Earlier this year, in line with its aim to assess research areas ripe for modernization, the National Institutes of Health (NIH) announced that it is reviewing the scientific utility of human embryonic stem cells (hESCs) in research.
To this end, the agency released a Request for Information (RFI), inviting comments from the public about in vitro platforms that could reduce or replace the use of hESCs in research. As it sought this input, NIH paused review and approval of new hESC lines to be added to its registry, which lists cell lines that scientists can use in NIH-supported research.
During the recently concluded comment period, many scientists and organizations such as the Federation of American Societies for Experimental Biology and International Society for Stem Cell Research responded. A majority of them emphasized the importance of hESCs in research as well as clinical applications, urging NIH to lift the pause on registering new hESC lines and pushing for continued investment in research using these cells.
Curtailing hESC research is “a mistake,” said Arnold Kriegstein, a neurologist and neuroscientist who studies neural stem cell and embryonic cortical development at the University of California, San Francisco. He is also the cofounder of a biotech company called Neurona, which is testing hESC-derived therapy in clinical trials. “[It’s] going to impair and slow down research in this country,” Kriegstein said.
Tenneille Ludwig, who oversees the banking, distribution, and characterization services of stem cells—including hESCs—at WiCell Research Institute, agreed. “I was very surprised [about the RFI],” she said. She also expressed concern that the framing of the RFI gave the impression that the NIH is looking for alternatives to hESCs. “The reality is, these cell lines are not replaceable. They’re biologically significant and very unique,” she said.
Revisiting the Basics as Stem Cell Science Evolves
There were a few reasons the NIH decided to re-evaluate hESCs’ utility in science research. “As a steward of taxpayer dollars, it is critical that NIH routinely reassesses long-standing research approaches to determine their relevance and value in today’s rapidly evolving scientific landscape,” an NIH spokesperson wrote to The Scientist in an email.
With this goal, NIH sought to identify research where hESCs are no longer needed, especially given the emergence of newer technologies such as human induced pluripotent stem cells.
Both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are undifferentiated pluripotent stem cells: They can undergo self-renewal and give rise to all cells of the body. Scientists first obtained hESCs from blastocysts, a type of early-stage embryonic tissue, in 1998, laying the foundation for using human pluripotent stem cells for research and clinical use.1
In 2006, in Nobel Prize-winning work, scientists showed that adult mouse skin cells could be reprogrammed into iPSCs using a concoction of four transcription factors dubbed the Yamanaka factors.2 Building on this, stem cell biologists successfully generated human iPSCs (hiPSCs) by reprogramming adult human skin cells into an undifferentiated, pluripotent state. This bypassed the need for using embryos and embryonic stem cells to generate pluripotent stem cells.
Since then, scientists all over the world have generated thousands of hESC and hiPSC lines. These have not only advanced the understanding of developmental biology but have also paved the way for regenerative medicine to treat a wide array of conditions, including diabetes, blindness, neurodegenerative disorders, and cardiovascular diseases.3
hiPSCs Gain Momentum and Surge Ahead
While initial research focused on hESCs, hiPSCs soon caught up, since this method of generating pluripotent stem cells bypassed the controversial need for using embryonic cells. Over time, the number of registered hiPSC lines has far surpassed those of registered hESCs.
Globally, the number of registered human embryonic stem cell (hESC) lines has largely plateaued over the last decade, while the number of human induced pluripotent stem cell (hiPSC) lines has increased significantly. Consistently, there has been a decline in the number of cell lines submitted for review to be added to the NIH hESC Registry, with the last approved cell line added in December 2023.
Designed by Erin Lemieux. Data from hPSCreg (https://hpscreg.eu/news)
In fact, according to NIH, the number of hESC lines submitted for review to be added to the NIH hESC Registry has declined in the past few years. The last approved cell line was added to the registry in December 2023. Consistent with this, NIH-supported research using hiPSC lines has steadily increased over time while NIH support for hESCs has plateaued since 2019.
“Informed by these trends, NIH paused its review and approval of new hESC lines to be added to the NIH Registry while it assesses public feedback,” the NIH spokesperson said.
However, Ludwig contested this being a rationale behind reviewing the cells’ utility. “Simply because new groups are not generating [hESC] lines and putting them on the registry doesn't mean that they're not still using them in their laboratories,” she said.
Kriegstein agreed, adding, “It is very nearsighted and self-defeating to say that because there are…fewer [NIH-funded] labs working on it now than there were years ago, that it doesn't need to be done anymore.” He added that banning hESC use in federally funded research would disrupt all NIH labs working on these cells, and “the impact on the field [would be] very large.”
hESCs Versus hiPSCs: The Ethical Debates and Fundamental Differences
Given that obtaining hESCs involves destroying human embryos, hESC research has always been embroiled in ethical and political issues.4 “So, my first reaction [to the first hiPSCs in 2007] was, ‘Oh, that's fantastic! We've solved the ethical problem,’” said Christine Mummery, a developmental biologist whose work at Leiden University focuses on both iPSCs and hESCs. So, when she saw the RFI, she was initially happy. “But I still had this, sort of, niggling doubt,” she said.
One of the factors at the root of this was the fact that iPSCs cannot be considered as a replacement for hESCs because the two cell types are fundamentally different. While both the cell types are pluripotent, “You can distinguish ESCs from iPSCs at the genome level,” said Mummery. “As long as you can do that, it means they're not the same.”
To Ludwig, however, ethics driving this RFI did not strike a chord. “The materials that have been approved by the US federal government are only materials that are left over from [in vitro fertilization] programs,” she said. “Personally, I view hESC research and the extraction of those cells to generate tissues [as work] that may in the future save lives.”
However, hESCs continue to be entangled in ethical debates due to their tissue of origin. Despite this dilemma, these cells are particularly useful to some researchers studying embryonic tissue. Rowan Karvas, who studies the development of the placenta at the University of Colorado Anschutz, is one of them. “If I were to utilize an iPSC model, I'd really like to be able to have…that embryonic stem cell next to it as a control, as a benchmark [of pluripotency],” she said.
Stem cell researchers also note that hESCs are the gold standard for pluripotency, offering the closest representation of natural, unmodified human pluripotency in vitro. In contrast, reprogramming cells to make them pluripotent involves epigenetic remodeling. As a result, Karvas said using iPSCs would always lead her to wonder whether what her team observes in an iPSC model is due to their experiment or due to the epigenetic changes.
Given this scientific background, Karvas admitted that the NIH RFI surprised her. “We already cannot use federal funds towards deriving the cells,” she said. Researchers have to rely on funding from other sources to obtain hESCs, and using NIH grants for their research requires them to use approved cell lines in the NIH registry. “Basically [the RFI] will prevent us from being able to submit any new lines,” she said. She added that the registry being closed to new submissions means that scientists from outside the US would not be able to add any new cell lines to the registry either, limiting NIH-funded American scientists from using those cell lines.
While NIH support for research using hESC lines has plateaued, the funding for hiPSC research is steadily increasing.
Designed by Erin Lemieux. Data from https://report.nih.gov/funding/categorical-spending#/
hESCs Remain Critical in Clinical Trials
The ability of pluripotent stem cells to repair damaged tissues in the body by differentiating into various cell types paved the way for their therapeutic use. Since the first clinical trial using human pluripotent stem cells began in 2010, new clinical trials have emerged every year.5
Given the modifications, such as the addition of oncogenes, required to generate hiPSCs, scientists were unsure about the cells’ safety for clinical use. “[We believed] it would be much safer to deal with an [hESC] line that wasn't engineered, wasn't artificially induced to become pluripotent,” said Kriegstein.
As a result, the majority of clinical trials—including one testing an hESC-derived cell therapy that Kriegstein helped develop—until 2019 relied on hESCs.6 Kriegstein noted that with the development of improved methods for inducing pluripotency yielding safer options, scientists have been turning to hiPSCs and hiPSC-derived material for clinical trials. However, he added that most stem cell trials currently advancing to the clinic are based on hESCs.
“There are currently clinical trials in Phase 3 that are going exceptionally well that use these materials,” agreed Ludwig. By cutting access to hESCs through federal funding, “You run the risk of disrupting some of these advanced clinical trials,” she added.
While pulling NIH funding for hESC research would not affect Kriegstein directly, he is uncertain about what this would mean for important basic research into these cells as well as for FDA approval for hESC-based therapies.
Mummery added that while generating patient-specific iPSCs is a promising therapeutic approach, the logistics behind it are really expensive. For instance, a project that derived five hiPSC lines cost her institute one million Euros. Given this, she believes that the inability to use hESCs for therapies would halt important clinical trials that are underway. “The cost alone would be prohibitive,” she said.
According to Karvas, it is still important to continue investment in better characterizing iPSCs for clinical use to ensure that even patients who have any misgivings about receiving hESC-based therapy have an alternative. “NIH is ultimately taxpayer dollars being funneled into our labs. We're generating hopefully the cures of the future with this money,” she said.
Scientists Urge NIH Not to Abandon hESC Research Yet
To Karvas, a potential ban on NIH funding for hESC research seems counterintuitive. “NIH has already put so much investment into these lines,” she said. The majority of this funding has also gone into sequencing and characterizing the cell lines. “It [would be] almost such a waste to now be limited and not able to be able to use them,” she said.
While she appreciated the fact that NIH took steps to gather public opinion about hESCs in research, she hopes that the agency takes the scientists’ feedback seriously.
Ludwig agreed, adding that she hopes that scientists are able to highlight the utility of hESCs. “They're irreplaceable as a scientific tool,” she said. A ban on using these cells through federal funding would prevent scientists from accessing “the most commonly used, the most well-characterized…cell lines that are now showing some of the most promise in clinical trials,” she said.
Despite her initial excitement regarding the potential change, Mummery said she hopes NIH does not go ahead with it. “Ethically, it would be good to move to iPSCs, but given the safety, the cost, and the fact that [hESCs] have been characterized for a much longer time than iPSCs, [I have] mixed feelings,” she said.
According to her, stem cell scientists must characterize iPSCs at a deeper level before revisiting the question of whether hESCs can be replaced. “The time for going over to iPSCs, in my opinion, is not there yet,” she said. “Not saying it never will be, but I think it's premature to take this on.”
- Thomson JA, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145-1147.
- Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-676.
- Romito A, Cobellis G. Pluripotent stem cells: Current understanding and future directions. Stem Cells Int. 2016;2016:9451492.
- Baldwin T. Morality and human embryo research. Introduction to the Talking Point on morality and human embryo research. EMBO Rep. 2009;10(4):299-300.
- Kirkeby A, et al. Pluripotent stem-cell-derived therapies in clinical trial: A 2025 update. Cell Stem Cell. 2025;32(1):10-37.
- Carpenter MK, Ludwig TE. Pluripotent stem cell lines available for use in clinical applications: A comprehensive overview. Stem Cell Reports. 2026;21(1):102741.
