Role of Mononuclear Cardiomyocytes in Cardiac Turnover and Regeneration

Abstract

Purpose of Review The typical remodeling process after cardiac injury is scarring and compensatory hypertrophy. The limited regeneration potential of the adult heart is thought to be due to the post-mitotic status of postnatal cardiomyocytes, which are mostly binucleated and/or polyploid. Nevertheless, there is evidence for cardiomyocyte turnover in the adult heart. The purpose of this review is to describe the recent findings regarding the proliferative potential of mononuclear cardiomyocytes and to evaluate their function in cardiac turnover and disease. Recent Findings There is overwhelming evidence from carbon-dating in humans and multi-isotope imaging mass spectrometry in mice that there is a very low but detectable level of turnover of cardiomyocytes in the heart. The source of this renewal is not clear, but recent evidence points to a population of mononuclear, diploid cardiomyocytes that are still capable of authentic cell division. Controversy arises when their role in cardiac repair is considered, as some studies claim that they contribute to repair by cell division while other studies do not find evidence for hyperplasia but hypertrophy. Stimulation of the mononuclear cardiomyocyte population has been proposed as a therapeutic strategy in cardiac disease. Summary The studies reviewed here agree on the existence of a low annual cardiomyocyte turnover rate which can be attributed to the proliferation of mononuclear cardiomyocytes. Potential roles of mononucleated cardiomyocytes in cardiac repair after injury are discussed.

Exercise, programmed cell death and exhaustion of cardiomyocyte proliferation in aging zebrafish

“…Underlying this constrained growth pattern in the zebrafish heart is continuous low-level cardiomyocyte proliferation, which remains throughout adult life, as also observed in the human heart ( Becker and Hesse, 2020 ). The cardiac metrics of ventricular length and compact myocardium thickness, measured in this study, support progressive growth of the heart under this constant proliferation, but it is the emergence of increased programmed cell death from 18 months that appears to halt overall organ growth.…”

“…Importantly, the heart also needs to be able to acutely increase pumping activity in response to a wide range of situations, including injury and infections. Previous studies have shown that throughout life the myocardium exhibits low rates of proliferation, which are concentrated in the mononuclear diploid cardiomyocyte component ( Becker and Hesse, 2020 ). In contrast to other organs, classical stem cell populations do not reside within the heart.…”

Proliferation and Maturation: Janus and the Art of Cardiac Tissue Engineering

“…Based on previous studies, mononucleated immature cardiomyocytes better preserve their proliferative potential during the postnatal period compared with binucleated counterparts. 64,65 Moreover, rare cardiomyocyte cell cycle events in adult hearts following injury are likely to originate from mononucleated cardiomyocyte. 65 Similarly, inhibition of cardiomyocyte cytokinesis and the subsequent increase in the number of binucleated cardiomyocytes diminishes the proliferative potential of zebra fish and neonatal…”

“…64,65 Moreover, rare cardiomyocyte cell cycle events in adult hearts following injury are likely to originate from mononucleated cardiomyocyte. 65 Similarly, inhibition of cardiomyocyte cytokinesis and the subsequent increase in the number of binucleated cardiomyocytes diminishes the proliferative potential of zebra fish and neonatal…”

The multifaceted nature of endogenous cardiac regeneration

“…The former allows hyperplastic growth, i.e., an increase in the number of cardiomyocytes (cell division and thus, proliferation) while the latter is associated with hypertrophic growth, that is to say an increase in cell size. In this context, it has been shown that cardiomyocyte nucleation and ploidy (the number of complete sets of chromosomes, n ) is critical ( 34 ). Indeed, mononucleated diploid cardiomyocytes have a lot more options regarding their future than tetraploid or binucleated cardiomyocytes ( Figure 4 ).…”