Animal and preliminary human studies of adult stem cell therapy, including therapies with endothelial progenitor cells (EPC), for myocardial repair have shown an overall improvement of cardiac function. However, repair of dead or injured myocardium and improvement of cardiac function remains a serious challenge. Emerging evidence from preclinical studies suggests that hostile micro-environment in the infarcted myocardium, including inflammation and oxidative damage, have adverse effects on stem cell survival and function. We have earlier demonstrated that interleukin-10 (IL-10) therapy greatly limits the remodeling in the infarcted myocardium of mice and significantly improves post-infarct cardiac function. Whether IL10 directly alters the biology of EPCs leading to their greater survival and function is not known and warrants an inquiry. The premise of our proposed research is based on our following published and preliminary observations that IL10 therapy: a) attenuates post-MI LV dysfunctions and remodeling, b) enhances the retention and survival of intra-myocardially transplanted EPCs in the ischemic myocardium;c) EPCs from IL-10 knockout mice are defective in number of functional properties, d) enhances neo-vascularization in the border zone of infarcted myocardium by enhancing STAT3-dependent expression of VEGF e) increases EPC-mediated neovascularization in the injured myocardial f) increases VEGF expression in EPC through STAT3, g) enhances ischemia-induced EPC mobilization from bone marrow and h) IL-10 regulates EPC function partly by inhibiting miR 375.These data provide convincing evidence that use of IL- 10 in EPC-and other stem cell based therapies may offer significant advantages, both by attenuating adverse myocardial inflammation and by enhancing survival and function of transplanted stem cells. Our central hypothesis is that IL-10 and the activation of its downstream signal transduction pathways, especially STAT3 activation, enhances mobilization, survival, retention and functional properties of EPCs. The experiments described in the current proposal are designed to extend these findings by testing a series of hypotheses grouped according to the following 3 specific aims: 1) Determine the role of IL-10 on EPC biology and function, 2) Elucidate the molecular and signaling mechanisms of IL-10-mediated EPC biology and function;and 3) Determine the role of IL-10 regulated miR-375 in EPC-mediated myocardial repair.
Certain diseases like myocardial infarction (MI) are the major cause of mortality in humans. IL-10 is a known cardio-protective cytokine that reduces inflammatory response and increases new blood vessel formation in the heart after injury. Interestingly, injured heart recruits bone-marrow derived endothelial progenitor/stem cells (EPC) for repair. However, it is not known how IL-10 enhances the benefits provided by progenitor cells in the injured heart. This proposal will test mechanisms by which IL-10 protects EPC against injured tissue hostile microenvironment in which these cells are injected and study its interaction with other signaling molecules in EPC that may affect their survival, biology and function during experimental heart injury. Since EPCs are currently used in clinical trials of patients with heart diseases and since poor survival of EPC in injured heart is significant barrier to the full benefits to stem cell based therapies, data obtained from proposed studies may potentially be crucial in overcoming these limitations and may directly enhanced the efficacy of EPC-based therapies.
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