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Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes.

Publication ,  Journal Article
Kikuchi, K; Holdway, JE; Werdich, AA; Anderson, RM; Fang, Y; Egnaczyk, GF; Evans, T; Macrae, CA; Stainier, DYR; Poss, KD
Published in: Nature
March 25, 2010

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.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

March 25, 2010

Volume

464

Issue

7288

Start / End Page

601 / 605

Location

England

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Regeneration
  • Myocytes, Cardiac
  • Heart
  • General Science & Technology
  • Gene Expression Regulation
  • GATA Transcription Factors
  • Electric Conductivity
  • Cell Proliferation
 

Citation

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Kikuchi, K., Holdway, J. E., Werdich, A. A., Anderson, R. M., Fang, Y., Egnaczyk, G. F., … Poss, K. D. (2010). Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature, 464(7288), 601–605. https://doi.org/10.1038/nature08804
Kikuchi, Kazu, Jennifer E. Holdway, Andreas A. Werdich, Ryan M. Anderson, Yi Fang, Gregory F. Egnaczyk, Todd Evans, Calum A. Macrae, Didier Y. R. Stainier, and Kenneth D. Poss. “Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes.Nature 464, no. 7288 (March 25, 2010): 601–5. https://doi.org/10.1038/nature08804.
Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, et al. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 2010 Mar 25;464(7288):601–5.
Kikuchi, Kazu, et al. “Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes.Nature, vol. 464, no. 7288, Mar. 2010, pp. 601–05. Pubmed, doi:10.1038/nature08804.
Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, Evans T, Macrae CA, Stainier DYR, Poss KD. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 2010 Mar 25;464(7288):601–605.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

March 25, 2010

Volume

464

Issue

7288

Start / End Page

601 / 605

Location

England

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Regeneration
  • Myocytes, Cardiac
  • Heart
  • General Science & Technology
  • Gene Expression Regulation
  • GATA Transcription Factors
  • Electric Conductivity
  • Cell Proliferation