String Theory of c-kitpos Cardiac Cells: A New Paradigm Regarding the Nature of These Cells That May Reconcile Apparently Discrepant Results

摘要

Although numerous preclinical investigations have consistently demonstrated salubrious effects of c-kit^pos cardiac cells administered after myocardial infarction, the mechanism of action remains highly controversial. We and others have found little or no evidence that these cells differentiate into mature functional cardiomyocytes, suggesting paracrine effects. In this review, we propose a new paradigm predicated on a comprehensive analysis of the literature, including studies of cardiac development; we have dubbed this conceptual construct “string theory of c-kit^pos cardiac cells” because it reconciles multifarious and sometimes apparently discrepant results. There is strong evidence that, during development, the c-kit receptor is expressed in different pools of cardiac progenitors (some capable of robust cardiomyogenesis and others with little or no contribution to myocytes). Accordingly, c-kit positivity, in itself, does not define the embryonic origins, lineage capabilities, or differentiation capacities of specific cardiac progenitors. C-kit^pos cells derived from the first heart field (FHF) exhibit cardiomyogenic potential during development, but these cells are likely depleted shortly before or after birth. The residual c-kit^pos cells found in the adult heart are probably of proepicardial origin, possess a mesenchymal phenotype, and are capable of contributing significantly only to non-myocytic lineages (fibroblasts, smooth muscle cells, endothelial cells). If these two populations (FHF and proepicardium) express different levels of c-kit, the cardiomyogenic potential of FHF progenitors might be reconciled with recent results of c-kit^pos cell lineage tracing studies. The concept that c-kit expression in the adult heart identifies epicardium-derived, non-cardiomyogenic precursors with a mesenchymal phenotype helps to explain the beneficial effects of c-kit^pos cell administration to ischemically damaged hearts despite the observed paucity of cardiomyogenic differentiation of these cells.