Advances in understanding the mechanism of zebrafish heart regeneration

Abstract

The adult mammalian heart was once believed to be a post-mitotic organ without any capacity for regeneration, but recent findings have challenged this dogma. A modified view assigns the mammalian heart a measurable capacity for regeneration throughout its lifetime, with the implication that endogenous regenerative capacity can be therapeutically stimulated in the injury setting. Although extremely limited in adult mammals, the natural capacity for organ regeneration is a conserved trait in certain vertebrates. Urodele amphibians and teleosts are well-known examples of such animals that can efficiently regenerate various organs including the heart as adults. By understanding how these animals regenerate a damaged heart, one might obtain valuable insights into how regeneration can be augmented in injured human hearts. Among the regenerative vertebrate models, the teleost zebrafish, Danio rerio, is arguably the best characterized with respect to cardiac regenerative responses. Knowledge is still limited, but a decade of research in this model has led to results that may help to understand how cardiac regeneration is naturally stimulated and maintained. This review surveys recent advances in the field and discusses current understanding of the endogenous mechanisms of cardiac regeneration in zebrafish.

The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis

“…In adult mammals, injuries to cardiac tissue usually cause irreversible damage and can lead to the formation of scars that affect cardiac function. By contrast, adult zebrafish cardiomyocytes exhibit a remarkable ability to proliferate and regenerate heart muscle even after substantial injuries Kikuchi, 2014;Poss et al, 2002). Notably, non-muscle tissues -including the endocardium -actively help to drive the regeneration of the zebrafish myocardium.…”

Using zebrafish as the model organism to understand organ regeneration

“…The initial studies focused on the ventricle of adult heart. Adult zebrafish ventricle is composed of three different muscle lineages, primordial, trabecular and cortical muscle [14,43]. Usually, the heart ventricle is partially injured by surgery (Figure 2A).…”

“…However, contribution of primordial muscle could still be detectable at this stage. Thus, after 60 days when the tissue was restored, both primordial and cortical muscle layers played roles and the cortical muscle was the major player [14,43]. The order of both muscle layers in this regeneration process is opposed to their sequences in heart development [14,43].…”

“…Thus, after 60 days when the tissue was restored, both primordial and cortical muscle layers played roles and the cortical muscle was the major player [14,43]. The order of both muscle layers in this regeneration process is opposed to their sequences in heart development [14,43]. Similar to that in the fin regeneration, the dedifferentiation of the cardiomyocyte of the injury sites is the dominant mechanism of zebrafish heart regeneration, because the cardiomyocytes present structural alterations after injury and the regenerating myocytes begin to express gata4, a gene essential for cardiac development [45].…”

“…Subsequently, these dedifferentiated cardiomyocyte functions as the cell source to support the regenerating tissue through extensive proliferation ( Figure 2A). During the process, epicardial cells also show functions to facilitate generation of new vascular components [1, 14,46]. In addition to the dedifferentiation mechanism when adult heart is partially damaged, recent study applied the transgenic-based assay to ablate large parts of the larvae heart ( Figure 2B).…”