Publication Date:
2010-03-26
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040215/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040215/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kikuchi, Kazu -- Holdway, Jennifer E -- Werdich, Andreas A -- Anderson, Ryan M -- Fang, Yi -- Egnaczyk, Gregory F -- Evans, Todd -- Macrae, Calum A -- Stainier, Didier Y R -- Poss, Kenneth D -- GM075846/GM/NIGMS NIH HHS/ -- HL007101/HL/NHLBI NIH HHS/ -- HL007208/HL/NHLBI NIH HHS/ -- HL054737/HL/NHLBI NIH HHS/ -- HL064282/HL/NHLBI NIH HHS/ -- HL081674/HL/NHLBI NIH HHS/ -- K08 HL068711/HL/NHLBI NIH HHS/ -- R01 HL081674/HL/NHLBI NIH HHS/ -- R01 HL081674-05/HL/NHLBI NIH HHS/ -- R01 HL081674-06/HL/NHLBI NIH HHS/ -- R01 HL109264/HL/NHLBI NIH HHS/ -- R21 GM075946/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Mar 25;464(7288):601-5. doi: 10.1038/nature08804.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20336144" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Animals, Genetically Modified
;
Cell Proliferation
;
Electric Conductivity
;
GATA Transcription Factors/*genetics/*metabolism
;
Gene Expression Regulation
;
Heart/*physiology
;
Myocytes, Cardiac/*cytology/*metabolism
;
Regeneration/genetics/*physiology
;
Zebrafish/genetics/metabolism/*physiology
;
Zebrafish Proteins/*genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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