Researchers restore sight in mice by turning skin cells into light-sensing eye cells

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Researchers restore sight in mice by turning skin cells into light-sensing eye cells

Researchers have discovered a technique for directly reprogramming skin cells into light-sensing rod photoreceptors used for vision, sidestepping the need for stem cells. The lab-made rods enabled blind mice to detect light after the cells were transplanted into the animals' eyes.

Researchers have discovered a technique for directly reprogramming skin cells into light-sensing rod photoreceptors used for vision. The lab-made rods enabled blind mice to detect light after the cells were transplanted into the animals' eyes. The work, funded by the National Eye Institute (NEI), published April 15 in Nature. The NEI is part of the National Institutes of Health. 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 -- rather than fetal tissue -- 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, which is a measure of photoreceptor function after transplantation. Under low-light conditions, constriction of the pupil is dependent on rod photoreceptor function. 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. Three months after transplantation, immunofluorescence studies confirmed the survival of the lab-made photoreceptors, as well as their synaptic connections to neurons in the inner retina. Further research is needed to optimize the protocol to increase the number of functional transplanted photoreceptors.

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