Abstract

Myocardial infarction is underoxygenation-driven limited necrosis of heart tissues which results in elimination of ca. 0.5 to 1 billion spontaneously contracting cardiomyocytes (CM). Since the ability of human heart to regenerate is limited, efforts have been undertaken to increase the number of cardiomyocytes in post-infarction myocardium. Theoretically, such proposals might involve transplantation of 1) skeletal myoblasts and cardiomyocytes, or 2) progenitor/stem cells, theoretically capable of differentiating into cardiomyocytes, or 3) pluripotent cells such as embryonal stem cells (ESC) and induced pluripotent stem cells (iPSC) differentiating into cardiomyocytes. The efforts to increase CM could also involve 4) in situ reprogramming of fibroblasts into active cardiomyocyte-like cells, or 5) stimulating in situ proliferation of cardiomyocytes using pharmacological agents. Only three proposals merit closer scrutiny (2, 4 and 5). However, preclinical and clinical data have demonstrated weak ability of progenitor cells to differentiate (proposal 2). Nevertheless, transplanted cell-induced paracrine effects accompanying such therapy do improve functioning of the damaged heart muscle. The proposals that would permit the number of CM to be increased include in situ reprogramming of fibroblasts into active cardiomyocytes (proposal 4), as well as in situ stimulation of quiescent cardiomyocytes’ proliferation (proposal 5). It appears that an optimized therapeutic solution (increasing left ventricular ejection fraction and decreasing the post-infarct scar) might combine agents stimulating paracrine effects and reprogramming of fibroblasts.

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