord, subcutaneous, and intramuscular, as well as the stem cell therapies themselves, have been diversifying, from autologous to homogenous to iPS. These stem cell treatments can vary in risk, depending on the cell type manufacturing process among other factors, and they differ in clinical experience, such that all types of stem cell treatments must be evaluate on the same basis. Furthermore, it should only be in limited and justified contexts that stem cells which can proliferate and have all-purpose differentiation remain in a final product.

Unfortunately, the only safe stem cells that have been employed in regenerative medicine so far are omnipotent stem cells, such as HSCs and MSCs, which are isolated from their self-origin [ 94 ]. Unfortunately, potential clinical applications using iPSCs and ESCs face many hurdles, as they present higher risk, including the possibility of rejection, teratoma formation, and genomic instability [ 95 ]. Hence, many researchers have attempted to overcome stem cell tracking for safety assessment. To check the engraftment and the remaining amount of stem cells, they have been labeled using BrdU, CM-Dil, and iron oxide nanoparticles, and visualized using Magnetic resonance imaging (MRI) [ 84 , 96 , 97 ].

A close analysis of the distribution patterns of administrative sites and target organs is required, as well as whether a distribution across the body is expected, and the organ that the cells are predicted to be distributed through should undergo a full-term analysis, including evaluation at administrative sites. To date, studies have reported assessments in the brain, lungs, heart, spleen, testicles, ovaries, kidneys, pancreas, bone marrow, blood, and lymph nodes, including areas of administration [ 98 ].

Some researchers have carried out the detection of transplanted UC-MSCs delivered by IV injection in the lung, heart, spleen, kidney, and liver. According to their results, the transplanted cells were not detected in other organs, except the lung and liver, for 7 days. In the lung and liver, the detected cells persisted at least 7 days after the transplant [ 99 ]. Furthermore, in a study comparing BM-MSCs and UC-MSCs in terms of cell tracking, they reported on the persistence of stem cells according to the route of administration used. In the results of the comparison of intracardiac and intravenous routes, the transplanted stem cells were detected in the lung for 10 days, but the signal disappeared after 21 days [ 100 ]. In other research, the stem cells were transplanted with using a biomaterial scaffold. The AD-MSCs were transplanted with hyaluronic acid/alginate hydrogel through intradermal injection, and could be detected by CM-Dil staining for 30 days [ 101 ]. These studies may show that the transplanted cells localized to the damaged organs through their homing ability, but the results of these previous studies seem to indicate that the residual volume and the residual date vary significantly depending on the target disease, organs, and type of stem cells. The cell residual means the survival of the cell, which represents the risk of formation of tumors. To overcome the problem of teratoma formation, the following results have been reported: According to one study, ESCs showed the following rates of teratoma formation: 100% under the kidney capsule, 60% intratesticular, 25–100% subcutaneous, and 12.5% intramuscular. To overcome this problem, the investigators performed a co-injection with Matrigel into an animal model. According to their results, subcutaneous implantation of ESCs in the presence of Matrigel appeared to be the most efficient, reproducible, and easiest approach for preventing teratoma formation, other than only using ESCs [ 102 ]. Moreover, cellular products derived from iPSCs have higher potential as potential cell sources in personalized medicine [ 103 ]. Their applicability is currently limited due to concerns regarding the potential risk of serious transplant-related side effects, such as tumor formation due to residual pluripotent cells [ 104 ]. Hence, a recent study reported the establishment of an optimized tool for therapeutic intervention that allows for controlled specific and selective ablation of iPSCs through the use of LVCAGs–transgenic iPSCs [ 104 ].

Unlike MSCs, which are generally considered immune-tolerant as an immunomodulator, transplantation of ESCs and HSCs requires close examination of the matching of histocompatibility antigen (HLA) between the donor and beneficiary [ 105 , 106 ]. Although homogeneous mesenchymal stem cells are known to have immunogenicity in immune-active rodent models and are quickly removed from the peripheral blood, studies have shown that a few MSCs remain for weeks to months. Therefore, it is recommended to conduct a study to assess the persistence of MSCs in the cell preparations administered, in order to assess the risk of stem cell removal. Therefore, for stem cell therapies that have undergone extensive in vitro manipulation such as long-term cell culture—including those derived from ESCs and iPSCs—both oncogenicity and genetic stability must be evaluated before clinical research begins. Furthermore, we must constantly review and study the latest research on safety, as well as the effects of regeneration using stem cells, and discuss and study the potential of regenerative medicine [ 107 , 108 , 109 , 110 , 111 ].

As discussed earlier, in vitro and in vivo preclinical studies are the direction of current research, and encompass the tasks that need to be completed. If we reinforce the current strengths and weaknesses based on the preceding content, we are already a step closer to developing stem cell treatments.

4. From Clinical Trial to Clinical Practice

Before a treatment is applied in humans (i.e., patients), preclinical study must involve checking whether the effect of treatment will be positive or negative and, if there are any negative effects, the researcher must check the safety possibilities at every step. Due to concerns relating to treatment using stem-cell-based products, deciding whether preclinical studies are sufficient for translating to clinical trials raises several issues that must be assessed by competent authorities. An application for a clinical trial should be submitted to the Food and Drug Administration (FDA), the European Medicine Agency (EMA), or another organization, based on the country [ 112 ].

The FDA is responsible for certifying clinical trial studies for stem-cell-based products in the United States [ 113 ]. If a new drug is introduced to a clinical investigator which has not been approved by the FDA, an Investigational New Drug (IND) application may need to be submitted [ 114 ]. The IND application includes data from animal pharmacology and toxicology studies, clinical protocols, and investigator information [ 115 ]. A lack of preclinical support (e.g., in vitro and in vivo studies) can lead to required modification or disapproval. If the FDA has announced that an IND requires modifications (meaning that the application is intended to secure approval but has not yet been approved), the results of the preclinical studies were deemed insufficient or inadequate for translation to clinical trial study, such that further study must be completed, after which an amended IND should be submitted.

The FDA has published guidelines for the submission of an IND in the Code of Federal Regulations (CFR). These regulations are presented in 21 CFR part 210, 211 (Current Good Manufacturing Practice (cGMP)), 21 CFR part 312 (Investigational New Drug Application), 21 CFR 610 (General Biological Product Standards), and 21 CFR 1271 (Human Cells, Tissues, and Cellular and Tissue-Based Products) [ 116 , 117 , 118 ]. These guidelines have been issued for the development of stem cell products with the highest standards of safety and potential effective translation to clinical trial studies.

The FDA issued 21 CFR parts 210 and 211to ensure the quality of the final products [ 119 ]. The 21 CFR part 210 contains the minimum current good manufacturing practice (cGMP) considered at the stages of manufacturing, processing, packing, or holding of a drug, while the 21 CFR part 211 contains the cGMP for producing final products. The 21 CFR 211 includes FDA guidelines for personnel, buildings and facilities, equipment, and control of components, process, packaging, labeling, holding, and so on, all of which are critical for pharmaceutical production [ 116 , 117 , 118 , 119 , 120 , 121 ]. The requirements for IND submission and conducting clinical trial studies, reviewed by the FDA in the 21 CFR part 312 (Investigational New Drug Applications), includes exemptions that are described in detail in 312.2 (general provisions). Such exemptions do not require an IND to be submitted, but other studies must present an IND based on 21 CFR part 312. The section, 21 CFR part 312, provides different information, including the requirements for an IND, its content and format, protocols, general principles of IND submission, and so on. In addition, the FDA describes the administrative actions of IND submission, the responsibilities of sponsors and investigators, and so on, in this section [ 116 , 117 , 122 ]. The 21 CFR part 610 contains general biological product standards for final product characterization. The master cell bank (MCB) or working cell bank (WCB) used as a source for stem-cell-based final products must be tested before the release or use of the product in humans. The MCB and WCB should be tested for sterility, mycoplasma, purity, identity, and potency, among other tests based on the final products (e.g., viability, stability, phenotypes), before use at the clinical level. The FDA provides all required information regarding general biological product standards in this section, including release requirements, testing requirements, labeling standards, and so on [ 116 , 117 , 123 , 124 ]. The 21 CFR part 1271 focuses on introducing the regulations for human cells, tissues, and cellular and tissue-based products (HCT/P’s), in order to ensure adequate control for preventing the transmission of communicable disease from cell/tissue products. Current Good Tissue Practice (GTP) is a part of 21 CFR part 1271, where the purpose of GTP is to present regulations for the establishment and maintenance of quality control for prevention of introduction, transmission, or spread of communicable diseases, including regulations for personnel, procedures, facilities, environmental control, equipment, and so on [ 125 , 126 , 127 , 128 ].

The EMA is an agency in the European Union (EU) which is responsible for evaluating any investigational medical products (IMPs) in order to make sure that the final product is safe and efficient for public use. When planning to introduce a new drug for a clinical trial in Europe, one may be required to submit clinical trial applications to the EMA for IMPs. Clinical trial applications for IMPs include summaries of chemical, pharmacological, and biological preclinical data (e.g., from in vivo and in vitro studies) [ 129 ]. The EMA has presented different regulations to support the development of safe and efficient products for public usage, including Regulation (EC) No. 1394/2007, Directive 2004/23/EC, Directive 2006/17/EC, Directive 2006/86/EC, Directive 2001/83/EC, Directive 2001/20/EC, and Directive 2003/94/EC.

Regulation (EC) No. 1394/2007 defines the criteria for regulation regarding ATMPs. Advanced therapy products (ATMPs) are focused on gene therapy medicinal products (GTMP), somatic cell therapy medicinal products (sCTMP), tissue-engineered products (TEP), and combined ATMPs, which refers to a combination of two different medical technologies. Regulation (EC) No. 1394/2007 includes the requirements to be used in development, manufacturing, or administration of ATMPS [ 130 , 131 , 132 ]. Directive 2004/23/EC, Directive 2006/17/EC, and Directive 2006/86/EC define standards for safety and quality, as well as technical requirements for donation, procurement, testing, preservation, storage, and distribution of tissue and cells intended for human applications [ 133 , 134 , 135 ]. Directive 2001/83/EC applies to medicinal products for human use [ 136 ]. Directive 2001/20/EC presents the regulations for the implantation of products in clinical trials in the EU [ 137 ]; however, this directive will be replaced by regulation (EU) No. 536/2014. Regulation (EU) No. 536/2014 was adapted by the European Parliament in 2014, and provides regulation for clinical trials on medical products intended for human use. The new EU regulation comes into effect on 31 January 2022 and aims to coordinate all clinical trials performed throughout the EU, using clinical trials submitted into CTIS (Clinical Trials Information System). The definition of regulation (EU) No. 536/2014 as a homogeneous regulation serves an important role in the EU, as all member states of the EU can be involved in multicenter clinical trials using international coordination, thus allowing larger patient populations [ 138 ]. Directive 2003/94/EC provides Good Manufacturing Practice (GMP) Guidelines in relation to medicinal products or IMPs intended for human use [ 139 ]. All process and application requirements for the IMP application are present in the regulations and directives of the EMA. After presenting an IND/IMP to the regulatory authority responsible for clinical trial oversight (FDA or EMA), the application will be reviewed in accordance with the FDA/EMA criteria and, if assured of the protection of humans enrolled in the clinical study, the application will be approved by the investigational review boards (IRBs) in the United States or Ethics Committees (ECs) in the European Union. Clinical trial studies are composed of different steps where, at each step, products are assessed using different quality and quantity measurements by the responsible agency. An efficient clinical trial study should address the safety and efficiency of new stem cell products in each of the different steps, and it is important to complete each step based on defined instructions and regulations, as the results of previous steps are needed to move forward.

Almost all clinical trial studies that have been approved for testing in humans have been registered online ( https://www.clinicaltrials.gov/ accessed 12 December 2021). Our search on this website revealed more than 6500 records for interventional studies registered using “Stem Cells” up to December 2021. The recorded clinical trials can be analyzed from different aspects.

Recruiting status: The recruiting status of these studies indicated that 18% of these studies were ongoing (recruitment) and 42% were completed ( Figure 1 ). Although completed, suspended, terminated, and withdrawn studies are all terms used for studies that have ended, each is used to describe a different status. Completed studies are those that have ended normally and the participants were completely enrolled in the study. Suspended, terminated, and withdrawn studies are studies that stopped early; however, the participant enrolment status differs between them. A suspended study may start again, but nobody can continue to participate in terminated or withdrawn studies [ 140 , 141 ].

Status of clinical trials using stem cells.

Type of disease: Stem-cell-based therapy is a new approach for the treatment of various diseases in different clinical trial studies. Blood and lymph diseases are the most common diseases that have benefited from this new approach ( Figure 2 ). Blood and lymph diseases refer to any type of disorder related to blood and lymph deficiency or abnormality, such as anemia, blood protein disorder, bone marrow disease, leukemia, hemophilia, thalassemia, thrombophilia, lymphatic disease, lymphoproliferative disease, thymoma, and so on. In addition, various clinical trial studies have been performed using stem cells to treat immune system disease; neoplasm, heart, and blood disease; and gland- and hormone-related disease ( Figure 2 ). However, this does not mean that all of these studies had great results, nor does it mean that all of these studies introduced a new treatment method; some of these clinical trial studies were only intended to increase treatment efficiency, compare different types of treatment methods, or analyze various parameters after the administration of stem cells into the body.

Diseases considered in clinical trials using stem cells.

Autologous vs. Allogenic: Stem-cell-based products for use in clinical trial studies can be divided into two categories: autologous and allogeneic stem cells. In autologous stem cell therapy, the stem cells are collected from the patient’s own body. Culture-expanded autologous stem cells are autologous stem cells that are expanded before transplantation, and can be divided into two groups: modified and unmodified expanded autologous stem cells. If autologous stem cells were transplanted to the donor immediately after collection, this is a nonexpanded autologous stem cell treatment. The use of these cells usually has fewer restrictions for receiving clinical trial authorization. The classification of allogenic stem cells is similar to that of autologous stem cells, except that allogeneic stem cells are collected from a healthy donor. The use of these cells requires more prerequisite tests, in order to check the donor’s health. Allogenic stem cells have been used more than autologous stem cells in the clinical trial studies (46.34% vs. 44.51%), as shown in Figure 3 .

Applied stem cell types in clinical trials using stem cells.

Phase: Clinical trial studies are conducted in different phases. In each phase, the purpose of study, the number of participants, and the follow-up duration may differ. A new phase of clinical trials should not be started unless the results of the completed phase(s) have been reviewed by competent authorities, in order to that certify the results of the completed phase(s) are valid for authorization of the start a new phase of the clinical trial. For this purpose, at the end of each phase of a clinical trial study, competent authorities evaluate whether the new drug is safe, efficient, and effective for the treatment of the target disease ( Figure 4 ).

Status of clinical phase within clinical trials using stem cells.

Early Phase I emphasizes the effects of the drug on the human body and how the drug is processed in the body.

Phase I of a clinical trial is carried out to ensure that a new treatment is safe and to determine how the new medicine works in humans. The FDA has estimated that about 70% of the studies pass this phase.

In Phase II, the accurate dose is determined and initial data on the efficiency and possible side effects are collected. The FDA has estimated that roughly 33% of the studies move to the next phase.

Phase III evaluates the safety and effectiveness of products. The result of this phase is submitted to the FDA/EMA for new product approval, which allows manufacturing and marketing of the drug. The FDA has estimated that 25%–30% of the drugs pass at this phase.

Phase IV take place after the approval of new products and is carried out to determine the public safety of the new product [ 142 , 143 , 144 ].

The number of participants and the duration: A new stem cell product is eligible for marketing after completing successful clinical trial phases. As the new product has been used on volunteers and the effects/side effects of the drug have also been followed for a long time throughout the different phases, it is now possible to make a decision regarding its introduction to the market for public use. The number of participants and the duration of long-term follow-up in each study and each phase differ ( Figure 5 and Figure 6 ). The number of volunteers that participate in each phase of a clinical trial study varies, as each phase has a different target. The FDA has recommended 20–80, 100–300, and several hundred to thousands of volunteers for Phase I, Phase II, and Phase III, respectively [ 144 , 145 ]. Although the FDA has defined a range for enrolments per phase, the number of participants can vary depending on the type of disease. The number of participants for clinical studies in rare diseases will be lower than when studying common diseases. Searching for stem cells in clinicaltrial.gov, studies can be found with only one participant (e.g., NCT02235844, NCT02383654, NCT03979898, and NCT01142856). The sponsor/investigator must provide the FDA with strong documentation regarding the selection of such a number of volunteers. The volunteers for each clinical trial study, before attending, should be informed about the enrolment criteria of each study, possible side effects, and the advantages of the study.

Enrolment of clinical trials using stem cells.

The duration of each clinical trial study using stem cells.

Age of participants: Roughly 190,000 people participated in all the completed clinical trial studies using stem cells that had been registered. Each clinical study was performed in different age groups, which differed among the various studies depending on the type of drug, type of disease, and sponsor decision, as shown in Figure 7 .

The age of patients participating in clinical trials using stem cells.

Number of clinical trial studies: The number of clinical trial studies increased gradually from 2000 to 2014, although it fluctuated after 2014 but did not change significantly ( Figure 8 ). The reason for this increase in 2014 is not clear, but it may have been related to the introduction of the first advanced medicinal therapy product containing stem cells (Holoclar) by the EMA in 2014–2015 [ 146 ].

The proportion of clinical trials using stem cells by year: ( A ) the proportion of new clinical trial studies using stem cells by year (green bar) and the proportion of registration results accordingly (orange color line); ( B ) the proportion of completed registered clinical trial studies using stem cells by year (blue bar) and the updated results of completed clinical trial studies using stem cells by year (orange line).

Place of study: According to economic website reports, the cell therapy market has grown significantly in recent years, and it is expected to grow more in the coming years; therefore, many countries have begun research in this field. Our data from clinicaltrial.gov showed that the United States has conducted the most clinical trials using stem cells ( Figure 9 ). Government agencies, industry, individuals, universities, and private organizations have all invested in stem-cell-based therapy. The number of stem-cell-based companies has rapidly increased in recent years, and a brief overview of the submitted clinical trial studies indicated that the studies were mostly aimed at introducing therapeutic products for clinical applications. Therefore, we can expect the introduction of stem-cell-based products to the market.

The registered and completed clinical trial studies using stem cells according to participating countries: ( A ) top 10 participating countries with registered clinical trials using stem cells; and ( B ) top 10 countries based on the completion of registered clinical trials using stem cells.

As indicated above, translational research from the laboratory to clinical services has many layers which must be passed through, each with its own requirements and measurements. Therefore, the only way to introduce a new stem-cell-based product onto the market is for competent authorities to make sure that the discovery is safe and effective for its intended human use, and that the product has successfully passed all of the clinical trial stages.

5. Challenges and Future Directions

One of the most important issues regarding the introduction of a new product for use in humans through a clinical trial is evaluation of its safety. Although many clinical trials have been performed using stem cells for the treatment of various diseases, as stem-cell-based therapies are one of the newest groups of therapeutic products in medicine, it is very hard to introduce new products based on stem cells onto the market, as many different parameters must be evaluated. There are several concerns regarding stem-cell-based therapies, including genetic instability after long-term expansion, stem cell migration to inappropriate regions of the body, immunological reaction, and so on. However, all challenges depend on the type of stem cell (e.g., embryonic stem cell, adult stem cell, iPS), type of disease, route of administration, and many other factors. Almost all researchers in the field of stem cell therapy believe that despite stem cells having great potential to treat disease through their intrinsic potential, unproven stem-cell-based therapies that have not been shown to be safe or effective may be accompanied by very serious health risks. In order to receive clinical trial approval from a competent regulatory authority, different tests must be performed for each study phase, and the results of one study should not be generalized to another study. The FDA and EMA have defined different regulations to ensure that stem-cell-based products are consistently controlled through the use of different preclinical studies (in vitro and in vivo). Based on these preclinical data, the FDA and EMA have the authority to approve a clinical trial study, as discussed in this review.

Another challenge that researchers and companies face is the duration of a clinical trial study before a stem-cell-based product can be introduced onto the market. At present, hematopoietic progenitor cells are the only FDA-approved product for use in patients with defects in blood production, while other stem-cell-based products used in clinical trials have not yet been introduced to the market.

In the past few years, several clinical trials have been conducted using stem cells, most of which have indicated the safety and high efficiency of stem-cell-based therapies. An attractive future option for regenerative medicine is the use of cell derivatives, including exosomes, amniotic fluid, Wharton’s jelly, and so on, for the treatment of diseases. Recently, the safety and efficiency of these products have been evaluated and optimized in preclinical studies. In addition, regenerative medicine using modified stem cells and combinations of stem cells with scaffolds and chemicals to overcome stem cell therapy challenges and increase the associated efficiency are two important future directions of research. However, establishing a safe method for stem cell modification and moving this technology toward clinical trial studies requires many preclinical studies.

The regenerative medicine market is developing and, due to encouraging findings in preclinical studies and predictable economic benefits, competition has increased between companies focused on the development of cell products. Therefore, government agencies, industries, individuals, universities, and private organizations have invested heavily into the development of the regenerative medicine market in recent years, such that we can be more hopeful about the future of stem-cell-based therapies.

6. Conclusions

In recent years, regenerative medicine has become a promising treatment option for various diseases. Due to their therapeutic potential, including the inhibition of inflammation or apoptosis, cell recruitment, stimulation of angiogenesis, and differentiation, stem cells can been seen as good candidates for regenerative medicine. In the last 50 years, more than 40,000 research papers have focused on stem-cell-based therapies. In this review study, we present a general overview of the translation of stem cell therapy from scientific ideas to clinical applications. Multiple mechanisms causing disease could be reversed by stem cells, due to their tremendous therapeutic potential. However, preclinical studies including in vitro and in vivo experiments are necessary to evaluate the potential of stem-cell-based treatments. Through preclinical research, it is possible to present scientific evidence and optimal treatment options for subsequent clinical studies. Before starting a clinical trial based on preclinical data, the application must be approved by a relevant regulatory administration, such as the FDA, EMA, or another organization. If the application is for the use of a new drug (including stem cells) which has never been tested before, the submission of an IND is required for FDA approval. Approximately 50% of clinical trials using stem cells take 2 to 5 years to complete. To minimize possible side effects, every new stem cell product should be approved for clinical marketing only after completing Phase I–IV clinical trials successfully. Interestingly, the number of stem-cell-based companies aimed at introducing clinical applications has rapidly increased in recent years. Therefore, it may be possible to find stem-cell-based products on the clinical market in the near future. As described in this paper, there are several steps that should be carried out on the path from the laboratory to the clinical setting. To develop new stem-cell-based medicine for the clinical market, researchers should follow the guidelines suggested by the relevant authorities. Through these well-controlled development processes, researchers can achieve safe and effective stem-cell-based therapies, thus brings their research ideas into the clinical field.

Author Contributions

All authors have read and agreed to the published version of the manuscript.

This review funded by National Institutes of Health grant: R01HD087417-01A1, R01HD094378-01, R01HD094380-01, R01HD100367-01, R01HD100563, R01HD100563.

Conflicts of Interest

The author has no conflicts of interest to declare.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.