A variety of tests showed that the photoreceptors in the retinal sheet matured properly after transplantation, and compared with normal retinal sheets, made better contact with the host eye. With this success, the researchers tested their theory by transplanting the new type of retinal sheet into degenerated rat retinas that lacked almost all photoreceptors. As hoped, the targeted bipolar cells eventually died off, which is what happens when they are not allowed to mature. All the different retinal cell types, particularly the photoreceptors, were present and organized in the correct way. Early on, these retinal sheets developed the same way as those grown from normal stem cells. Then, they grew retinal organoid sheets from these clones. They began with a line of human stem cells and made clones that lacked the ISLET1 gene. The researchers targeted ISLET1, a gene necessary for maturation of bipolar cells that connect to photoreceptors. This allows transplanted photoreceptors to connect better with host bipolar cells. Looking at the bottom right image of each panel, we can see that the new type of retinal sheet lacks bipolar cells. "But it's their very connection to the bipolar cells in the retinal sheet that prevents the photoreceptors from connecting to the bipolar cells in the host." The solution was to engineer retinal sheets that would lose their bipolar cells during the final stages of photoreceptor maturation.Ī view of the retina after transplanting a retinal sheet grown from normal human stem cells (top) or the modified stem cells lacking the ISL1 gene (bottom). "Bipolar cells are inevitably born when the retinal sheet develops properly and photoreceptors mature," says Mandai. But the retinal sheets naturally contain their own bipolar cells. For this regenerative cell therapy to work, the new light receptors in the graft must connect to neurons in the host retina, allowing light from the outside world to be relayed to the brain, which is how we see.īased on their previous studies, the team at RIKEN BDR knew that connecting the grafted sheet to bipolar cells in the host retina is critical. One promising therapy is to replace the part of the retina at the back of the eye with a new retinal sheet, including the photoreceptors, grown from stem cells. Retinitis pigmentosa is a hereditary disease in which photoreceptors in the retina die, leaving people with complete loss of vision or progressive loss in certain spots. The study was published in the scientific journal iScience. Because the retinal sheets were generated from stem cells of human origin, this represents one of the final steps necessary before this technique can be tested in human clinical trials for repairing retinal degeneration. After transplant into damaged mouse retinas, timed removal of certain cells from the grafts allowed better connections to host retinas, which resulted in more responsiveness to light in the damaged eyes. Researchers led by Michiko Mandai at the RIKEN Center for Biosystems Dynamics Research (BDR) in Japan have used a genetic modification to improve human-derived retina transplants grown in the lab. recordings were made from the ganglion cells in response to light (red voltage trace). Host bipolar cells connect to host ganglion cells (top gray cells), which send axons to the brain as the optic nerve. Photoreceptors (peach cells at the bottom) in the graft connect to bipolar cells (graft bipolar cells: green host bipolar cells: pink). The result is that all ganglion cells on the right respond to light, and responses are higher than those on the left. On the right, the graft bipolar cells have died off, and the receptors connect to host bipolar cells (pink). On the left, the transplanted photoreceptors (peach cells) are connected to transplanted bipolar cells (green) as part of the retinal sheet. Retinal sheets were grown from wild type human stem cells (left) or human stem cells missing the ISL1 gene (right). Schematic showing the experimental results.
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