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MAPK/ERK signalling mediates VEGF‐induced bone marrow stem cell differentiation into endothelial cell

Journal of Cellular and Molecular Medicine (Impact Factor: 3.7). 02/2008; 12(6a):2395 - 2406. DOI: 10.1111/j.1582-4934.2008.00266.x

ABSTRACT 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.

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    • "ERK MAP kinase is traditionally thought to lie at the heart of signaling networks that govern proliferation, differentiation , and cell survival (Kolch, 2000). For progenitor cells, similar ERK activation profiles have been described for IL-6 and EPCs (Fan et al, 2008) and for VEGF-induced endothelial differentiation (Xu et al, 2008). "
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    • "ency marker Oct - 4 expression correlated with the endothelial differentiation potential of MAPCs in vitro ( Luttun et al . , 2005 ; Ulloa - Montoya et al . , 2007 ) . In a recently published study , we found that Oct - 4 expression was decreased dramatically at the very early phase when MAPCs were induced to differentiate into endothelial cells ( Xu et al . , 2008 ) . Our finding that NO increases Oct - 4 expressions in bone marrow stem cells suggests that NO may be important to maintaining their plu - ripotency . Recently , Danalache et al . ( 2007 ) showed that NO synthase inhibitor N , G - nitro - L - arginine - methyl - ester decreased the expression of anti - stage specific embryonic antigen"
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