Molecular mechanisms of heart regeneration

Abstract

The adult mammalian heart is incapable of clinically relevant regeneration. The regenerative deficit in adult mammalian heart contrasts with the fetal and neonatal heart, which demonstrate substantial regenerative capacity after injury. This deficiency in adult mammals is attributable to the lack of resident stem cells after birth, combined with an inability of pre-existing cardiomyocytes to complete cytokinesis. Studies of neonatal heart regeneration in mammals suggest that latent regenerative potential can be re-activated. Dissecting the cellular and molecular mechanisms that promote cardiomyocyte proliferation is key to stimulating true regeneration in adult humans. Here, we review recent advances in our understanding of cardiomyocyte proliferation that suggest molecular approaches to heart regeneration.

Keywords: Cardiomyocyte proliferation; Growth factors; Heart regeneration; Hippo-YAP; Wnt.

Figure 1:. Response to cardiac injury in neonatal and adult mammals.

In this figure, we summarize the response to injury in neonatal and adult mammalian hearts. Following injury, neonatal mice have the ability to successfully regenerate their heart by cardiomyocyte proliferation and neovascularization to replace lost tissue and restore cardiac function. On the other hand, adult mammals are not capable of regenerating significant amounts of heart tissue. Instead, injury in the adult mammalian heart leads to scarring and loss of function. Due to the low cell turnover rate, the adult mammalian heart is incapable of replacing the lost cardiomyocytes. Instead, injury results in cardiomyocyte hypertrophy, replacement fibrosis and chronic inflammation, compromising cardiac function.

Figure 2:. Strategies for adult mammalian heart regeneration.

In this figure, we highlight therapeutic strategies to augment cardiac regeneration in adult mammalian hearts after injury. Several therapeutic approaches have been described to achieve cardiac regeneration either by stimulation of cardiomyocyte cell cycle re-entry by stimulation of endogenous pathways or by cell-therapy to deliver in-vitro produced induced pluripotent stem cell (iPSC) – derived cardiomyocytes possibly with engineered scaffolds. Stimulation of endogenous pathways of cardiomyocyte proliferation involve administration of mitogens like miR-199a, cyclins, cyclin dependent kinases (CDKs) to induce cardiomyocyte proliferation. Cell therapy comprises of application of 3D engineered scaffolds or extracellular matrix scaffolds to the heart at the site of injury and delivery of iPSC-derived cardiomyocytes at the site of injury.

Figure 3:. Signaling pathways that modulate cardiomyocyte proliferation.

Here, we outline the major signaling pathways that have been identified to modulate adult cardiomyocyte cell-cycle re-entry. Well-characterized endogenous pathways regulating cardiomyocyte proliferation include Wnt – ß-catenin signaling, neuregulin and Hippo-YAP signaling. Activation of Wnt signaling by the binding of Wnt to its receptor frizzled, results in the translocation of ß-catenin to the nucleus, activating transcriptional activity for cell proliferation. Binding of neuregulin to its receptors ErbB2 and ErbB4 mediate translocation of Yap to the nucleus and activation of transcriptional events that lead to cell proliferation. On the other hand, reactive oxygen species – mediated DNA damage results in cell cycle arrest via Atm phosphorylation and Weel activation.