Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling.
Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling.
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DOI：
10.1161/circresaha.110.235531
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发表时间：
2011-06-10
影响因子：
20.1
通讯作者：
Tallquist MD
中科院分区：
文献类型：
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作者：
Smith CL;Baek ST;Sung CY;Tallquist MD
在早期心脏发育中，血小板衍生生长因子（PDGF）受体在心脏心室的表达仅限于心外膜。先前，我们发现PDGFRβ是冠状血管平滑肌细胞（cVSMC）发育所必需的，但PDGFRα的作用尚未确定。因此，我们研究了这些受体在心外膜发育中的联合和独立作用。了解PDGF受体在心外膜发育和心外膜来源细胞命运决定中的作用。通过产生心外膜PDGF受体特异性缺失的小鼠，我们发现心外膜EMT存在缺陷。Sox9是一种sry相关的转录因子，在PDGF受体缺失的心外膜细胞中减少，Sox9的过表达恢复了心外膜迁移、肌动蛋白重组和EMT基因表达谱。心外膜EMT失败导致心脏缺乏心外膜源性心脏成纤维细胞和cVSMC。PDGFRα的缺失导致心脏成纤维细胞发育的特异性中断，而cVSMC的发育未受干扰。通过两种PDGF受体的信号传导对于心外膜EMT和心外膜间质衍生物的形成是必要的。PDGF受体在特定心外膜源性细胞命运的发展中也具有独立的功能。
In early heart development, platelet derived growth factor (PDGF) receptor expression in the heart ventricles is restricted to the epicardium. Previously, we showed that PDGFRβ is required for coronary vascular smooth muscle cell (cVSMC) development, but a role for PDGFRα, has not been identified. Therefore, we investigated the combined and independent roles of these receptors in epicardial development. To understand the contribution of PDGF receptors in epicardial development and epicardial derived cell fate determination. By generating mice with epicardial specific deletion of the PDGF receptors, we found that epicardial EMT was defective. Sox9, an SRY-related transcription factor, was reduced in PDGF receptor-deficient epicardial cells, and overexpression of Sox9 restored epicardial migration, actin reorganization, and EMT gene expression profiles. The failure of epicardial EMT resulted in hearts that lacked epicardial-derived cardiac fibroblasts and cVSMC. Loss of PDGFRα, resulted in a specific disruption of cardiac fibroblast development, while cVSMC development was unperturbed. Signaling through both PDGF receptors is necessary for epicardial EMT and formation of epicardial mesenchymal derivatives. PDGF receptors also have independent functions in the development of specific epicardial derived cell fates.