Grant: Project Grant

In retinal degenerative diseases, the progressive loss of retinal cells like the light-sensing photoreceptors eventually leads to blindness. Stem cell based therapies are generating excitement for the treatment of retinal degenerative diseases, but despite recent advances, this approach still faces major challenges. Photoreceptor cells are highly specialized neurons and generating them from stem cells remains inefficient. While some improvement was achieved 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 temporal 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 believe that manipulating the temporal identity of stem cell-derived retinal progenitors could trick them to expand the cone- or rod-producing window. Our general objectives in this project is to 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 normal retinal development. This work is an essential first step to identifying small molecules targeting the temporal identity pathways involved that could be used in stem cell differentiation protocols for replacement therapies.