Stem Cells and the Regenerating Heart

In response to functional stress, the heart can increase its muscle mass through cellular hypertrophy, but a damaged heart needs a rapid response to repair damage to the muscle wall and maintain adequate blood flow to the rest of the body. In contrast to the mammalian skeletal muscle that regenerates injured tissue through activation of quiescent myogenic precursor or multipotent adult stem cell populations, the heart does not appear to retain equivalent reserve cell populations to promote myofiber repair. The relative scarcity of progenitor cells residing in the adult myocardium has prompted a search for a renewable source of circulating somatic progenitor cells that might home to the heart in response to damage. The capacity of the heart to regenerate may not be a common attribute shared by all cardiomyocytes. Although longitudinal analyses of single cultured new cardiomyocytes revealed that many cells enter into S phase in response to serum-activated pathways dependent on the phosphorylation of the Rb protein, the majority of these cells stablely arrest at either entry to mitosis or during cytokinesis. After surgical removal of the ventricular apex and rapid clotting at the site of amputation, proliferating cardiac myofibers replace the clot and regenerate missing tissue, with minimal scarring. The requirement for cell cycle reentry in this model is supported by the decreased regeneration and increased fibrosis in a temperature-sensitive mutant of a mitotic checkpoint kinase, mps. It is still formally possible that the activation of cardiac progenitor cells is largely responsible for the extraordinary capacity of the adult zebrafish to restore extensive portions of the heart.