Cardiomyocyte Proliferation as a Source of New Myocyte Development in the Adult Heart

Abstract

Cardiac diseases such as myocardial infarction (MI) can lead to adverse remodeling and impaired contractility of the heart due to widespread cardiomyocyte death in the damaged area. Current therapies focus on improving heart contractility and minimizing fibrosis with modest cardiac regeneration, but MI patients can still progress to heart failure (HF). There is a dire need for clinical therapies that can replace the lost myocardium, specifically by the induction of new myocyte formation from pre-existing cardiomyocytes. Many studies have shown terminally differentiated myocytes can re-enter the cell cycle and divide through manipulations of the cardiomyocyte cell cycle, signaling pathways, endogenous genes, and environmental factors. However, these approaches result in minimal myocyte renewal or cardiomegaly due to hyperactivation of cardiomyocyte proliferation. Finding the optimal treatment that will replenish cardiomyocyte numbers without causing tumorigenesis is a major challenge in the field. Another controversy is the inability to clearly define cardiomyocyte division versus myocyte DNA synthesis due to limited methods. In this review, we discuss several studies that induced cardiomyocyte cell cycle re-entry after cardiac injury, highlight whether cardiomyocytes completed cytokinesis, and address both limitations and methodological advances made to identify new myocyte formation.

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.…”

Restoring the Cell Cycle and Proliferation Competence in Terminally Differentiated Skeletal Muscle Myotubes

“…As to the second pillar, the lack of evidence of proliferation cannot exclude that cells might divide under rare or special conditions. As a relevant example, adult cardiomyocytes, long considered postmitotic, are now established as being endowed with a limited but definite proliferative potential [1]. Indeed, there is ample evidence that at least the cell cycle-or even proliferation-can be reactivated in nearly any cell type, in natural or experimental conditions, and that the postmitotic state can no longer be considered irreversible.…”

Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

“…Since the latest findings in inducing cardiomyocyte cell cycle re-entry have been already extensively reviewed elsewhere in this special issue [8,9], here we will summarize the recent progress in the development of innovative therapeutic strategies based on manipulation of cardiac cell fate plasticity in combination with bioengineering and nanotechnology-based approaches for targeting the failing heart.…”