Abstract 15491: Myocardial Infarction-Induced Mobilization of Bone Marrow-Endothelial Progenitor Cells is Modulated By IL-10 Signaling and is Influenced by SDF1-CXCR4 Signaling Axis
Endothelial progenitor cells (EPC) transplantation has been shown to enhance neovascularization and improve myocardial infarction (MI)-induced ventricular dysfunction. However, EPC mobilization, survival and function in the injured myocardium is adversely influenced by pro-inflammatory cytokine response, thereby compromising full benefits of EPC-mediated myocardial repair. We hypothesized that modulation of IL-10 signaling in EPCs influences their mobilization, survival and function in ischemic myocardium after MI. Myocardial infarction (MI)-induced mobilization of bone marrow EPC (Sca1+Flk1+ cells) into the circulation was higher in WT-mice as compared to IL-10 KO-mice (P<0.05). Bone marrow transplantation (BMT) to replace IL-10 KO-marrow with WT-marrow attenuated these effects. Expression of SDF-1 in the myocardium following MI was higher in WT-mice as compared to KO-mice. In vitro, CoCl2-induced hypoxia increased CXCR4 expression in EPCs, which was lower in IL-10 KO-EPC as compared to WT-EPC. Furthermore hypoxia-induced (CoCl2) apoptosis in EPCs was higher in IL-10 KO-EPCs as compared to WT-EPCs. IL-10 treatment induced VEGF expression in WT-EPCs which was abrogated by STAT3 inhibition (using curcurbitacin I). To further study the effect of IL-10 on in vivo EPC survival and engraftment into vascular structures, GFP-labeled EPC were injected intramyocardially after induction of MI, and the mice were treated with either saline or recombinant IL-10. IL-10 treatment enhanced EPC survival (reduced cell death) and engraftment into the vascular structure. The above findings were corroborated with reduced infarct size, fibrosis and enhanced LV function (echocardiography) in IL-10+EPC group as compared to EPC+saline group. Furthermore, microRNA (miR) profile experiments identified significant increases in a number of pro-apoptotic and anti-angiogenic-related miRs in EPCs from IL-10 deficient mice. Taken together, our studies demonstrate that IL-10 enhances EPC mobilization possibly in an SDF1-CXCR4-dependent manner and increased their survival and neovascularization and the associated myocardial repair, in part via activation of STAT3 signaling cascades.
- © 2011 by American Heart Association, Inc.