Cardiomyogenesis in the Adult Heart

Abstract

In recent years, a novel conceptual view has emerged; the heart is no longer considered a post-mitotic organ, but is viewed as an organ permissive for tissue regeneration mediated by exogenous and/or endogenous progenitor cells. One of the major biological controversies of the last decade has involved the plasticity of c-kit-positive bone marrow cells and their ability to acquire cell lineages different from the organ of origin. The possibility that c-kit-positive bone marrow cells can form cardiomyocytes and coronary vessels repairing the injured heart experimentally was accepted with great enthusiasm by cardiologists, resulting in the clinical implementation of bone marrow mononuclear cells in patients with acute and chronic ischemic cardiomyopathy. A series of negative animal studies, however, has challenged the concept of bone marrow cell transdifferentiation. Conflicting results may be attributed to several factors, including differences in the protocol of cell isolation and administration, animal model of cardiac injury, and methodologies employed for the characterization of the restored cardiac tissue. Importantly, these technical variables cannot account entirely for the reported failure of c-kit-positive bone marrow cells to form de novo myocardium after infarction. The molecular and functional heterogeneity commonly observed in hematopoietic stem/progenitor cells imposes the use of clonal assays for the characterization of c-kit-positive bone marrow cells at the single cell level. Population-based analyses of stem cell behavior fall short in the recognition of the mechanisms of replication and commitment that are unique to distinct progenitor cell subsets. Based on this approach, a restricted class of cardiopoietic c-kit-positive bone marrow cells with a specific molecular signature has been identified. These hematopoietic progenitors transdifferentiate into cardiomyocytes, resistance arterioles and capillaries, repairing the infarcted mouse heart. In contrast, the majority of c-kit-positive bone marrow cells retain their hematopoietic fate in vivo and form only occasionally scattered vascular structures. These findings offer a novel understanding of the long-term controversy on the plasticity and therapeutic efficacy of c-kit-positive bone marrow cells