Eyeworld

EW NEWS & OPINION 14 November 2015 suppressor gene, Dr. Dyer reported, adding that this has worked for all the different types of retinal neurons that they have tried. "We haven't tried neurons from different parts of the brain, but I suspect that it would be the same for other kinds of neurons," he said. Others have previously shown that epigenetic memory is import- ant here. The way the DNA is coiled up is part of that memory, Dr. Dyer explained. "We did a whole series of studies to try to figure out what the details of the epigenetic memory are in the stem cells from the retina versus those from the fibroblast," he said. "What we think is going on is that there are some components of the memory that are permissive of making retina." However, there's also a repressive component from those stem cells made from other types of tissue. Skin stem cells were prevented from making some neu- rons in the retina that were missing, Dr. Dyer thinks. New standards In addition, investigators spent 1.5 years developing a set of standard measurements called STEM-RET. Dr. Dyer described this as a compre- hensive, stepwise scoring system to tell investigators if they are mak- ing good early retina that continue to grow and ultimately result in a complete, mature retina. This STEM-RET system will allow individual labs to compare differ- ent stem cell lines so that they are all talking the same language, he explained. "I hope that the retina and the vision field will adopt this as the clinical development moves forward and people start thinking about what are the best stem cells to use," Dr. Dyer concluded. EW Editors' note: Dr. Dyer has no financial interests related to this article. Contact information Dyer: frannie.marmorstein@stjude.org by Maxine Lipner EyeWorld Senior Contributing Writer Indeed, investigators found that retina made from the rod photore- ceptor was better overall than that made from skin stem cells, Dr. Dyer said. "Not only were they better but the retinas were different," he said, adding that the retinas made from the skin cells were missing some of the needed retinal neuron types. However, initially investigators were unsure whether they could even take a retinal neuron such as a rod photoreceptor and make this into a stem cell. "No one had done that before," Dr. Dyer said. "The only time anyone had made stem cells from any kind of neuron be- fore, it didn't work." To get these to reprogram into stem cells in the first place, investigators had to mutate a very important tumor suppressor gene, he explained, adding that this is not a great strategy for making stem cells because it involves knock- ing out a gene that can promote tumor genesis. "We wanted to know if we can reprogram the retinal neuron without knocking out that gene," he said. Investigators found that they were able to do this using a different approach. It takes about 2 weeks for cells to go through the reprogram- ming process necessary to become stem cells. "If you just take a neuron and put it in a dish all by itself and wait 2 weeks and hope that it reprograms, it can't," Dr. Dyer said. "It will die before it gets a chance to reprogram." This is because neurons like to be around other neurons and not in a culture dish alone. Investigators here tried to preserve the neuron environment during the reprograming process. "What we do is purify the program- mable cells, but before we start reprogramming them, we mix them with other neurons from the reti- na," he said. "Those neurons can't reprogram; they're just there to keep them alive while they reprogram." With these other neurons in place in a 3-D culture, investigators found that it was indeed possible to grow the stem cells from rod photorecep- tors without knocking out the tumor Considering epigenetic memory "Typically, they use skin fibroblasts, reprogram these into stem cells, and those can be used to make retinal cells," he said. "But the truth is that it's not clear if retina made from stem cells that came from skin are the same as retina made from other sources." More specifically, some investigators have shown that stem cells can remember just where they came from, Dr. Dyer continued. "Stem cells made from the skin have memory that they came from the skin, and stem cells made from blood cells remember that they came from blood," he said, adding that this is called epigenetic mem- ory. One question that investigators wanted to tackle was the impact of epigenetic memory on the ability of a stem cell to make retina. Inves- tigators were trying to understand whether a cell derived from skin as well as one from some other sources could make retinal cells. "I think that this will be very important long term to help us sort out what is going to be the best stem cell pop- ulation for individuals who might benefit from stem cell therapy," Dr. Dyer said. Differences between stem cell types found D oes it matter where a ret- inal stem cell for treating degenerative disease such as macular degeneration or retinitis pigmentosa comes from in the body? Investi- gators have found that there can indeed be a difference. Research published in an issue of Cell Stem Cell reveals which type of stem cell might be better for treating retinal degeneration, according to Michael Dyer, PhD, investigator, Howard Hughes Medical Institute, and member of developmental neurobi- ology, St. Jude Children's Research Hospital, Memphis. One of the challenges inves- tigators face with such therapy is that the stem cells need to come from the individual him- or herself, Dr. Dyer pointed out, adding that if these are taken from someone else, the patient's immune system might reject them. What investiga- tors want to do is make stem cells from the patient into retinal cells or pigmented cells to support the particular disease and then put them back into the individual's eye, he explained. Stemming the retinal degeneration tide James Xiang Chen, PhD and Dan Hiler, PhD look on as Dr. Dyer explains how stems cells are extracted. Source: St. Jude Children's Research Hospital/Peter Barta

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