Whale Müller glia create a permissive environment supporting retinal ganglion cell survival and neurite outgrowth

Summary: The adult central nervous system has limited regenerative capacity, with retinal ganglion cells (RGCs) particularly refractory to repair. The extracellular glial environment can critically influence neuronal survival and regenerative responses. Here, using cross-species co-culture, conditioned-medium approaches, quantitative proteomics, and functional perturbation, we characterize a Müller glial phenotype from large baleen whales that supports RGC survival and neurite extension. Whale Müller glia enhanced neuronal viability and neurite elongation compared with pig and rat Müller glia. Proteomic analyses revealed species-dependent differences in conditioned-medium composition, including greater abundance of mesencephalic astrocyte-derived neurotrophic factor (MANF) in whale conditioned medium and detection of the axon-repulsive protein fibronectin leucine-rich transmembrane protein 2 (FLRT2) in pig conditioned medium. FLRT2 suppression combined with MANF enhanced neurite outgrowth in a subset of cells within RGC-enriched cultures only in the presence of Müller glia. These findings identify glia-dependent molecular signals associated with a permissive retinal environment supporting neuronal survival and neurite outgrowth.