Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes

By Kazu Kikuchi, Jennifer E. Holdway, A. Werdich, Ryan M. Anderson, Yi Fang, G. Egnaczyk, T. Evans, Calum A. MacRae, D. Stainier, K. Poss. Nature, 2010

1,068 citations recorded by the source corpus.

Recent studies indicate that mammals, including humans, maintain some capacity to renew cardiomyocytes throughout postnatal life. Yet, there is little or no significant cardiac muscle regeneration after an injury such as acute myocardial infarction. By contrast, zebrafish efficiently regenerate lost cardiac muscle, providing a model for understanding how natural heart regeneration may be blocked or enhanced. In the absence of lineage-tracing technology applicable to adult zebrafish, the cellular origins of newly regenerated cardiac muscle have remained unclear. Using new genetic fate-mapping approaches, here we identify a population of cardiomyocytes that become activated after resection of the ventricular apex and contribute prominently to cardiac muscle regeneration. Through the use of a transgenic reporter strain, we found that cardiomyocytes throughout the subepicardial ventricular layer trigger expression of the embryonic cardiogenesis gene gata4 within a week of trauma, before expression localizes to proliferating cardiomyocytes surrounding and within the injury site. Cre-recombinase-based lineage-tracing of cells expressing gata4 before evident regeneration, or of cells expressing the contractile gene cmlc2 before injury, each labelled most cardiac muscle in the ensuing regenerate. By optical voltage mapping of surface myocardium in whole ventricles, we found that electrical conduction is re-established between existing and regenerated cardiomyocytes between 2 and 4 weeks post-injury. After injury and prolonged fibroblast growth factor receptor inhibition to arrest cardiac regeneration and enable scar formation, experimental release of the signalling block led to gata4 expression and morphological improvement of the injured ventricular wall without loss of scar tissue. Our results indicate that electrically coupled cardiac muscle regenerates after resection injury, primarily through activation and expansion of cardiomyocyte populations. These findings have implications for promoting regeneration of the injured human heart.

Subfields: Electrical and Electronic Engineering, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fad0c34b35db029933f0345ecc443f8505fc3801

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Citations in the corpus

Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration (2011, background): “During this process, differentiated cardiomyocytes that are still present in the heart dedifferentiate and proliferate to regenerate the missing tissu”
Mammalian Heart Renewal by Preexisting Cardiomyocytes (2012, positive): “Such an explanation excludes a role for endogenous progenitors in cardiac repair and would be consistent with data emerging from lower vertebrates 8,26 and the neonatal mouse 27 in which preexisting cardiomyocytes are the cellular source for cardiomyocyte repletion.”
Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration (2016, background): “Collagens can be further cross-linked enzymatically by lysyl oxidases (LOX) or by a reduction in the response to the formation of advanced glycation end-products (AGEs).”
Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family (2012, background): “Cardiomyocyte proliferation appears to be the major cellular mechanism driving cardiac regeneration in neonatalmice (8) and adult zebrafish (9, 10).”