Direct Reprogramming of Skin Cells into Photoreceptors to Restore Light Sensitivity in Mice

Researchers here demonstrate a direct form of cellular reprogramming, converting skin cells directly into another cell type without going through intermediary stages of induced pluripotency and differentiation. In this case the goal is to produce patient-matched photoreceptor cells to treat retinal degeneration. Proof of concept is demonstrated in blind mice that exhibit restored light sensitivity following treatment. The degree to which vision can be restored via this approach is an open question - that is much harder to assess in mice. In principle this type of reprogramming should be much more efficient, but it remains to be seen as to which approaches to building sources of patient-matched cells will emerge first into widespread clinical practice.

Up until now, researchers have replaced dying photoreceptors in animal models by creating stem cells from skin or blood cells, programming those stem cells to become photoreceptors, which are then transplanted into the back of the eye. In the new study, scientists show that it is possible to skip the stem-cell intermediary step and directly reprogram skins cells into photoreceptors for transplantation into the retina.

Scientists have studied induced pluripotent stem (iPS) cells with intense interest over the past decade. IPSCs are developed in a lab from adult cells and can be used to make nearly any type of replacement cell or tissue. But iPS cell reprogramming protocols can take six months before cells or tissues are ready for transplantation. By contrast, the direct reprogramming described in the current study coaxed skin cells into functional photoreceptors ready for transplantation in only 10 days. The researchers demonstrated their technique in mouse eyes, using both mouse- and human-derived skin cells.

Direct reprogramming involves bathing the skin cells in a cocktail of five small molecule compounds that together chemically mediate the molecular pathways relevant for rod photoreceptor cell fate. The result are rod photoreceptors that mimic native rods in appearance and function. The researchers performed gene expression profiling, which showed that the genes expressed by the new cells were similar to those expressed by real rod photoreceptors. At the same time, genes relevant to skin cell function had been downregulated.

The researchers transplanted the cells into mice with retinal degeneration and then tested their pupillary reflexes. Within a month of transplantation, six of 14 (43%) animals showed robust pupil constriction under low light compared to none of the untreated controls. Moreover, treated mice with pupil constriction were significantly more likely to seek out and spend time in dark spaces compared with treated mice with no pupil response and untreated controls. Preference for dark spaces is a behavior that requires vision and reflects the mouse's natural tendency to seek out safe, dark locations as opposed to light ones.



I think that since the eye is immune privileged we could have mass-produced more or less universal retinal cells ready for transplantation. Of course , it has to work.

Posted by: cuberat at May 4th, 2020 12:26 PM

I am only 46 years old and i have macular edema. I dont have diabetes. I have undergone 5 avastin eye injections. My last injection was january this year. My doctor advised me to have laser treatment but was not able to do so because of the covid outbreak. Right now i am experiencing dry eyes (accordingly because of my menopausal) making my eyes itchy and sticky. I am sad because my vision has not improved. I am hopeful with this new breakthrough. Pls update me because I am interested. Thank you.

Posted by: Ailine Daral at June 16th, 2020 8:54 PM
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