Clinical translation of cell therapy has been hindered by i) lack of understanding of basic mechanisms, and ii) borderline or inconsistent results in clinical trials. The overarching objective of this renewal application is to directly address these two problems; specifically, to advance our understanding of the mechanism of action of cell therapy and to develop strategies that optimize its therapeutic efficacy. We will focus on cardiac mesenchymal cells (CMCs), a promising new population of heart-derived cells that we have recently discovered and that appears to be particularly suitable for clinical translation. Four closely inter-related and inter-dependent Projects will address different facets of this theme. Project 1 (Bolli) will carefully evaluate the use of repeated treatments to maximize therapeutic benefit, including translational studies in a preclinical porcine model. The central hypothesis is that repeated administrations of CMCs dramatically increase the beneficial effects of cell therapy via repetitive bursts of extracellular vesicle (EV) release. Project 2 (Wysoczynski) will elucidate the role of immune cells in mediating the beneficial effects of cell therapy and test the hypothesis that CMCs and EVs facilitate recruitment of monocytes and activation of reparative macrophages, which are endogenous mediators of repair. Project 3 (Jones) will illuminate the role of the stromal compartment (including fibroblast activation and hyaluronan metabolism) in the reparative actions of CMCs and EVs and identify and correct defects in CMCs rendered incompetent by heart failure (HF). The overarching hypothesis is that CMCs attenuate remodeling by favorably enhancing hyaluronan metabolism, which is defective in HF. Project 4 (Bhatnagar) will determine how diabetes affects CMC-mediated myocardial repair and how CMC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetes compromises the therapeutic efficacy of CMCs by increasing glycolysis, which alters paracrine mechanisms, and that Sirt1 improves CMC repair capacity by decreasing glycolysis. Thus, all four Projects focus cohesively on CMCs. These Projects will be supported by four Cores that will provide expertise in mouse and pig surgery, cell transplantation, CMC culture and phenotyping, pathology, flow cytometry, and cell sorting. This highly- focused PPG will be led by investigators who have collaborated productively for many years. Their long history of collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. Throughout the four Projects, the effects of CMCs will be systematically compared with those of EVs. These will be the first studies to systematically examine the effects of repeated doses and the role of immune and stromal cells, glycolysis, and Sirt1 in the salubrious effects of cell therapy; thus, the results will be entirely new. The pig studies (3 Projects) will lay the groundwork for translational investigations of CMC therapy in patients with HF. This PPG may generate disruptive new knowledge, including two new therapeutic paradigms (repeated treatments and use of cell-free EV products), either of which, in itself, would revolutionize cell therapy.
The goal of this application is to study cardiac mesenchymal cells (CMCs), a promising new population of heart-derived cells that we have recently discovered and that appears to be particularly suitable for clinical application. The overall objective of this renewal application is to advance our understanding of the mechanism of action of CMCs and to develop strategies that optimize their efficacy for treating heart failure caused by a heart attack (myocardial infarction). The results of these studies will lay the groundwork for first-in-human clinical trials of CMCs.
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