Why has the name of the NIH Human Embryonic Stem Cell Registry been changed?
President George W. Bush required that the name of the registry be changed in his Executive Order #13435 (96.4 KB PDF; get Adobe Reader), issued on June 20, 2007. As a result of this Executive Order, the former National Institutes of Health Human Embryonic Stem Cell Registry will now be called the "National Institutes of Health Human Pluripotent Stem Cell Registry." The registry will now include both human embryonic stem cells that were derived consistent with the President’s policy of August 9, 2001 and human pluripotent stem cells derived from non-embryonic sources.
What is meant by the term "pluripotency"?
Pluripotency is defined as the ability of stem cells to give rise to all of the various cell types that make up the body.
What are the properties of pluripotent stem cells?
Current scientific understanding of how to assess pluripotency is based on extensive studies of mouse embryonic stem (ES) cells. In mice, the gold standard test for the ability to form derivatives of all three germ layers (ectoderm, mesoderm, and endoderm) is injecting putative pluripotent cells (labeled to permit tracking of daughter cells) into a mouse blastocyst. If the injected cells are truly pluripotent, labeled daughter cells will be seen in tissues derived from all germ layers throughout the embryo. This method, however, is not practical in non-human primates, nor ethical when it involves the use of human cells or blastocysts. Consequently, scientists typically demonstrate the formation of all three germ layers by primate stem cells via teratoma formation. As our understanding of pluripotency and its molecular characteristics advances, alternative methods are likely to be developed and accepted.
Where do pluripotent stem cells come from?
At present, scientists are able to derive human pluripotent stem cells from the inner cell mass of a 5-day-old pre-implantation blastocyst-stage embryo obtained after in vitro fertilization; the cells derived in this manner are called human embryonic stem cells (hESCs). Recent publications report that scientists are now able to reprogram human adult skin cells to behave in many respects like hESCs. These reprogrammed human adult skin cells are known as induced pluripotent stem cells (iPSCs). Scientists continue to pursue additional ways to derive pluripotent human stem cells. NIH anticipates the need to continue to compare and evaluate new and existing sources of human pluripotent stem cells.
How did NIH determine what standards should be used to establish a cell's pluripotency?
The characterization of stem cells and the definition of pluripotency are under active investigation by scientists today. NIH examined the current literature for: 1) properties correlated with pluripotency; and 2) methods used to characterize human cells as pluripotent. The most commonly described properties were:
- Formation of a teratoma
- Unlimited self-renewal in culture
- Expression of a specific set of transcription factors (for example OCT4, SOX2, NANOG and POU5F1)
- Expression of a unique set of cell surface markers (such as SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81)
- Formation of embryoid bodies
- A specific pattern of gene expression assayed by whole genome profiling
- A specific epigenetic profile
Two of these properties or methods were chosen as being most widely used and accepted as evidence of pluripotency: formation of a teratoma and unlimited self-renewal in culture. In addition, derivers should provide information on the expression of the transcription factors and cell surface markers that are widely used to characterize human pluripotent stem cells. NIH will update these criteria as additional and/or new standards are developed to establish pluripotency.
What kinds of pluripotent stem cell lines will now be added to the National Institutes of Health Human Pluripotent Stem Cell Registry?
Pluripotent cell lines derived from non-embryonic sources will be considered. Pluripotent cell lines derived from human embryos that meet the eligibility criteria established by President George W. Bush on August 9, 2001 will also be considered. NIH will add cell lines to the new NIH Human Pluripotent Stem Cell Registry if derivers:
- Provide evidence that cells from the proposed cell line form a teratoma that contains cells from all 3 embryonic germ layers (endoderm, mesoderm, and ectoderm). This method was chosen because it is currently the gold standard for determining whether a human line is pluripotent. If cells from the line have not been demonstrated to form a teratoma, the derivers may provide alternative evidence of pluripotentiality for consideration by the NIH.
- Provide evidence that the cell line is capable of unlimited self-renewal.
How will NIH determine what pluripotent cell lines meet these standards?
The NIH Stem Cell Task Force has established a Pluripotency Standards Working Group that will evaluate submissions of cells and cell lines and assess them with respect to required properties. The Pluripotency Standards Working Group will also advise NIH on updating the criteria for establishing pluripotency as new science emerges. If appropriate, lines listed on the registry will be tested to determine that they meet the new standards.
How can a scientist get her or his pluripotent cell lines listed on the NIH Human Pluripotent Stem Cell Registry?
Scientists wishing to get their cell lines listed on the NIH Human Pluripotent Stem Cell Registry must submit evidence that their cells meet the minimum requirements listed in FAQ #6, consider the items mentioned in FAQ #12, and have the lines approved by the NIH Pluripotency Standards Working Group.
Does a pluripotent cell line need to be listed on the NIH Human Pluripotent Stem Cell Registry in order for the research on it to be eligible for Federal Funding?
Research using pluripotent stem cells derived from non-embryonic sources has been and continues to be eligible for Federal funds whether or not the cells are listed on the Registry. The August 9, 2001 policy limitation applies specifically to pluripotent stem cells derived from human embryos. Therefore, research using embryo-derived pluripotent stem cells is only eligible for Federal funding if it is listed on the NIH Human Pluripotent Stem Cell Registry.
Will NIH be distributing the human pluripotent stem cell lines listed on the new NIH Human Pluripotent Stem Cell Registry?
No, these lines remain the property of the scientists and/or institutions that generated them. Scientists wishing to obtain these cells for their experiments should contact the Principal Investigator listed on the Registry.
- What human subjects regulations and policies must I follow in order to have my pluripotent cell lines, whether derived from adult or fetal tissue, listed on the NIH Human Pluripotent Stem Cell Registry?
Certain Federal regulations and policies may apply to the derivation of pluripotent cell lines from adult or fetal tissue. The Department of Health and Human Services (HHS) regulations for the protection of human subjects at 45 CFR part 46 apply to non-exempt human subjects research that is conducted or supported by HHS, and also may apply to non-exempt human subjects research that is performed at an institution that has agreed to apply HHS regulations to all of its human subjects research through its assurance of compliance with the Office for Human Research Protections (OHRP). The Food and Drug Regulations at 21 CFR parts 50 and 56 generally apply to biomedical research involving an unapproved drug, device or biologic and may apply to certain studies of approved products. Additional information on FDA regulations is available at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm. The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule at 45 CFR 160 and 164 Subparts A and E may also apply to certain health information used for research.
Investigators deriving pluripotent cell lines should consult their institutional review boards (IRBs) and/or Privacy Boards for specific guidance about whether and how Federal, state and local regulations and policies apply to their work. Additionally, since some of the same regulations and policies may apply to the use of the cell line for subsequent research, guidance about these requirements and later use of these cell lines should be sought from the local IRB and/or Privacy Board.
Research involving the derivation of pluripotent cell lines from non-embryonic sources that is conducted or supported by the HHS or performed at an institution that has agreed to apply the HHS regulations to all of its human subjects research through its assurance of compliance with OHRP may be subject to the HHS regulations for the protection of human subjects (45 CFR part 46). The requirement for IRB review for derivation of the cell lines depends on whether the research involves human subjects, and if so, whether the human subjects research is exempt under 45 CFR 46.101(b). The HHS regulations for the protection of human subjects only cover human subjects research that is not exempt.
The HHS human subjects regulations define a human subject as follows:
Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains
- Data through intervention or interaction with the individual, or
- Identifiable private information.
When using stored tissue or cells that were not collected specifically for the proposed derivation of pluripotent cell lines through an interaction or intervention with a living individual, and that retain no links to the identity of the individual from whom the tissue or cells were originally obtained, the derivation of the cell line is not considered human subjects research under the HHS regulations. Therefore, IRB approval and informed consent would not be required for the derivation of the cell line.
When using stored tissue or cells from a deceased donor, the derivation of the cell line would not be considered human subjects research under the HHS regulations because those regulations apply only to living individuals. However, state or local laws may apply (e.g., if material is obtained from autopsy).
When using stored tissue or cells that can be linked by the investigators to the identity of the individual from whom the tissue was obtained, the derivation of the cell line constitutes human subjects research under the HHS regulations. However, such human subjects research may be exempt under 45 CFR 46.101(b). Specifically, the exemption at 45 CFR 46.101(b)(4), which pertains to certain research involving the collection or study of existing data or specimens. may be applicable. If the derivation of the cell line involves non-exempt human subjects research, then IRB review and approval and informed consent would be required from the subject, unless the IRB determines that the criteria for a waiver of informed consent have been met. However, the derivation of the cell line may not constitute human subjects research if the stored tissues or cells are coded and certain other conditions are met. See the HHS Office for Human Research Protections (OHRP) Guidance on Research Involving Coded Private Information or Biological Specimens, August 10, 2004.
When tissues or cells for cell line derivation are obtained specifically for the proposed derivation of pluripotent cell lines through an interaction or intervention with a living individual, IRB review is required and informed consent must be obtained, unless the IRB waives the requirement for obtaining informed consent in accordance with the requirements of the HHS regulations at 45 CFR 46.116(d).
When using tissues or cells from human fetal tissue, federal regulations (e.g. 45 CFR part 46, the FDA human subjects regulations, and/or the HIPAA Privacy Rule) and state and local laws must be followed, where applicable. In addition, Sections II. B. and Section III of the NIH Guidelines for Research Using Human Pluripotent Stem Cells also apply.OHRP information on how the HHS human subjects protection regulations apply to cells and specimens used for research is provided in:
The Health Insurance Portability and Accountability Act (HIPAA) Standards for Privacy of Individually Identifiable Health Information (Privacy Rule) 45 CFR 160 and 164 Subparts A and E does not apply to specimens or cells per se, but may apply to information about individuals that is associated with the specimen or cells. The full text of the Privacy Rule can be found at the HIPAA Privacy Website of the Office for Civil Rights (OCR). Additional information about the Privacy Rule and research is available on the NIH Privacy Rule website.
NIH Recombinant DNA Guidelines:
If the derivation of your pluripotent cell line involves recombinant DNA, you should consult the NIH Guidelines for Research Involving Recombinant DNA Molecules to determine whether they apply. The Guidelines are available for download at http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html.
- What kind of information will help NIH determine if cell lines can be included on the NIH Human Pluripotent Stem Cell Registry?
For NIH to determine if your cell lines can be included on the Human Pluripotent Stem Cell Registry, NIH would be interested in knowing the following information:
Cell Line Information
- Cell line name or identifier
- Detailed protocol of derivation process and source of cell line
- Individual or institution who derived the cell line
- Individual or institution who owns the cell line
- Any published, peer-reviewed scientific journal article that includes experiments demonstrating the pluripotency of the human cell type or line being considered for inclusion on the NIH Human Pluripotent Stem cell Registry
- Whether the cell line is available for distribution
- Whether feeder cells were used during the isolation and the source of the feeder cells
- Passage number of the cell line
- Whether the cell line had normal or abnormal karyotype and the abnormality
- Whether the cells exhibit any of the following markers: SSEA-1, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, Oct-4, Alkaline Phosphatase, Nanog
- Whether a DNA fingerprint analysis of the cell line was performed
Demonstration of Pluripotency
- Whether or not your cells demonstrated the ability to give rise to a teratoma, ectoderm, mesoderm, endoderm, or other tissue type
Demonstration of Self Renewal
- Whether your cell line is capable of dividing to produce more undifferentiated stem cells in culture, and the number of cell divisions the line has undergone
- Who will be reviewing information about your cell line?
NIH Stem Cell Task Force
Human Pluripotent Stem Cell Registry Committee
31 Center Drive, Room 3C27, MSC (2320)
Bethesda, Maryland 20892-2320