Document Detail


In vivo monitoring of cardiomyocyte proliferation to identify chemical modifiers of heart regeneration.
MedLine Citation:
PMID:  23293297     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Adult mammalian cardiomyocytes have little capacity to proliferate in response to injury, a deficiency that underlies the poor regenerative ability of human hearts after myocardial infarction. By contrast, zebrafish regenerate heart muscle after trauma by inducing proliferation of spared cardiomyocytes, providing a model for identifying manipulations that block or enhance these events. Although direct genetic or chemical screens of heart regeneration in adult zebrafish present several challenges, zebrafish embryos are ideal for high-throughput screening. Here, to visualize cardiomyocyte proliferation events in live zebrafish embryos, we generated transgenic zebrafish lines that employ fluorescent ubiquitylation-based cell cycle indicator (FUCCI) technology. We then performed a chemical screen and identified several small molecules that increase or reduce cardiomyocyte proliferation during heart development. These compounds act via Hedgehog, Insulin-like growth factor or Transforming growth factor β signaling pathways. Direct examination of heart regeneration after mechanical or genetic ablation injuries indicated that these pathways are activated in regenerating cardiomyocytes and that they can be pharmacologically manipulated to inhibit or enhance cardiomyocyte proliferation during adult heart regeneration. Our findings describe a new screening system that identifies molecules and pathways with the potential to modify heart regeneration.
Authors:
Wen-Yee Choi; Matthew Gemberling; Jinhu Wang; Jennifer E Holdway; Meng-Chieh Shen; Rolf O Karlstrom; Kenneth D Poss
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  140     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-07     Completed Date:  2013-03-07     Revised Date:  2013-08-09    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  660-6     Citation Subset:  IM    
Affiliation:
Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Genetically Modified / embryology,  metabolism,  physiology
Biological Markers / metabolism
Catechols / pharmacology
Cell Count
Cell Proliferation*
Cyclohexylamines / pharmacology
Embryo, Nonmammalian / cytology,  drug effects,  physiology
Female
Heart / embryology,  physiology*
Hedgehog Proteins / agonists,  genetics,  metabolism
High-Throughput Screening Assays / methods*
Isoquinolines / pharmacology
Male
Myocytes, Cardiac / cytology*,  drug effects,  metabolism
Recombinant Fusion Proteins / genetics,  metabolism
Regeneration*
Signal Transduction
Thiophenes / pharmacology
Transforming Growth Factor beta / genetics,  metabolism
Transgenes
Ubiquitination
Zebrafish / genetics,  injuries,  physiology
Grant Support
ID/Acronym/Agency:
F32 HL106987/HL/NHLBI NIH HHS; F32 HL106987/HL/NHLBI NIH HHS; NS039994/NS/NINDS NIH HHS; R01 HL081674/HL/NHLBI NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Catechols; 0/Cyclohexylamines; 0/Hedgehog Proteins; 0/Isoquinolines; 0/NBI 31772; 0/Recombinant Fusion Proteins; 0/SAG compound; 0/Thiophenes; 0/Transforming Growth Factor beta
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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