Ischemic heart failure (IHF) remains the leading cause of death in patients over age 65, despite advancements in interventions and medical therapy. Cellular cardiomyoplasty using mesenchymal stem cells (MSCs) has been shown to be a viable strategy for limiting LV remodeling following MI and/or regenerating necrotic myocardium. At the same time, there is a growing body of literature to suggest that endogenous mechanisms of stem cell mediated myocardial repair become defective with age and that this may limit the application of cellular cardiomyoplasty to the population most in need. Preliminary results from our group show that MSCs delivered intravenously dramatically improve post-MI structure and function in young, but not old, rats. We propose a series of experiments to study this defect further by characterizing the efficacy of the four primary stem-cell-related treatment strategies in an aging rat model of permanent coronary artery occlusion. We will investigate the following therapies 1) stem cells (MSC) injected intravenously post-MI 2) administration of a cytokine cocktail (G-CSF/SCF) over the first week after MI 3) stem cells plus cytokines delivered simultaneously 4) direct injection of stem cells into the left ventricle immediately after MI. These experiments will help to identify which treatment strategy is most effective in the aging heart. They will also help to identify whether there are age-related defects in stem cell mobilization, homing, engraftment and/or survival. In a second series of experiments we will further investigate these defects at the cellular and molecular level by determine age-related differences in the differentiation of MSCs at the infarct, their anti-apoptotic effects on surrounding tissues and the expression levels of two proposed injury signals (nitric oxide and SDF-1) by the native myocardium. In the last step we will further investigate targets for counter-measures that may be useful in improving MSC engraftment and survival in old animals towards that seen in young. We will test which injury signals are required for MSCs homing and we will conduct a trial using the cytokine erythropoietin to enhance MSC survival at the infarct in old rats. Taken together, our studies will help guide the development of age-specific treatment strategies employing cellular cardiomyoplasty.
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