title: In vivo cardiac reprogramming contributes to zebrafish heart regeneration.
abstract: Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the developed world due to the limited capacity of adult mammalian ventricular cardiomyocytes to divide and replace ventricular myocardium lost from ischaemia-induced infarct. Hence there is great interest to identify potential cellular sources and strategies to generate new ventricular myocardium. Past studies have shown that fish and amphibians and early postnatal mammalian ventricular cardiomyocytes can proliferate to help regenerate injured ventricles; however, recent studies have suggested that additional endogenous cellular sources may contribute to this overall ventricular regeneration. Here we have developed, in the zebrafish (Danio rerio), a combination of fluorescent reporter transgenes, genetic fate-mapping strategies and a ventricle-specific genetic ablation system to discover that differentiated atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Using in vivo time-lapse and confocal imaging, we monitored the dynamic cellular events during atrial-to-ventricular cardiomyocyte transdifferentiation to define intermediate cardiac reprogramming stages. We observed that Notch signalling becomes activated in the atrial endocardium following ventricular ablation, and discovered that inhibiting Notch signalling blocked the atrial-to-ventricular transdifferentiation and cardiac regeneration. Overall, these studies not only provide evidence for the plasticity of cardiac lineages during myocardial injury, but more importantly reveal an abundant new potential cardiac resident cellular source for cardiac ventricular regeneration.
authors.affiliation: Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Ruilin
authors.initials: R
authors.lastname: Zhang
authors.forename: Peidong
authors.initials: P
authors.lastname: Han
authors.forename: Hongbo
authors.initials: H
authors.lastname: Yang
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.forename: Derek
authors.initials: D
authors.lastname: Lee
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lin
authors.forename: Karen
authors.initials: K
authors.lastname: Ocorr
authors.forename: Guson
authors.initials: G
authors.lastname: Kang
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: Deborah
authors.initials: D
authors.lastname: Yelon
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
mesh_terms: D000818:Animals; D016923:Cell Death; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming; D006321:Heart / Q000196:embryology / Q000502:physiology*; D006325:Heart Atria / Q000166:cytology / Q000196:embryology; D006352:Heart Ventricles / Q000166:cytology; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology / Q000502:physiology*
chemical_list: D051881:Receptor, Notch1