In vivo cardiac reprogramming contributes to zebrafish hearT regeneration

Ruilin Zhang, Peidong Han, Hongbo Yang, Kunfu Ouyang, Derek Lee, Yi Fan Lin, Karen Ocorr, Guson Kang, Ju Chen, Didier Y.R. Stainier, Deborah Yelon, Neil C. Chi*

*Corresponding author for this work

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

Despite current treatmenTregimens, 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.

Original languageEnglish (US)
Pages (from-to)497-501
Number of pages5
JournalNature
Volume498
Issue number7455
DOIs
StatePublished - Jun 21 2013
Externally publishedYes

ASJC Scopus subject areas

  • General

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