title: The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion.
abstract: Natural models of heart regeneration in lower vertebrates such as zebrafish are based on invasive surgeries causing mechanical injuries that are limited in size. Here, we created a genetic cell ablation model in zebrafish that facilitates inducible destruction of a high percentage of cardiomyocytes. Cell-specific depletion of over 60% of the ventricular myocardium triggered signs of cardiac failure that were not observed after partial ventricular resection, including reduced animal exercise tolerance and sudden death in the setting of stressors. Massive myocardial loss activated robust cellular and molecular responses by endocardial, immune, epicardial and vascular cells. Destroyed cardiomyocytes fully regenerated within several days, restoring cardiac anatomy, physiology and performance. Regenerated muscle originated from spared cardiomyocytes that acquired ultrastructural and electrophysiological characteristics of de-differentiation and underwent vigorous proliferation. Our study indicates that genetic depletion of cardiomyocytes, even at levels so extreme as to elicit signs of cardiac failure, can be reversed by natural regenerative capacity in lower vertebrates such as zebrafish.
authors.affiliation: Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jinhu
authors.initials: J
authors.lastname: Wang
authors.forename: Daniela
authors.initials: D
authors.lastname: Panáková
authors.forename: Kazu
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Holdway
authors.forename: Matthew
authors.initials: M
authors.lastname: Gemberling
authors.forename: James S
authors.initials: JS
authors.lastname: Burris
authors.forename: Sumeet Pal
authors.initials: SP
authors.lastname: Singh
authors.forename: Amy L
authors.initials: AL
authors.lastname: Dickson
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lin
authors.forename: M Khaled
authors.initials: MK
authors.lastname: Sabeh
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Werdich
authors.forename: Deborah
authors.initials: D
authors.lastname: Yelon
authors.forename: Calum A
authors.initials: CA
authors.lastname: Macrae
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Poss
mesh_terms: D000818:Animals; D016923:Cell Death; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D012038:Regeneration; D015027:Zebrafish / Q000235:genetics* / Q000502:physiology*