Improvement of human donor retinal ganglion cell survival through modulation of microglia

Stem cell–derived retinal ganglion cell (RGC) transplantation offers a potential strategy to restore vision in patients with severe RGC loss, but donor cell survival remains a key challenge. Here, we show that host retinal microglia and macrophages play a pivotal role in the rejection, acceptance, and survival of human donor RGCs. To identify therapeutic targets in microglia–RGC interactions, we compiled single-cell atlases of the mouse retina across development, aging, maturation, and neurodegenerative conditions. Pathway analysis highlighted phagocytosis, neuroinflammation, and other mechanisms associated with microglial activation and RGC damage, which we hypothesized also drive donor cell clearance. We demonstrate that pretreating human stem cell–derived RGCs with annexin V and/or soluble Fas ligand before transplantation increases donor cell survival by 2.5-fold and promotes axonal outgrowth toward the optic nerve head. Post-transplantation analysis revealed microglial and macrophage activation morphologies consistent with neuroinflammation. These results indicate that annexin V and soluble Fas ligand can enhance neuronal transplantation outcomes in the retina and potentially in the broader central nervous system.