Journal
DEVELOPMENTAL CELL
Volume 36, Issue 1, Pages 36-49Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2015.12.010
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Funding
- Netherlands Cardiovascular Research Initiative
- Dutch Heart Foundation
- Dutch Federation of University Medical Centers
- Netherlands Organisation for Health Research and Development
- Royal Netherlands Academy of Sciences
- CVON [CVON2011-12 HUSTCARE]
- Klaus-Georg und Sigrid Hengstberger-Forschungsstipendium by the German Cardiac Society
- Deutsche Forschungsgemeinschaft [CRC 1149]
- EuFishBioMed Short-Term Fellowship
- Emerging Fields Initiative for Cell Cycle in Disease and Regeneration from the Friedrich-Alexander-Universitat Erlangen-Nurnberg
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In contrast to mammals, zebrafish regenerate heart injuries via proliferation of cardiomyocytes located near the wound border. To identify regulators of cardiomyocyte proliferation, we used spatially resolved RNA sequencing (tomo-seq) and generated a high-resolution genome-wide atlas of gene expression in the regenerating zebrafish heart. Interestingly, we identified two wound border zones with distinct expression profiles, including the re-expression of embryonic cardiac genes and targets of bone morphogenetic protein (BMP) signaling. Endogenous BMP signaling has been reported to be detrimental to mammalian cardiac repair. In contrast, we find that genetic or chemical inhibition of BMP signaling in zebrafish reduces cardiomyocyte dedifferentiation and proliferation, ultimately compromising myocardial regeneration, while bmp2b overexpression is sufficient to enhance it. Our results provide a resource for further studies on the molecular regulation of cardiac regeneration and reveal intriguing differential cellular responses of cardiomyocytes to a conserved signaling pathway in regenerative versus non-regenerative hearts.
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