Abstract 1516: Insulin-Like Growth Factor 1 Enhances the Migratory Capacity of Mesenchymal Stem Cells via CXCR4/SDF Upregulation: Implication for its Anti-Atherosclerotic Effects
Atherosclerosis is a chronic inflammatory disease, and we have recently shown that insulin-like growth factor (IGF-1) infusion, but not sham infusion, significantly reduced atherosclerotic lesion formation, markedly decreased circulating levels of inflammatory cytokines, and increased circulating endothelial progenitor cells (EPC) in an established mouse model of atherosclerosis, ApoE −/ − mice (C57BL6 background). To determine the molecular mechanisms underlying these effects, we isolated and cultured mesenchymal stem cell (MSC) derived from C57BL6 green mice, and found that these MSC expressed high levels of IGF-1 receptor (IGF-1R), Akt and pAkt (western blot), c-kit (flow cytometry), very low levels of VEGFR2 and CD14 (flow cytometry), did not express eNOS protein (western blot) or generate NO as detected by Griess assay. IGF-1 (10 ng/ml, 48 h) reduced MSC inflammatory gene expression (TNF-alpha, ICAM and VCAM) as determined by real-time PCR. Although IGF-1 (10 ng/ml, 0 -48 h) did not stimulate MSC proliferation, IGF-1 increased levels of the chemokine receptor CXCR4 (receptor for stromal cell-derived factor-1α, SDF-1α) as measured by flow cytometry, and increased the levels of matrix metalloproteinase-9 (MMP9) and stem cell factor (SCF) in culture media at 48 h. IGF-1 (0–100 ng/ml) was not chemotactic for MSC, however, IGF-1 markedly increased the migratory response of MSC to SDF-1 but not VEGF. The IGF-1 induced increase in MSC migration in response to SDF-1 was attenuated by PI3 kinase inhibition (LY294002). Our data demonstrate that IGF-1 increases MSC migratory responses via a SDF-1/CXCR4 and MMP9/SCF mediated mechanism which is PI3/Akt dependent. The ability of IGF-1 to increase the migratory capacity of MSC may play a critical role in reparative mechanisms important for the anti-atherosclerotic effects of IGF-1.