Abstract
Irreversible cardiac fibrosis, cardiomyocyte death and chronic cardiac dysfunction after myocardial infarction pose a substantial global health-care challenge, with no curative treatments available. To regenerate the injured heart, cardiomyocytes must proliferate to replace lost myocardial tissue — a capability that adult mammals have largely forfeited to adapt to the demanding conditions of life. Using various preclinical models, our understanding of cardiomyocyte proliferation has progressed remarkably, leading to the successful reactivation of cell cycle induction in adult animals, with functional recovery after cardiac injury. Central to this success is the targeting of key pathways and structures that drive cardiomyocyte maturation after birth — nucleation and ploidy, sarcomere structure, developmental signalling, chromatin and epigenetic regulation, the microenvironment and metabolic maturation — forming a complex regulatory framework that allows efficient cellular contraction but restricts cardiomyocyte proliferation. In this Review, we explore the molecular pathways underlying these core mechanisms and how their manipulation can reactivate the cell cycle in cardiomyocytes, potentially contributing to cardiac repair.
Key points
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The capacity for mammalian cardiomyocyte proliferation is rapidly lost shortly after birth to make way for an antiproliferative maturation programme that is necessary for survival and to sustain adult life.
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Manipulation of this maturation process holds the potential to trigger cardiomyocyte proliferation in adult animals, providing a foundation for regenerative strategies that could improve healing after injury.
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Six major influences on cardiomyocyte maturation are nucleation and ploidy, sarcomere structure, developmental signalling, epigenetic regulation, the microenvironment and metabolic maturation; targeted manipulation can yield diverse effects on the proliferative capacity of adult cardiomyocytes.
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Metabolic interventions that promote increased glucose utilization with a concomitant reduction in oxidative phosphorylation seem to be both safe and effective in unlocking adult cardiomyocyte proliferation.
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Epigenetic strategies can be similarly effective, but encompass a wide array of regulatory responses, for which our understanding remains limited.
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The cardiac microenvironment and the non-parenchymal cell population in the heart are crucial to guiding the adult cardiomyocyte proliferative response, whereby transient inflammatory and senescence signalling events shape an environment that is conducive to proliferation events.
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E.v.R. acknowledges funding from the European Union’s Horizon 2020 research and innovation programme (grant agreement 874764).
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Koopmans, T., van Rooij, E. Molecular gatekeepers of endogenous adult mammalian cardiomyocyte proliferation. Nat Rev Cardiol 22, 857–882 (2025). https://doi.org/10.1038/s41569-025-01145-y
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DOI: https://doi.org/10.1038/s41569-025-01145-y
