Non-neuronal cell microenvironment control retinal vascular remodeling by CST3 in the oxygen-induced retinopathy in mice.

Retinopathy of prematurity (ROP) remains the leading cause of blindness in premature infants owing to abnormal retinal blood vessels development,but molecular mechanisms are still not fully elucidated. Oxygen-induced retinopathy (OIR) mouse is the extensively used angiogenesis model for the study of ROP pathogenesis. In this study, we investigated five cell types that composed the microenvironment of retinal vessels in OIR mice by single-cell RNA sequencing (scRNA-seq) and revealed a complex and time-dependent regulation of vascular arrest and angiogenesis in the OIR microenvironment. Importantly, we also observe that Müller glia exhibit robust expression of CST3 (cysteine protease inhibitor cystatin C) during the early phase of hypoxic adaptation, leading to capillary morphogenesis in the hyaloid, disrupting physiological vascular patterning and contributing to OIR development. Altogether, our study reveals pivotal roles of the retinal microenvironment in both normal vascularization and ROP progression, suggesting that CST3 is a potential therapeutic target for ROP.