Vascular endothelial growth factor stimulates endothelial differentiation from mesenchymal stem cells via Rho/myocardin-related transcription factor-A signaling pathway
Vascular endothelial growth factor stimulates endothelial differentiation from mesenchymal stem cells via Rho/myocardin-related transcription factor-A signaling pathway
复制标题
血管内皮生长因子通过 Rho/心肌素相关转录因子 A 信号通路刺激间充质干细胞向内皮分化
DOI：
10.1016/j.biocel.2013.04.021
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发表时间：
2013-07-01
影响因子：
4
通讯作者：
Zhang, Tong-Cun
中科院分区：
文献类型：
--
作者：
Wang, Nan;Zhang, Rui;Zhang, Tong-Cun
间充质干细胞（MSC）是多能祖细胞，可以分化成多种细胞类型。血管内皮生长因子（VEGF）是启动和调节血管生成的主要因子之一。据报道，VEGF可诱导MSCs分化为内皮细胞(ECs)。然而，VEGF诱导MSC分化的机制尚不完全清楚。在这里，我们发现 VEGF 诱导人和大鼠骨髓来源的 MSC 分化为 EC。 Rho家族在VEGF诱导的内皮细胞迁移和血管生成中发挥重要作用。我们的结果表明，在 MSC 中，VEGF 激活 Rho/ROCK 信号通路并促进心肌素相关转录因子-A (MRTF-A) 的核转位，这是由 Rho/ROCK 信号传导控制的。此外，Rho抑制剂0转移酶、ROCK抑制剂Y27632或内源性MRTF-A的消耗消除了VEGF诱导的MSC向EC的分化。此外，VEGF还增强了CYR61/CCN1的表达水平，作为血管发育和血管生成的调节剂，内源性MRTF-A的敲低可减少VEGF诱导的CYR61/CCN1的上调。对 CYR61/CCN1 启动子进行定点突变分析的报告表明，MRTF-A 主要依赖 CArG 盒反式激活 CYR61/CCN1 启动子。在这项研究中，我们确定 Rho/MRTF-A 信号通路是控制 VEGF 诱导人和大鼠骨髓来源的 MSC 分化为内皮细胞的主要因素。 (C) 2013 Elsevier Ltd. 保留所有权利。
Mesenchymal stem cells (MSCs) are pluripotent progenitors that can differentiate into a variety of cell types. Vascular endothelial growth factor (VEGF) is one of the major factors of initiating and regulating angiogenesis. It has been reported that VEGF can induce MSCs differentiated into endothelial cells (ECs). However, the mechanism that VEGF-induced MSC differentiation is not completely understood. Here, we showed that VEGF induced human and rat bone marrow-derived MSCs differentiation to ECs. Rho family plays an important role in VEGF-induced endothelial cell migration and angiogenesis. Our results indicated that in MSCs, VEGF activated Rho/ROCK signaling pathway and promoted nuclear translocation of myocardin-related transcription factor-A (MRTF-A), which is controlled by Rho/ROCK signaling. In addition, Rho inhibitor 0 transferase, ROCK inhibitor Y27632 or depletion of endogenous MRTF-A abolished the VEGF-induced differentiation of MSCs into ECs. Furthermore, VEGF also enhanced the expression levels of CYR61/CCN1, as a regulator of vascular development and angiogenesis, and knockdown of endogenous MRTF-A reduced VEGF-induced the upregulation of CYR61/CCN1. Report assays with site-direct mutation analysis of CYR61/CCN1 promoter demonstrated that MRTF-A transactivated CYR61/CCN1 promoter mainly depending on CArG box. In this study, we identify the Rho/MRTF-A signaling pathway as a main actor in controlling VEGF-induced differentiation of human and rat bone marrow-derived MSCs into endothelial cells. (C) 2013 Elsevier Ltd. All rights reserved.