Cardiac Regeneration

Abstract

Palliative surgery for congenital heart disease has allowed patients with previously lethal heart malformations to survive and, in most cases, to thrive. However, these procedures often place pressure and volume loads on the heart, and over time these chronic loads can cause heart failure. Current therapeutic options for initial surgery and chronic heart failure that results from failed palliation are limited, in part, by the mammalian heart’s low inherent capacity to form new cardiomyocytes (CMs). Surmounting the heart regeneration barrier would transform the treatment of congenital, as well as acquired, heart disease, and likewise would enable development of personalized, in vitro cardiac disease models. Although these remain distant goals, studies of heart development are illuminating the path forward and suggest unique opportunities for heart regeneration, particularly in fetal and neonatal periods. Here we review major lessons from heart development that inform current and future studies directed at enhancing cardiac regeneration.

Divergent Requirements for EZH1 in Heart Development Versus Regeneration

“…Recent studies highlight strategies that redeploy developmental signaling pathways to achieve the goals of cardiac regeneration 4 and point to epigenetic barriers to effective regeneration in mammalian hearts 17 Previous work by us and others suggested that Ezh1 is functionally redundant with Ezh2 in differentiated cardiac myocytes 13, 18, 19 . Here, we provide direct evidence that Ezh1 and Ezh2 complement each other in heart development.…”

“…This regenerative capacity is lost rapidly, as similar injury at P7 induces scar rather than myocardial regeneration. The mechanisms responsible for CM cell cycle exit remain incompletely understood 4 . Reactivation of some transcriptional regulatory networks essential for heart development, such as those controlled by YAP and TBX20, have been shown to promote adult CM cell cycle activity 4–7 .…”

Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor

“…Adult cardiomyocytes (CMs) generate forceful contractions billions of times during the lifespan of an adult human. Specialized features that adapt CMs for this unique activity include their large rod-like shape, nearly crystalline sarcomere organization, robust oxidative metabolic capacity, expression of mature sarcomere gene isoforms, exit from the cell cycle, and an extensive network of transverse tubules (T-tubules), which are plasma membrane invaginations that facilitate synchronized calcium release 1 , 2 . In contrast to adult CMs, these specialized features are absent or underdeveloped in fetal and neonatal CMs, which are smaller, proliferative, glycolytic cells with less organized sarcomeres, fewer and smaller mitochondria, and no T-tubules.…”

Determinants of Cardiac Growth and Size

“…Several recent reports have revealed that growth factors, intrinsic signaling pathways, and cell-cycle regulators coordinate cardiomyocyte proliferation during cardiogenesis. The expansion of the two cardiac progenitor fields during early cardiogenesis transpires under the tight control of extrinsic growth regulatory signals, which include the fibroblast growth factor, bone morphogenetic protein, and both canonical and noncanonical Wnt signaling pathways (for a review, see Galdos et al 2017). For example, data from mice revealed that the genetic deletion of the Wnt effector β-catenin in the second heart field gives rise to hearts bearing stunted right ventricles (Ai et al 2007), underscoring the importance of this pathway during early stages of cardiac growth.…”