The developing epicardium regulates cardiac chamber morphogenesis by promoting cardiomyocyte growth
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Giulia Boezio Shengnan Zhao Josephine Gollin Rashmi Priya Shivani Mansingh Stefan Guenther Nana Fukuda Felix Gunawan Didier YR StainierAbstract
The epicardium, the outermost layer of the heart, is an important regulator of cardiac regeneration. However, a detailed understanding of the crosstalk between the epicardium and myocardium during development requires further investigation. Here, we generated three models of epicardial impairment in zebrafish by mutating the transcription factor genes tcf21 and wt1a, and ablating tcf21+ epicardial cells. Notably, all three epicardial-impairment models exhibit smaller ventricles. We identified the initial cause of this phenotype as defective cardiomyocyte growth, resulting in reduced cell surface and volume. This failure of cardiomyocyte growth is followed by decreased proliferation and increased abluminal extrusion. By temporally manipulating its ablation, we show that the epicardium is required to support cardiomyocyte growth mainly during early cardiac morphogenesis. By transcriptomic profiling of sorted epicardial cells, we identified reduced expression of FGF and VEGF ligand genes in tcf21-/- hearts, and pharmacological inhibition of these signaling pathways partially recapitulated the ventricular growth defects. Altogether, these data further reveal the distinct roles of the epicardium during cardiac morphogenesis and the signaling pathways underlying epicardial-myocardial crosstalk.
Journal details
Journal Disease Models and Mechanisms
Volume 16
Issue number 5
Pages dmm049571
Available online
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Publisher website (DOI) 10.1242/dmm.049571
Europe PubMed Central 36172839
Pubmed 36172839
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