Prerequisite endocardial-mesenchymal transition for murine cardiac trabecular angiogenesis.
Prerequisite endocardial-mesenchymal transition for murine cardiac trabecular angiogenesis.
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DOI：
10.1016/j.devcel.2023.03.009
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发表时间：
2023-05-08
影响因子：
11.8
通讯作者：
Zhou, Bin
中科院分区：
文献类型：
--
作者：
Lu, Pengfei;Wu, Bingruo;Wang, Yidong;Russell, Megan;Liu, Yang;Bernard, Daniel J.;Zheng, Deyou;Zhou, Bin
冠心病对心肌小梁有损伤作用，心肌小梁血管再生可减轻缺血性损伤。然而，小梁血管的起源和发育机制仍然未知。在这里，我们表明，小鼠心室内膜细胞产生小梁血管通过“血管EMT”机制。时间进程的命运映射定义了一个特定的波的小梁血管化的心室内膜细胞。单细胞转录组学和免疫荧光鉴定了一个心室内膜细胞亚群，这些细胞在产生小梁血管之前经历了心内膜间质转化（EMT）。离体药理学激活和体内遗传失活实验确定了涉及SNAI 2-TGFB 2/TGFBR 3的心室内膜细胞中的EMT信号，这是后来小梁血管形成的先决条件。其他功能丧失和获得的遗传学研究表明，VEGFA-NOTCH 1信号通过心室内膜细胞调节EMT后小梁血管生成。我们发现，小梁血管起源于心室内膜细胞通过两步血管EMT机制，可以为冠心病提供更好的再生药物。Lu等人在小鼠心脏的小梁和致密心肌中发现了两种冠状血管形成波。他们的工作发现，小梁血管起源于心室内膜细胞，并表征了该过程的两步血管EMT机制，这可能为冠心病提供更好的再生药物。
Coronary heart disease damages the trabecular myocardium, and the regeneration of trabecular vessels may alleviate ischemic injury. However, the origins and developmental mechanisms of trabecular vessels remain unknown. Here, we show that murine ventricular endocardial cells generate trabecular vessels through an “angioEMT” mechanism. Time course fate mapping defined a specific wave of trabecular vascularization by ventricular endocardial cells. Single-cell transcriptomics and immunofluorescence identified a subpopulation of ventricular endocardial cells that underwent endocardial-mesenchymal transition (EMT) before these cells generated trabecular vessels. Ex vivo pharmacological activation and in vivo genetic inactivation experiments identified an EMT signal in ventricular endocardial cells involving SNAI2-TGFB2/TGFBR3, which was a prerequisite for later trabecular-vessel formation. Additional loss- and gain-of-function genetic studies showed that VEGFA-NOTCH1 signaling regulated post-EMT trabecular angiogenesis by ventricular endocardial cells. Our finding that trabecular vessels originate from ventricular endocardial cells through a two-step angioEMT mechanism could inform better regeneration medicine for coronary heart disease. Lu et al. identify two waves of coronary-vessel formation at trabecular and compact myocardium of the murine heart. Their work finds that trabecular vessels arise from ventricular endocardial cells and characterizes a two-step angioEMT mechanism underlying the process that may inform better regeneration medicine for coronary heart disease.
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