Grant: Foundation Grant

In retinal degenerative diseases, the progressive loss of the light-sensing photoreceptor cells eventually leads to blindness. Cell-based therapies are generating excitement for the treatment of retinal degeneration, as they offer the potential to restore vision. But this approach still faces major challenges. Photoreceptor cells are highly specialized neurons and generating them from stem cells remains inefficient. While some improvement was made in recent years to increase rod photoreceptor production from various populations of stem cells, the generation of a large number of cone photoreceptors, essential for daylight vision, remains a challenge. Our hypothesis to explain this limited success is that current protocols do not take into consideration the intrinsic identity of stem cell-derived progenitors. As in normal retinal development, we believe that stem cell-derived retinal progenitors have an intrinsic temporal identity that restricts their competence to generate specific populations of cell types produced during a given time window. Cone photoreceptors, for example, are produced at early stages during retinal development, whereas rod photoreceptors are produced late. Understanding how progenitors change over time to switch from cone-producing phase to a rod-producing phase is essential towards improving cell replacement protocols. We posit that manipulating the temporal identity of stem cell-derived retinal progenitors will increase cone production, which could be used for grafting or disease modelling. We will test this idea using human embryonic stem cell-derived retinal progenitors and provide mechanistic insights on how temporal identity is regulated in retinal progenitors during retinal development using mouse models. We will also test whether temporal factors can be used to reprogram retinal glial cells into photoreceptors, which would bypass the need for costly stem cell culture and grafting by stimulating endogenous regeneration.