Cardiomyocyte proliferation, a target for cardiac regeneration

Abstract

Cardiac diseases, characterized by cardiomyocyte loss, lead to dramatic impairment of cardiac function and ultimately to congestive heart failure. Despite significant advances, conventional treatments do not correct the defects in cardiac muscle cell numbers and the prognosis of congestive heart failure remains poor. The existence, in adult mammalian heart, of low but detectable cardiomyocyte proliferative capacities has shifted the target of regenerative therapy toward new therapeutical strategy. Indeed, the stimulation of terminally differentiated cardiomyocyte proliferation represents the main therapeutic approach for heart regeneration. Increasing evidence demonstrating that the loss of mammalian cardiomyocyte renewal potential shortly after birth causes the loss of regenerative capacities, strongly support the hypothesis that a detailed understanding of the molecular mechanisms controlling fetal and postnatal cardiomyocyte proliferation is essential to identify targets for cardiac regeneration. Here, we will review major developmental mechanisms regulating fetal cardiomyocyte proliferation and will describe the impact of the developmental switch, operating at birth and driving postnatal heart maturation, on the regulation of adult cardiomyocyte proliferation, all these mechanisms representing potential targets for cardiac repair and regeneration.

RUNX1: an emerging therapeutic target for cardiovascular disease

“… 143–145 Understanding the developmental mechanisms of cardiomyocyte proliferation and regeneration and how these are altered in the adult heart may therefore be a crucial step towards the identification of reparative pathways that could be harnessed to improve cardiac regeneration in the future. 146 Indeed, a recent study has provided promising evidence that stimulation of endogenous cardiomyocyte proliferation programmes in large mammals is a valid approach to facilitate cardiac repair by increasing myocardial mass and contractility after MI. 147 …”

Metabolic Determinants in Cardiomyocyte Function and Heart Regenerative Strategies

“…Indeed, fetal, neonatal, and adult hearts exhibit very specific expression patterns of cardiomyocyte proliferation regulators, including gene expression, cell cycle regulators, metabolic and signaling pathways, extracellular matrix proteins and growth factors. As expected, manipulating these factors has become a strategy to force adult cardiomyocytes to re-enter the cell cycle [90,91]. Several studies have focused on the overexpression of cyclins to force mammalian (particularly mouse) cardiomyocytes to re-enter the cell cycle.…”

“…The re-entry of cardiomyocytes into the cell cycle has become one of the employed strategies to regenerate cardiac tissue (for review, see [90,91]) (Figure 3a). Indeed, fetal, neonatal, and adult hearts exhibit very specific expression patterns of cardiomyocyte proliferation regulators, including gene expression, cell cycle regulators, metabolic and signaling pathways, extracellular matrix proteins and growth factors.…”

DAND5 Inactivation Enhances Cardiac Differentiation in Mouse Embryonic Stem Cells

“…From inherited cardiomyopathies, myocardial infarction to oncological treatments, the causes for cardiomyocyte death are vast, and its regeneration scarce or null (Leone et al, 2015;Yuan and Braun, 2017). The natural replication of cardiomyocytes is present during mammalian embryo and fetus development, but stops irreversibly within the first weeks of postnatal life (Payan et al, 2020). Cardiac development starts on both sides of the embryo, with cells from the heart-forming regions migrating from the anterior region of the primitive streak to the midline, forming the heart tube (Buckingham et al, 2005;Kelly et al, 2014;Meilhac et al, 2015).…”