New Myocyte Formation in the Adult Heart: Endogenous Sources and Therapeutic Implications

Abstract

Death of adult cardiac myocytes and supportive tissues resulting from cardiovascular diseases such as myocardial infarction is the proximal driver of pathological ventricular remodeling that often culminates in heart failure. Unfortunately, no currently available therapeutic barring heart transplantation can directly replenish myocytes lost from the injured heart. For decades, the field has struggled to define the intrinsic capacity and cellular sources for endogenous myocyte turnover in pursuing more innovative therapeutic strategies aimed at regenerating the injured heart. Although controversy persists to this day as to the best therapeutic regenerative strategy to use, a growing consensus has been reached that the very limited capacity for new myocyte formation in the adult mammalian heart is because of proliferation of existing cardiac myocytes but not because of the activity of an endogenous progenitor cell source of some sort. Hence, future therapeutic approaches should take into consideration the fundamental biology of myocyte renewal in designing strategies to potentially replenish these cells in the injured heart.

Keywords: cell proliferation; heart failure; myocardial infarction; regeneration; stem cell.

Figure. Therapeutic sources for new myocyte generation in the adult heart

Summary of current and proposed strategies discussed throughout the review that aim to directly replenish cardiac myocytes lost following ischemic injury or in the setting of progressive heart failure. Potential strategies include direct reactivation of the myocyte cell cycle program through genetic or pharmacological manipulations (yellow arrows), reprogramming of non-myocytes by manipulation of cellular states (green dashed arrows), or indirect cell cycle reactivation through myocyte-autonomous or extracellular mechanisms (blue arrow). Therapeutic and mechanistic advantages to each strategy are highlighted, as well as crucial limitations, risks, or other considerations.