Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
Centre de Recherche, CHU St. Justine, Montréal, QC H3T 1C5, Canada.
Dev Cell. 2021 Aug 9;56(15):2237-2251.e6. doi: 10.1016/j.devcel.2021.06.021. Epub 2021 Jul 16.
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.
内皮细胞尖端细胞引导组织血管生成，是血管生成治疗的主要靶点。尖端细胞是否需要不同的信号来发展其复杂的分支模式仍然未知。在这里，我们表明，侵入小鼠神经视网膜的潜水尖端细胞（D-尖端细胞）与引导浅层视网膜血管丛的尖端细胞（S-尖端细胞）不同。D-尖端细胞具有独特的转录特征，包括高水平的 TGF-β 信号转导，并且它们开始获得血视网膜屏障特性。内皮细胞中 TGF-β 受体 I（Alk5）的缺失抑制了 D-尖端细胞的特征获得和深层血管丛的形成。内皮细胞中 ALK5 的缺失，而不是经典的 SMAD 效应物的缺失，导致异常收缩性周细胞分化和出血性血管畸形。氧诱导的视网膜病变血管表现出 S 样尖端细胞，而 Alk5 的缺失会阻碍视网膜再血管化。我们的数据揭示了特定阶段的尖端细胞异质性是视网膜血管发育的要求，并表明非经典-TGF-β 信号可能改善缺血性视网膜病变中的视网膜再血管化和神经功能。
