Zebrafish as a Smart Model to Understand Regeneration After Heart Injury: How Fish Could Help Humans

Abstract

Myocardial infarction (MI) in humans is a common cause of cardiac injury and results in irreversible loss of myocardial cells and formation of fibrotic scar tissue. This fibrotic tissue preserves the integrity of the ventricular wall but undermines pump function, leading to congestive heart failure. Unfortunately, the mammalian heart is unable to replace cardiomyocytes, so the life expectancy for patients after an episode of MI is lower than for most common types of cancers. Whereas, humans cannot efficiently regenerate their heart after injury, the teleost zebrafish have the capability to repair a “broken” heart. The zebrafish is probably one of the most important models for developmental and regenerative biology of the heart. In the last decades, the zebrafish has become increasingly important for scientific research: it has many characteristics that make it a smart model for studying human disease. Moreover, adult zebrafish efficiently regenerate their hearts following different forms of injury. Due to these characteristics, and to the availability of genetic approaches, and biosensor zebrafish lines, it has been established useful for studying molecular mechanisms of heart regeneration. Regeneration of cardiomyocytes in zebrafish is not based on stem cells or transdifferentiation of other cells but on the proliferation of preexisting cardiomyocytes. For this reason, future studies into the zebrafish cardiac regenerative mechanisms could identify specific molecules able to regulate the proliferation of preexisting cardiomyocytes; these factors may be studied in order to understand regulation of myocardial plasticity in cardiac repair processes after injury and, in particular, after MI in humans.

Multiaxial Lenticular Stress-Strain Relationship of Native Myocardium is Preserved by Infarct-Induced Natural Heart Regeneration in Neonatal Mice

“…Indeed, LAD ligation induces myocardial ischemia and better simulates the pathophysiology of MI and ischemic cardiomyopathy than cryoinjury, which may in fact produce an injury response distinct from that of ischemia 38,39 . Furthermore, the 4-chambered mouse heart is structurally and physiologically similar to the human heart, while the 2-chambered zebrafish heart represents a more evolutionarily distant model 40 .…”

Zebrafish cardiac regeneration—looking beyond cardiomyocytes to a complex microenvironment

“…Though regeneration mechanisms are generally believed to be tissue-specific (reviewed by Beffagna 2019 ), there is also evidence from zebrafish to suggest that there may in fact be some common regulatory elements, with the discovery by Pfefferli and Jaźwińska of careg, a regulatory element that contains a ctgfa upstream sequence that is transiently activated but common to both heart and fin regeneration, and induced by TGF-β/Activin-β signalling (Pfefferli and Jaźwińska 2017 ).…”

Bioactive Lipid Signaling in Cardiovascular Disease, Development, and Regeneration

“…Much of this work has been conducted using zebrafish, an excellent model for studying vertebrate regeneration. Zebrafish have the ability to efficiently regenerate injured cardiac cells and tissues as adults, a process that is limited at best in mammals [ 280 , 281 ]. This naturally occurring phenomenon can provide valuable information related to the potential reactivation of regeneration in mammalian studies.…”

“…Translating these factors could be helpful for the development of new alternative strategies that promote cardiomyocyte proliferation [ 303 ]. In the past, various molecular pathways have been investigated for their ability to cause cardiomyocyte proliferation both in mammals and fish: Wnt/β-catenin, TGFβ-activin, CDK9/PTEFb, insulin-like growth factor (IGF), reactive oxygen species (ROS), Hippo/Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), Meis1, miRNAs, hypoxia, and macrophages [ 281 ]. The Hippo/Yap/Taz pathway appears to be crucial in improving cardiac regeneration, as this pathway has an important role both in heart development and in postnatal cardiomyocyte proliferation [ 304 , 305 ].…”