Programming Retinal Stem Cells into Cone Photoreceptors

In this grant, we sought to investigate the mechanisms that regulate the earliest events in cone photoreceptor development and to exploit this knowledge to program human stem cells directly into cones. Using RNA-seq, we identified several genes that are upregulated in advance of the earliest photoreceptor gene, Otx2. Two of these genes appeared to promote Otx2 expression in the developing mouse retina. These results provided a key link between what is occurring in retinal stem cells and the gene network expressed in nascent cone photoreceptors. We also found that transiently delivering the mRNA for three transcription factors promoted cone photoreceptor formation in retinal stem cells derived from human embryonic stem cells. These results are an important first step towards generating synchronized cone photoreceptor populations in the dish that could be used therapeutically to reverse vision loss.