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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL078825-12
Application #
9551407
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Bolli, Roberto; Hare, Joshua (2018) Introduction to a Compendium on Regenerative Cardiology. Circ Res 123:129-131
Gibb, Andrew A; Hill, Bradford G (2018) Metabolic Coordination of Physiological and Pathological Cardiac Remodeling. Circ Res 123:107-128
Hindi, Sajedah M; Sato, Shuichi; Xiong, Guangyan et al. (2018) TAK1 regulates skeletal muscle mass and mitochondrial function. JCI Insight 3:
Mehra, Parul; Guo, Yiru; Nong, Yibing et al. (2018) Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair. Basic Res Cardiol 113:46
Baba, Shahid P; Zhang, Deqing; Singh, Mahavir et al. (2018) Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice. J Mol Cell Cardiol 118:183-192
Fulghum, Kyle; Hill, Bradford G (2018) Metabolic Mechanisms of Exercise-Induced Cardiac Remodeling. Front Cardiovasc Med 5:127
Hosen, Mohammed Rabiul; Militello, Giuseppe; Weirick, Tyler et al. (2018) Airn Regulates Igf2bp2 Translation in Cardiomyocytes. Circ Res 122:1347-1353
Dassanayaka, Sujith; Zheng, Yuting; Gibb, Andrew A et al. (2018) Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload. Redox Biol 17:440-449
Osuma, Edie A; Riggs, Daniel W; Gibb, Andrew A et al. (2018) High throughput measurement of metabolism in planarians reveals activation of glycolysis during regeneration. Regeneration (Oxf) 5:78-86
Lindsey, Merry L; Bolli, Roberto; Canty Jr, John M et al. (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812-H838

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