Specialized endothelial tip cells guide neuroretina vascularization and blood-retina-barrier formation

作者：Georgia Zarkada, Joel P. Howard, Xue Xiao, Hyojin Park, Mathilde Bizou, Séverine Leclerc, Steffen Emil Künzel, Blanche Boisseau, Jinyu Li, Gaël Cagnone, Jean Sébastien Joyal, Grégor Andelfinger, Anne Eichmann, Alexandre Dubrac · 发表于：Developmental Cell · 年份：2021 · DOI：10.1016/j.devcel.2021.06.021 · 被引用次数：131 · 研究领域：Retinal Development and Disorders、Barrier Structure and Function Studies、Retinal Diseases and Treatments

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 diving tip cells invading the mouse neuroretina (D-tip cells) are distinct from tip cells guiding the superficial retinal vascular plexus (S-tip cells). D-tip cells have a unique transcriptional signature, including high TGF-β signaling, and they begin to acquire blood-retina barrier properties. Endothelial deletion of TGF-β receptor I (Alk5) inhibits D-tip cell identity acquisition and deep vascular plexus formation. Loss of endothelial ALK5, but not of the canonical SMAD effectors, leads to aberrant contractile pericyte differentiation and hemorrhagic vascular malformations. Oxygen-induced retinopathy vasculature exhibits S-like tip cells, and Alk5 deletion impedes retina revascularization. Our data reveal stage-specific tip cell heterogeneity as a requirement for retinal vascular development and suggest that non-canonical-TGF-β signaling could improve retinal revascularization and neural function in ischemic retinopathy.