MAPK/ERK signalling mediates VEGF-induced bone marrow stem cell differentiation into endothelial cell.
MAPK/ERK signalling mediates VEGF-induced bone marrow stem cell differentiation into endothelial cell.
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DOI：
10.1111/j.1582-4934.2008.00266.x
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发表时间：
2008-12
影响因子：
5.3
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Xu J;Liu X;Jiang Y;Chu L;Hao H;Liua Z;Verfaillie C;Zweier J;Gupta K;Liu Z
多能成体祖细胞（MAPCs）在血管内皮生长因子（VEGF）的存在下分化为内皮细胞（ECs）。VEGF诱导MAPCs分化为EC的机制尚不清楚。因此，我们研究了丝裂原活化蛋白激酶/细胞外信号调节激酶（p42/44-MAPK/ERK 1/2）信号在骨髓干细胞内皮分化中的作用。我们观察到MAPCs的VEGF刺激14天导致内皮特异性基因和/或蛋白质的显著表达，包括血管性血友病因子（vWF）、血管内皮钙粘蛋白（VE-钙粘蛋白）、VEGF受体-2（VEGFR 2）和CD 31。EC特异性标志物的上调伴随着鹅卵石形态、内皮型一氧化氮合酶（eNOS）表达和Dil-Ac-LDL摄取，这是EC形态和功能的典型特征。在MAPCs分化过程中，VEGF诱导p42 MAPK/ERK持续激活，而p44 MAPK/ERK不激活，并呈时间依赖性，最长可达14 d。VEGF诱导的p42 MAPK/ERK的激活也导致MAPK/ERK 1/2的核转位。MAPK/ERK 1/2磷酸化抑制剂PD 98059可阻断VEGF诱导的MAPK/ERK 1/2磷酸化及其核转位。PD 98059对MAPK/ERK 1/2磷酸化的抑制也阻断了这些细胞中EC特异性基因的表达及其向EC的分化。这些数据表明，VEGF诱导MAPC分化为EC通过a. MAPK/ERK 1/2信号通路介导的体外机制。
Multi-potent adult progenitor cells (MAPCs) differentiate into endothelial cells (ECs) in the presence of vascular endothelial growth factor (VEGF). The mechanism(s) of VEGF-induced differentiation of MAPCs to ECs are not yet known. We, therefore, examined the role of mitogen-activated protein kinase/extracellular signal-regulated kinase (p42/44-MAPK/ERK1/2) signalling in endothelial differentiation from bone marrow stem cells. We observed that VEGF stimulation of MAPCs for 14 days results in a significant expression of endothelial-specific gene and/or proteins including von Willebrand factor (vWF), vascular endothelial-cadherin (VE-cadherin), VEGF receptor-2 (VEGFR2), and CD31. Up-regulation of EC-specific markers was accompanied by a cobblestone morphology, expression of endothelial nitric oxide synthase (eNOS), and Dil-Ac-LDL uptake, typical for EC morphology and function. VEGF induced a sustained activation of p42 MAPK/ERK, but not that of p44 MAPK/ERK during the course of MAPCs differentiation in a time-dependent manner up to 14 days. VEGF-induced activation of p42 MAPK/ERK also led to the nuclear translocation of MAPK/ERK1/2. Incubation of MAPCs with MAPK/ERK1/2 phosphorylation inhibitor PD98059 blocked the sustained VEGF-induced MAPK/ERK1/2 phosphorylation as well as its nuclear translocation in the differentiating MAPCs. Inhibition of MAPK/ERK1/2 phosphorylation by PD98059 also blocked the expression of EC-specific genes in these cells and their differentiation to ECs. These data suggest that VEGF induces MAPC differentiation into EC via a. MAPK/ERK1/2 signalling pathway-mediated mechanism in vitro.