Abstract 158: Assessing the Paracrine Hypothesis in Cardiac Regeneration Through Endogenous c-Kit+ Cells

Abstract

Multiple studies have shown an innate capacity of the adult mammalian heart to partially regenerate following stress or injuries such as myocardial infarction (MI). However, this modest capacity is insufficient to resolve the significant damage that occurs post-MI, thus efforts have centered on bolstering this regenerative potential by delivery of various stem or progenitor cell types. To-date, over fifty clinical trials have evaluated cell-based therapeutics to induce regeneration in the setting of ischemic heart disease - mostly using bone marrow mononuclear cells (BM-MNCs) although c-Kit⁺ cardiac progenitor cells (CPCs) and mesenchymal stromal cells (MSCs) from bone were also evaluated. Collectively, cell therapy has demonstrated clinical safety; yet overall effectiveness has been questioned, as evidence that transplanted cells differentiate into cardiomyocytes is lacking. Hence, studies showing some functional benefit have ascribed it to enhanced endogenous regeneration via paracrine factors secreted by the implanted cells. One hypothesis is that these factors stimulate resident c-Kit⁺ progenitors to generate new myocardium. We recently developed an inducible genetic system to trace endogenous c-Kit⁺ cells in the murine heart. We now use this system to evaluate whether delivery of different progenitor-like cell types can enhance c-Kit⁺-derived myocyte or vessel formation in the uninjured heart; using a dual-reporter strategy to differentially fate map transplanted cells versus endogenous c-Kit⁺ cells. We observed that BM-MNCs induced a modest increase in c-Kit⁺-derived, CD31⁺ vessels proximal to the site of injection, although no new myocytes were observed. There was no evidence for fusion between BM-MNCs and host myocardium, or for prolonged engraftment, as by 6 weeks virtually all injected cells were cleared. Taken together, this suggests that BM-MNCs are capable of inducing an acute c-Kit⁺-mediated vascular response in the uninjured heart. We are also currently evaluating CPCs, bone marrow or adipose-derived MSCs, and bone stromal cells for their capacity to stimulate c-Kit⁺ cells, either without injury or after MI. Our goal is to better define the paracrine hypothesis, improving cell-based therapies for application in humans.