The developing epicardium regulates cardiac chamber morphogenesis by promoting cardiomyocyte growth

Author:

Boezio Giulia L. M.123ORCID,Zhao Shengnan1ORCID,Gollin Josephine1ORCID,Priya Rashmi13ORCID,Mansingh Shivani1ORCID,Guenther Stefan34ORCID,Fukuda Nana1,Gunawan Felix123ORCID,Stainier Didier Y. R.123ORCID

Affiliation:

1. Max Planck Institute for Heart and Lung Research 1 Department of Developmental Genetics , , 61231 Bad Nauheim , Germany

2. DZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main 2 , 61231 Bad Nauheim , Germany

3. Cardio-Pulmonary Institute 3 , Aulweg 130, 35392 Giessen , Germany

4. Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research 4 , 61231 Bad Nauheim , Germany

Abstract

ABSTRACT 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 exhibited 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 was 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 in wild type partially recapitulated the ventricular growth defects. Taken together, these data reveal distinct roles of the epicardium during cardiac morphogenesis and signaling pathways underlying epicardial-myocardial crosstalk.

Funder

Max-Planck-Gesellschaft

EMBO

Canadian Institutes of Health Research

Alexander von Humboldt-Stiftung

Cardio-Pulmonary Institute

Max Planck Society

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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