Zebrafish heart regeneration: 15 years of discoveries

Abstract

Cardiovascular disease is the leading cause of death worldwide. Compared to other organs such as the liver, the adult human heart lacks the capacity to regenerate on a macroscopic scale after injury. As a result, myocardial infarctions are responsible for approximately half of all cardiovascular related deaths. In contrast, the zebrafish heart regenerates efficiently upon injury through robust myocardial proliferation. Therefore, deciphering the mechanisms that underlie the zebrafish heart's endogenous regenerative capacity represents an exciting avenue to identify novel therapeutic strategies for inducing regeneration of the human heart. This review provides a historical overview of adult zebrafish heart regeneration. We summarize 15 years of research, with a special focus on recent developments from this fascinating field. We discuss experimental findings that address fundamental questions of regeneration research. What is the origin of regenerated muscle? How is regeneration controlled from a genetic and molecular perspective? How do different cell types interact to achieve organ regeneration? Understanding natural models of heart regeneration will bring us closer to answering the ultimate question: how can we stimulate myocardial regeneration in humans?

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

“…While zebrafish, neonatal mouse and neonatal human hearts can replace dead or lost cardiomyocytes rapidly with new heart muscle (1)(2)(3)(4)(5), medaka (6,7), cave fish (8), as well as adult mice and human hearts (9) show only poor repair. Numerous studies are, therefore, looking into the underlying principles and mechanisms that promote, or prevent, effective cardiac regeneration to establish a basis for therapeutic intervention (10). In models of successful regeneration, remaining cardiomyocytes have been shown to proliferate and replace the scar tissue with new heart muscle (2,(11)(12)(13).…”

“…In models of successful regeneration, remaining cardiomyocytes have been shown to proliferate and replace the scar tissue with new heart muscle (2,(11)(12)(13). This is dependent on a fine balance of interaction with other cell-types, including the epicardium and endocardium (10,14). Due to the complexity of this interaction, we still lack a clear understanding of how the scar tissue can be broken down and replaced by proliferating myocardial cells.…”

Pre-existent adult sox10+cardiomyocytes contribute to myocardial regeneration in the zebrafish

“…Adult mammalian CMs have a poor capacity to proliferate and an efficient contribution of an adult stem cell pool for myocardial replacement has not been demonstrated (Lerman, et al, 2016). By contrast, zebrafish have an extraordinary capacity for heart regeneration after injury (Gonzalez-Rosa, et al, 2017;Kikuchi, 2014). Lineage tracing studies have revealed that pre-existing CMs are the origin of de novo formed cardiac muscle (Jopling, et al, 2010;Kikuchi, et al, 2010).…”

FishNET: An automated relational database for zebrafish colony management

“…gCaMP, lifeact) 18,28 have made zebrafish the premier model system for studying vertebrate biology in real-time. These features, combined with their impressive regenerative capacity, also make zebrafish ideal for studying vertebrate tissue and organ regeneration 29,30 .…”