Zebrafish heart regeneration as a model for cardiac tissue repair

doi:10.1016/j.ddmod.2007.09.002

Drug Discovery Today: Disease Models

Volume 4, Issue 4, Winter 2007, Pages 219-225

https://doi.org/10.1016/j.ddmod.2007.09.002 Get rights and content

Heart disease remains a leading cause of mortality throughout the world. Mammals have an extremely limited capacity to repair lost or damaged heart tissue, thus encouraging biologists to seek out models for heart regeneration. The robust capacity of zebrafish to regenerate a variety of tissues position it as an ideal genetic model system for understanding the molecular and cellular events governing regeneration. Future studies will utilize functional approaches to tease apart zebrafish heart regeneration in the hope of unlocking our own regenerative potential.

Section editors:

Rahul Kakkar and Richard T. Lee – Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA, USA

Introduction

Tissue regeneration has fascinated biologists for centuries. Despite this interest, the cellular and molecular events driving the recovery of lost tissues are poorly understood. At the root of many of these events lie potent progenitor or stem cells capable of reconstituting cell populations of the newly regenerated tissue. This potential, along with the isolation of these progenitor cells from a wide variety of tissues, has impelled the field of regeneration with the hope of future uses in medicine.

Although robust replacement of structural cells has been discovered in mammalian tissues, such as the liver, blood and skin, most tissues do not share this remarkable ability [1, 2, 3, 4]. Perhaps most prominently, the mammalian heart is incapable of significant regeneration following an injury such as acute myocardial infarction [5, 6]. Loss of oxygenation to ventricular muscle, usually because of occlusion of a coronary artery, will result in necrosis of that tissue. Too often, these injuries result in immediate death. Those fortunate to survive a myocardial infarction replace lost muscle with a scar, and typically are susceptible to compensatory pathology and/or future infarctions. Unlike the mammalian heart, the injured zebrafish heart normally undergoes minimal scarring [7]. Instead, a transient fibrin clot is replaced with new contractile muscle (Fig. 1). This review will focus on recent progress in the field of cardiac regeneration with an emphasis on the zebrafish model system.

Section snippets

Mammalian and amphibian heart regeneration

As discussed above, mammalian species have little or no ability to replace lost cardiac muscle. This poor regenerative capacity is due in part to the failure of adult cardiomyocytes to undergo proliferation [8]. It is possible that the proliferation of adult cardiomyocytes may be therapeutically stimulated. In support of this, recent reports have shown that although adult mammalian cardiomyocytes show very little or no proliferation when cultured, FGF1 treatment concomitant with p38 MAP kinase

Teleost heart regeneration

A combination of forward genetic screens, large clutch size and external development has made the zebrafish a popular model system for ontogenetic development [28]. In particular, our understanding of heart development has benefited greatly from zebrafish mutants that specifically disrupt cardiovascular form and function [29, 30, 31]. Genetic approaches also make zebrafish a favored model system for studying tissue regeneration [32]. Indeed, it remains the only laboratory model system that is

The role of the epicardium during zebrafish heart regeneration

Recent results have shed light on the role of the outer non-muscle layer of the heart, the epicardium, in cardiac regeneration. During embryogenesis, the epicardium migrates out as a sheet from the proepicardium, a cluster or mesoderm-derived cells near the liver primordium and the septum transversum, to envelop the developing myocardial tube [43]. Following this encasement, some epicardial-derived cells undergo an epithelial-to-mesenchymal transition (EMT) into the subepicardial space and

Genetic approaches to heart regeneration in zebrafish

Genetic approaches in zebrafish have revealed a large number of mutants affecting embryonic development. Most of these mutants exhibit embryonic or larval lethality, thus making it impossible to assess roles for specific genes in adult tissue regeneration, unless such mutations have effects in heterozygous animals. Investigators have circumvented this issue in a small number of studies by searching for conditional (temperature-sensitive) or hypomorphic alleles of genes that may be important for

Conclusions

Within the past few years, we have witnessed a growing interest in regeneration biology. Amphibians, mammals and teleosts have different capacities to repair lost cardiac tissue, and it is from these differences we can learn best how to minimize scarring and maximize regeneration after injury. Zebrafish represent a highly useful system because of the combination of available genetic tools and a robust regenerative capacity. Through continued studies of zebrafish heart regeneration, we stand to

Acknowledgements

We thank Felix Engel, Ellen Lien and Paul Riley for original figure panels, and the National Heart, Lung, and Blood Institute, the American Heart Association, the Whitehead Foundation, and the Pew Charitable Trusts for funding our research on heart regeneration.

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Cardiovascular diseasesZebrafish heart regeneration as a model for cardiac tissue repair

Section editors:

Introduction

Section snippets

Mammalian and amphibian heart regeneration

Teleost heart regeneration

The role of the epicardium during zebrafish heart regeneration

Genetic approaches to heart regeneration in zebrafish

Conclusions

Acknowledgements

Cell

Semin. Cell Dev. Biol.

Cell

Trends Genet

Semin. Cell Dev. Biol.

Curr. Biol.

Vision. Res.

Cell

J. Biol. Chem.

Trends Cardiovasc. Med.

Dev. Biol.

Dev. Biol.

Mech. Dev.

Dev. Biol.

Dev. Biol.

Dev. Cell

Liver regeneration: from myth to mechanism

Nat. Rev. Mol. Cell Biol.

Hematopoietic stem and progenitor cells: clinical and preclinical regeneration of the hematolymphoid system

Annu. Rev. Med.

The role of stem cells in physiology, pathophysiology, and therapy of the liver

Stem. Cell Rev.

Cardiac imaging to identify patients at risk for developing heart failure after myocardial infarction

Curr. Heart Fail Rep.

Interrelations of the proliferation and differentiation processes during cardiac myogenesis and regeneration

Int. Rev. Cytol.

Heart regeneration in zebrafish

Science

Cardiomyocyte cell cycle regulation

Circ. Res.

p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes

Genes Dev

FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction

Proc. Natl. Acad. Sci. U. S. A.

Postnatal is l1+ cardioblasts enter fully differentiated cardiomyocyte lineages

Nature

Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction

Proc. Natl. Acad. Sci. U. S. A.

Cardiovascular development: towards biomedical applicability: Biology of Isl1 (+) cardiac progenitor cells in development and disease

Cell Mol. Life Sci.

Tail regeneration in the Xenopus tadpole

Dev. Growth Differ.

Cardiovascular diseases
Zebrafish heart regeneration as a model for cardiac tissue repair