A Roadmap to Heart Regeneration Through Conserved Mechanisms in Zebrafish and Mammals

Abstract

Purpose of review: The replenishment of lost or damaged myocardium has the potential to reverse heart failure, making heart regeneration a goal for cardiovascular medicine. Unlike adult mammals, injury to the zebrafish or neonatal mouse heart induces a robust regenerative program with minimal scarring. Recent insights into the cellular and molecular mechanisms of heart regeneration suggest that the machinery for regeneration is conserved from zebrafish to mammals. Here, we will review conserved mechanisms of heart regeneration and their translational implications.

Recent findings: Based on studies in zebrafish and neonatal mice, cardiomyocyte proliferation has emerged as a primary strategy for effecting regeneration in the adult mammalian heart. Recent work has revealed pathways for stimulating cardiomyocyte cell cycle reentry; potential developmental barriers for cardiomyocyte proliferation; and the critical role of additional cell types to support heart regeneration. Studies in zebrafish and neonatal mice have established a template for heart regeneration. Continued comparative work has the potential to inform the translation of regenerative biology into therapeutics.

Keywords: Cardiomyocyte proliferation; Heart failure; Regeneration.

Figure 1:. A roadmap to heart regeneration.

A. Capacity for heart regeneration by species. Zebrafish and neonatal mice have a high capacity for regeneration while adult mammals have little to no ability for regeneration after injury. B. Conserved mechanisms for cardiomyocyte proliferation in zebrafish and neonatal mice. Following injury, mature CMs re-enter the cell cycle and undergo sarcomere remodeling before completing mitosis to generate new cardiomyocytes. Factors that promote CM proliferation at each stage are shown in green and inhibitory factors are shown in red.