Permanent fibrosis and chronic deterioration of heart function in patients after myocardial infarction present a major health-care burden worldwide. In contrast to the restricted potential for cellular and functional regeneration of the adult mammalian heart, a robust capacity for cardiac regeneration is seen during the neonatal period in mammals as well as in the adults of many fish and amphibian species. However, we lack a complete understanding as to why cardiac regeneration takes place more efficiently in some species than in others. The capacity of the heart to regenerate after injury is controlled by a complex network of cellular and molecular mechanisms that form a regulatory landscape, either permitting or restricting regeneration. In this Review, we provide an overview of the diverse array of vertebrates that have been studied for their cardiac regenerative potential and discuss differential heart regeneration outcomes in closely related species. Additionally, we summarize current knowledge about the core mechanisms that regulate cardiac regeneration across vertebrate species.
Cardiac regeneration potential tends to be robust in fish, amphibians and neonatal mammals, but is restricted in adult mammals; however, cardiac regeneration potential in several model organisms defies this trend.
Cardiac regeneration potential is determined by multiple highly interconnected processes, including cardiomyocyte proliferation, cardiac fibrosis, neovascularization, immune response and energy metabolism.
Mammalian cardiomyocytes exit the cell cycle postnatally due to changes in structure and energy metabolism; partial in vivo reprogramming of adult mammalian cardiomyocytes can increase their proliferation capacity.
Fibrosis in the injured heart is both beneficial and detrimental; altering fibrotic tissue composition and mechanical properties might improve adult mammalian heart regeneration.
Rapid neovascularization of the wound is a hallmark of heart regeneration and is absent in the adult mammalian heart; lymphatic coronary vessels modify the immune response after myocardial infarction via immune cell clearance.
The immune response to cardiac injury consists of multiple phases; restricting the initial inflammatory phase and promoting the subsequent reparative phase represents a strategy to improve heart regeneration.
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The authors declare no competing interests.
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Weinberger, M., Riley, P.R. Animal models to study cardiac regeneration. Nat Rev Cardiol (2023). https://doi.org/10.1038/s41569-023-00914-x
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