Cardiac Myocyte Cell Cycle Control in Development, Disease, and Regeneration

Abstract

Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle soon after birth in mammals. Although the extent to which adult cardiac myocytes are capable of cell cycle reentry is controversial and species-specific differences may exist, it appears that for the vast majority of adult cardiac myocytes the predominant form of growth postnatally is an increase in cell size (hypertrophy) not number. Unfortunately, this limits the ability of the heart to restore function after any significant injury. Interest in novel regenerative therapies has led to the accumulation of much information on the mechanisms that regulate the rapid proliferation of cardiac myocytes in utero, their cell cycle exit in the perinatal period, and the permanent arrest (terminal differentiation) in adult myocytes. The recent identification of cardiac progenitor cells capable of giving rise to cardiac myocyte-like cells has challenged the dogma that the heart is a terminally differentiated organ and opened new prospects for cardiac regeneration. In this review, we summarize the current understanding of cardiomyocyte cell cycle control in normal development and disease. In addition, we also discuss the potential usefulness of cardiomyocyte self-renewal as well as feasibility of therapeutic manipulation of the cardiac myocyte cell cycle for cardiac regeneration.

Engineered Early Embryonic Cardiac Tissue Increases Cardiomyocyte Proliferation by Cyclic Mechanical Stretch via p38-MAP Kinase Phosphorylation

“…17 p38-mitogen-activated protein kinase (p38MAPK) is a highly conserved signal transduction molecule that mediates extracellular signals to a variety of intracellular responses. p38MAPK has been extensively studied in postnatal CM growth (hypertrophy) and survival.…”

Molecular regulation of autophagy and apoptosis during ischemic and non-ischemic cardiomyopathy

“…This, coupled with the detection of cardiac progenitor cells each suggest the exciting possibility of myocyte self-renewal, recently reviewed in refs. [7][8][9] However, the number of independent replicative events appears to be low and the ability to re-populate the injured myocardium with exogenous pluripotent stem cells remains tentative at best. The imbalance of cell loss vs. cell regeneration is believed to be a contributing factor and underlying cause of ventricular remodeling and heart failure.…”

Cell death in the pathogenesis and progression of heart failure

“…The term 'mitotic catastrophe' defines cell death which occurs in mitosis as a mechanism avoiding genetic instability [4,37,38]. Since the extent to which adult cardiac myocytes are capable of cell cycle reentry is controversial and species-specific differences may exist [39] presently, a discussion on 'mitotic catastrophe' is beyond the scope of this spotlight issue.…”