Article ID Journal Published Year Pages File Type
2094582 Stem Cell Research 2014 17 Pages PDF
Abstract

•S1P increased mouse ES cell proliferation in S1P1/3-dependent manner.•S1P stimulated the signaling complex between S1P1/3 and Flk-1.•S1P enhanced Flk-1 transactivation and VEGF synthesis in mouse ES cell.•S1P-induced Flk-1 transactivation stimulated ERK and JNK phosphorylation.•S1P stimulated proliferation through VEGF-dependent/-independent Flk-1 activation.

Although recent findings showed that the bioactive lipid metabolites can regulate the ES cell functions, the physiological relevance of interaction between sphingosine-1-phosphate (S1P) and Flk-1 and its related signaling molecules are not yet clear in ES cell proliferation. In the present study, S1P1–5 receptors were expressed in mouse ES cells and S1P increased S1P1–3 receptor expression level. S1P treatment stimulated the cellular proliferation in S1P1/3-dependent manner, located in lipid rafts. In response to S1P, β-arrestin was recruited to S1P1/3 receptor and c-Src was activated. S1P also increased the binding of S1P1/3 receptor with Flk-1. Similar to responses for VEGF, S1P increased Flk-1 phosphorylation, which was blocked by β-arrestin siRNA, and PP2, but not by VEGF-A164 antibody or VEGF siRNA. In addition, S1P induced VEGF expression and VEGFR2 kinase inhibitor (SU1498) blocked the S1P-induced cellular proliferation. However, VEGF-A164 antibody or VEGF siRNA partially blocked S1P-induced cellular proliferation, suggesting that both VEGF-dependent Flk-1 activation and VEGF-independent Flk-1 activation are involved in S1P-induced ES cell proliferation. S1P and VEGF-induced phosphorylation of ERK and JNK were blocked by pretreatment with SU1498. Moreover, inhibition of ERK and JNK blocked S1P-induced cellular proliferation. In conclusion, S1P-elicited transactivation of Flk-1 mediated by S1P1/3-dependent β-arrestin/c-Src pathways stimulated mouse ES cell proliferation.

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