Stage-Associated Microglial Subpopulations and Dynamics in Vascular Pathogenesis of Oxygen-Induced Retinopathy

Retinal neovascularisation (RNV) is manifested in various retinal pathological conditions, often leading to irreversible blindness. The oxygen-induced retinopathy (OIR) mouse model proves to be a useful tool for understanding RNV pathogenesis. In this model, retinal vascular phenotype undergoes two distinct stages: neovascular formation, followed by spontaneous regression. While microglial functions in the neovascular formation stage have been extensively studied, their behaviors and roles during regression remain unclear. In this study, we characterise the spatiotemporal dynamics and molecular heterogeneity of retinal microglia across both stages. During RNV formation, microglia exhibit an outer-to-inner and central-to-midperipheral migration pattern, whereas a reversed migration trend is observed during regression. We confirm a highly glycolytic microglia (HGM) subpopulation during RNV formation and demonstrate its pro-angiogenic role by targeting a highly expressed pyruvate kinase M2 (Pkm2), a crucial enzyme for glycolysis. Importantly, we find that microglia exhibit enhanced phagocytic activity during regression, constituting a distinct phagocytosis-associated microglia (PAM) subtype, expressing mannose receptor C-type 1 (Mrc1/CD206). Altogether, our findings reveal stage-specific microglial functional dynamics, providing novel insights into RNV pathogenesis and intervention.