Noncanonical TGFβ Signaling Promotes Specialized Neuroretina Tip-Cell Sprouting and Blood-Retina Barrier Formation

Endothelial tip cells guiding tissue vascularization are primary targets for angiogenic therapies. Whether tip cells require differential signals to develop their complex branching patterns remained unknown. Here we show that tip cells invading the neuroretina (D-tip cells) are distinct from tip cells guiding the superficial plexus (S-tip cells). D-tip cells have a unique transcriptional signature, display blood-retina barrier properties and TGFβ signaling requirements. Endothelial deletion of TGFβ receptor I (ALK5) inhibits D-tip cell differentiation and diving vessels. ALK5 endothelial deficiency results in a dysfunctional S-like tip cell molecular signature, aberrant contractile pericytes, and hemorrhagic vascular malformations, while SMAD mutants do not develop this phenotype. Oxygen-induced retinopathy retinas exhibit S-like tip cells with increased Alk5 signaling, and Alk5 deletion impedes retina revascularization. Our data reveal stage-specific tip cell heterogeneity as a requirement for retinal vascular development and suggest that noncanonical-TGFβ signaling could improve retinal revascularization and neural function in ischemic retinopathy.