Scientists say they have found a long–sought-after population of stem cells in the retina of human fetuses that could be used to develop therapies for one of the leading causes of blindness. The use of fetal tissue, a source of ethical debate and controversy in some countries, likely wouldn’t be necessary for an eventual therapy: Transplanting similar human cells generated in the lab into the eyes of mice with retinal disease protected the animals’ vision, the team reported this week in Science Translational Medicine.
“I see this as potentially a very interesting advancement of this field, where we are really in need of a regenerative treatment for retinal diseases,” says Anders Kvanta, a retinal specialist at the Karolinska Institute who was not involved in the work. He and others note that more evidence is needed to show the therapeutic usefulness of the newly described cells.
The retina, a layer of light-sensing tissue at the back of the eye, can degenerate with age or because of an inherited condition such as retinitis pigmentosa, a rare disease that causes gradual breakdown of retinal cells. Hundreds of millions of people worldwide are affected by retinal degeneration, and many suffer vision loss or blindness as a result. Most forms can’t be treated.Scientists have long seen a potential solution in stem cells, which can regenerate and repair injured tissue. Several early-stage clinical trials are already evaluating the safety and efficacy of transplanting stem cells derived from cell lines established from human embryos, for example, or adult human cells that have been reprogrammed to a stem-like state. Other approaches include transplanting so-called retinal progenitor cells (RPCs)—immature cells that give rise to photoreceptors and other sorts of retinal cells—from aborted human fetuses.
Some researchers have argued that another type of cell, sometimes referred to as retinal stem cells (RSCs), could also treat retinal degeneration. These cells’ long lifespans and ability to undergo numerous cells divisions could make them better candidates to regenerate damaged tissue than RPCs. RSCs have been found in the eyes of zebrafish and some other vertebrates, but evidence for their existence in mammals has been controversial. Reports announcing their discovery in adult mice in the early 2000s were later discounted.
Since then, methods to identify individual cell types in delicate tissues such as the retina have improved, notes biomedical researcher Jianzhong Su, a co-author on the new paper and a biomedical researcher at Wenzhou Medical University. In the new work, he and his colleagues precisely measured individual cells’ gene expression in eye samples from fetuses donated after terminated pregnancies. They found a distinct population of cells that differed from previously described RPCs, and, when grown in a dish, could rapidly proliferate and develop into various other retinal cells. The team dubbed them human neural retinal stem-like cells (hNRSCs).The team also explored whether hNRSCs could be produced without using fetal tissue. China has not had the same divisive debates about the medical use of fetal tissue as the United States and some other countries—President Donald Trump’s administration banned research using cells from aborted fetuses, for example—but such tissue remains a rare and ethically sensitive resource.
The researchers studied human retinal organoids, tiny balls of cells derived from embryonic cell lines that develop into 3D retinalike structures in a dish. Sure enough, there were cells within those organoids whose gene expression was very similar to that of hNRSCs. When transplanted into the eyes of mice with a condition resembling retinitis pigmentosa, these human cells generated RPCs and other cell types in the retina over the course of roughly 4 months, the team found. What’s more, mice that got transplants scored better on a virtual reality vision test than mice that had a sham procedure, suggesting their retinal degeneration had abated.
Majlinda Lako, a stem cell scientist at Newcastle University, says the findings resolve the earlier debate in this field by showing retinal stem cells exist in humans, at least in early development. She suggests the work has “significant implications for regenerative medicine and cell-based therapies for retinal degenerative disease.”
But some researchers remain skeptical. Michael Dyer, a developmental neurobiologist at St. Jude Children’s Research Hospital whose research contradicted those early reports of mouse retinal stem cells and who has also highlighted flaws in several retinal transplantation studies, says he needs to see more evidence that hNRSCs are distinct from RPCs. Future studies will also have to confirm that hNRSCs “are in fact integrating and functionally restoring vision in the murine models of retinal degeneration.”
Su argues his team has provided extensive evidence that hNRSCs are indeed stem cells. And he says they could offer a good alternative to the experimental cell-based therapies currently being explored for retinal degeneration: They are better at self-renewing than RPCs, and it’s easier to make the organoid-derived versions than to reprogram mature cells to a stem-like state.
Kvanta agrees hNRSCs could have some therapeutic advantages. For example, they may be less likely than some cell therapies derived from reprogrammed adult cells to form tumors, though the risk is thought to be low for any of these strategies. Still, studies comparing the approaches are needed to establish which is best, he says.
Su and his colleagues are now working to improve their methods of growing and transplanting hNRSCs, and testing their effects in larger animals such as monkeys. Such work, he says, provides “a critical bridge to future clinical trials.”
