Blocking apoptosis promotes survival and alters developmental dynamics of human retinal ganglion cells in retinal organoids.

Retinal ganglion cells (RGCs) are the projection neurons connecting the retina to the brain. In many species, a substantial proportion of RGCs are eliminated by programmed cell death during development to regulate their final number, but how cell death impacts human RGC development remains poorly understood. Here, we characterized cell death in human fetal retinas and retinal organoids. Both retinas and organoids exhibited two waves of apoptosis: an early wave targeting neurogenic retinal progenitor cells and neuronal precursors and a late wave affecting RGCs and other neurons. Additionally, organoids displayed a distinct wave of necrosis. Blocking apoptosis in organoids via BAX/BAK double knockout improved RGC survival but delayed RGC neurogenesis and maturation. Our results highlight the roles of apoptosis in human RGC development and the challenges in retinal organoid design. Addressing these limitations will improve the utility of organoids for studying human retinal development and modeling optic neuropathies such as glaucoma.