Two decades of heart regeneration research: Cardiomyocyte proliferation and beyond

Abstract

Interest in vertebrate cardiac regeneration has exploded over the past two decades since the discovery that adult zebrafish are capable of complete heart regeneration, contrasting the limited regenerative potential typically observed in adult mammalian hearts. Undercovering the mechanisms that both support and limit cardiac regeneration across the animal kingdom may provide unique insights in how we may unlock this capacity in adult humans. In this review, we discuss key discoveries in the heart regeneration field over the last 20 years. Initially, seminal findings revealed that pre-existing cardiomyocytes are the major source of regenerated cardiac muscle, drawing interest into the intrinsic mechanisms regulating cardiomyocyte proliferation. Moreover, recent studies have identified the importance of intercellular interactions and physiological adaptations, which highlight the vast complexity of the cardiac regenerative process. Finally, we compare strategies that have been tested to increase the regenerative capacity of the adult mammalian heart. This article is categorized under: Cardiovascular Diseases > Stem Cells and Development.

Keywords: cardiomyocyte proliferation; heart regeneration; immune system; stem cells.

Figure 1.. Cardiomyocyte polyploidization correlates with the loss of cardiomyocyte proliferative and heart regenerative capacity.

Adult zebrafish (A) and neonatal mice (B) retain a high frequency diploid cardiomyocytes that are capable of proliferation, correlates with their robust abilities to regenerate their hearts. Adult mice (C) retain much lower diploid cardiomyocyte frequency. Rather, their hearts contain mostly terminally differentiated polyploid binucleated cardiomyocytes that lack the ability to divide. This correlates with decreased heart regenerative potential.

Figure 2.. Cardiac regeneration requires intercellular communication between other cell types in the heart.

Though the proliferation of pre-existing cardiomyocytes to regenerate new cardiac muscle is required for cardiac regeneration, interactions between immune cells (A), the epicardium (B), and endothelium (C) are necessary to support the reparative process.

Figure 3.. The shift towards fatty acid oxidation to support increasing metabolic demand may inversely correlate with cardiac regenerative potential.

(A) After birth, the hearts of neonatal mice shift from utilizing glycolysis to fatty acid oxidation. (B) Animal metabolic needs increase both during mammalian postnatal development and during the evolution of endothermic mammals. (C) The shift to fatty acid metabolism and the increase in animal metabolic needs inversely correlate with the loss of heart regenerative capacity.

Figure 4.. Strategies to replace lost cardiomyocytes after injury.

(A) Reactivation of cell cycle activity and proliferation of mature adult cardiomyocytes. (B) Heterocellular reprogramming and transdifferentiation of other cell types in the heart (e.g., cardiac fibroblasts) towards a cardiomyocyte-like fate. (C) Derivation of cardiomyocytes from patient-derived induced pluripotent stems (iPSCs).