Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Abstract

Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium.

Keywords: cardiomyocyte dedifferentiation; cardiomyocyte proliferation; direct cardiogenesis; endogenous cardiac repair; heart development; heart regeneration.

Figure 1

Developmental regulation of cardiomyocyte cell cycle activity in mammals. Schematic representation of mammalian cardiomyocyte growth in prenatal and postnatal life. Most cardiomyocytes during the early postnatal period become bi/multi-nucleated and/or polyploid, withdraw from the cell cycle, and continue to grow in size (hypertrophic growth). An approximate percentage of bi/multi-nucleated, polyploidy, and diploid cardiomyocytes in different mammalian species at the adult stage is provided (it may not add up to 100% because cardiomyocytes can have several polyploid nuclei and because these values are derived from different reports) along with the estimated cardiomyocyte annual turnover.

Figure 2

Cardiac regenerative strategies based on direct stimulation of cardiomyocyte dedifferentiation and proliferation. Modulation of external, systemic, micro-environmental, and intrinsic molecular mechanisms can re-activate cardiomyocyte proliferative and regenerative potential. Locally produced growth factors and cytokines, extracellular matrix rigidity and components, direct cell-to-cell contacts, maternal factors, systemic hormones, oxygen levels, physical exercise, miRNAs and epigenetic regulations modulate a variety of signaling pathways and transcription factors that control cardiomyocyte dedifferentiation and proliferation by regulating cell cycle checkpoints, cytoarchitectural organization and energetic metabolism.

Figure 3

Developmental regulation of cardiomyocyte cell cycle in mammals. (A) Cyclins and Cdks expression levels by bioinformatic analysis of the gene expression profile of the mouse heart at different developmental stages [P1, P4, P9, and P23 from Talman et al. (39)]; (B) Cyclins and CDKs whose modulation has been demonstrated to be sufficient to induce postnatal cardiomyocyte cell cycle progression (in bold cell cycle factors that were reported to induce adult cardiomyocyte regeneration after major injuries).