Summary Cardiovascular diseases like myocardial infarction (MI) are the leading cause of mortality in patients with diabetes. In infarcted heart, efficient clearance of dying cells (called efferocytosis) by activated neighboring phagocytes (primarily infiltrating macrophages) is essential for inflammation resolution and tissue repair. However, improper clearance of dying cells leads to secondary postapoptotic necrosis and therefore may precipitate the transition to heart failure. Our preliminary study demonstrates that diabetic condition impairs efferocytosis of dead cardiomyocytes by macrophages, in vitro and in human diabetic heart as compared to non-diabetics. However, the molecular players in diabetes-mediated defective efferocytosis and its effect on cardiac remodeling and outcome are surprisingly not studied yet. Therefore, studying the mechanisms of diabetes-mediated impairment in efferocytosis of dead cells (specifically cardiomyocytes) and strategies to enhance resolution of inflammation leading to efficient cardiac healing and recovery are clinically relevant and therapeutically novel. In this regard, therapy with paracrine factors (exosomes) from mesenchymal stem cells (MSC), a potent immunomodulator and clinically tested for safety and efficacy in ischemic heart failure patients, holds great promise. However, the effect of MSC and its derivatives on macrophage efferocytosis of cardiomyocytes either with or without diabetes in a small/larger animal model of MI has never been studied so far. Our preliminary data shows that MSC- derived exosomes increase macrophage efferocytosis of dead cardiomyocytes, in vitro. Based on these preliminary data coupled with our published and existing literature, our central hypothesis is that i) diabetes impairs macrophage efferocytosis of dead cardiomyocytes leading to delay in resolution of inflammation and cardiac repair in diabetics, ii) MSC-derived exosomes are enriched in factors (RNA/miRNA/proteins) that promote efferocytosis, therefore iii) intramyocardial delivery of MSC- derived exosomes in a small/large animal model of MI enhances efferocytosis and wound healing leading to efficient regeneration and repair. We will test our hypotheses under the following three aims: Aim 1: Determine the effect of diabetes on clearance of dead cardiomyocyte (efferocytosis) after myocardial ischemic injury. Aim 2: Elucidate the molecular mechanism of MSC-exosome effect on macrophage-mediated efferocytosis. Aim 3: a. Delineate the invivo effect of MSC-exosome on efferocytosis after myocardial infarction a) in mice and b) in a translationally realistic large animal (pig) model of heart failure.