The mechanism by which cell therapy improves cardiac function remains unclear. Although injected cells minimally differentiate into cardiomyocytes or vessels, and only a small fraction survive long term in the recipient, common beneficial effects are observed regardless of injected cell type: improvement in pump function, reduction of fibrosis, and enhanced angiogenesis. These results are consistent with the idea that cell therapy recruits endogenous repair mechanisms which, however, have not been identified. The immune system has been implicated in a variety of sterile diseases, including processes regulating myocardial damage and repair. Although unresolved inflammatory processes controlled by infiltrating and tissue-resident immune cells worsen heart failure, depletion of macrophages in the infarcted myocardium leads to LV rupture and death. Thus, immune cells appear to play diametrically opposite roles in the heart. Macrophages have been shown to be required for spontaneous regeneration of neonatal mammalian myocardium after injury, and recent findings implicate them as direct contributors to cell therapy-mediated myocardial repair. Nevertheless, how immune cells regulate myocardial repair and what determines their harmful versus salutary actions remains unknown. Furthermore, the impact of cell therapy on reparative immune cells has not yet been studied in the heart. Our preliminary data show that injection of cardiac mesenchymal cells (CMCs) into the infarcted heart promotes accumulation of reparative macrophages. Thus, the central hypothesis of this proposal is that CMCs facilitate recruitment of monocytes and activation of reparative macrophages, which are essential endogenous mediators of repair. By generating detailed flow cytometric analyses of immune cell populations following CMC administration, we will not only resolve the time course of immune cell recruitment, but also determine how inflammation is eventually extinguished in the heart after cell therapy. To elucidate the mechanism whereby CMCs regulate inflammatory processes in monocyte-derived macrophages, we will determine how these cells regulate NF?B-p65 subunit expression, with emphasis on horizontal transfer of miRNAs to macrophages through CMC-derived EVs. Finally, using macrophage genetic fate mapping and genetically modified CMCs, we will elucidate the role of monocyte-derived macrophages in CMC-induced myocardial repair. This project will be the first systematic analysis of how cell therapy modulates immune cells ? a mechanism that has been relatively understudied. The results will provide novel insights not only into the mechanisms regulating cell therapy-mediated myocardial repair, but also into how endogenous reparative activities of macrophages are recruited. We will also determine whether EVs recapitulate the salutary effects of CMCs on immune cells. Thus, these studies have far-reaching implications for our understanding of how the immune system regulates myocardial homeostasis in general.
PROJECT 2 NARRATIVE The immune system is an important component of myocardial repair after myocardial infarction. In this project, we will examine how CMC treatment affects the immune system and delineate strategies to improve cell therapy for patients with heart failure.
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