Resident human cardiac stem cells: role in cardiac cellular homeostasis and potential for myocardial regeneration.

Current treatments for myocardial infarction have significantly reduced the acute mortality of ischemic cardiomyopathy. This reduction has resulted in the survival of a large cohort of patients left with a significant 'myocyte deficit'. Once this deficit leads to heart failure there is no available therapy to improve long-term cardiac function. Recent developments in stem cell biology have focused on the possibility of regenerating contractile myocardial tissue. Most of these approaches have entailed the transplantation of exogenous cardiac-regenerating cells. Recently, we and others have reported that the adult mammalian myocardium, including that in humans, contains a small pool of cardiac stem and progenitor cells (CSCs) that can replenish the cardiomyocyte population and, in some cases, the coronary microcirculation. The human CSCs (hCSCs) are involved in maintaining myocardial cell homeostasis throughout life and participate in remodeling in cardiac pathology. They can be isolated, propagated and cloned. The progeny of a single cell clone differentiates in vitro and in vivo into myocytes, smooth muscle and endothelial cells. Surprisingly, in response to different forms of stress, hCSCs acquire a senescent, dysfunctional phenotype. Strikingly, these nonfunctional CSCs constitute around 50% of the total CSC pool in older individuals-those most likely to be candidates for hCSC-based myocardial regeneration. Therefore, the challenge to develop clinically effective therapies of myocardial regeneration is twofold: to produce the activation of the hCSCs in situ in order to obviate the need for cell transplantation, and to elucidate the mechanisms responsible for hCSC senescence in order to prevent or reverse its development.