CCBE1 Is Essential for Epicardial Function during Myocardium Development

The epicardium is a single cell layer of mesothelial cells that plays a critical role during heart development contributing to different cardiac cell types of the developing heart through epithelial-to-mesenchymal transition (EMT). Moreover, the epicardium is a source of secreted growth factors that...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-10, Vol.23 (20), p.12642
Main Authors: Bonet, Fernando, Añez, Sabrina Brito, Inácio, José Manuel, Futschik, Matthias E., Belo, José Antonio
Format: Article
Language:English
Subjects:
Ablation
Antibodies
Cardiomyocytes
CCBE1
Cell culture
Cell growth
Cell proliferation
Collagen
Defects
Deregulation
EMT
epicardial derived cells
Epicardium
Explants
Extracellular matrix
Fibroblasts
Growth factors
Heart
heart development
Matrix protein
Mesenchyme
Morphology
Mutants
myocardial growth
Myocardium
Smooth muscle
Ventricle
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Summary:The epicardium is a single cell layer of mesothelial cells that plays a critical role during heart development contributing to different cardiac cell types of the developing heart through epithelial-to-mesenchymal transition (EMT). Moreover, the epicardium is a source of secreted growth factors that promote myocardial growth. CCBE1 is a secreted extracellular matrix protein expressed by epicardial cells that is required for the formation of the primitive coronary plexus. However, the role of CCBE1 during epicardial development was still unknown. Here, using a Ccbe1 knockout (KO) mouse model, we observed that loss of CCBE1 leads to congenital heart defects including thinner and hyper-trabeculated ventricular myocardium. In addition, Ccbe1 mutant hearts displayed reduced proliferation of cardiomyocyte and epicardial cells. Epicardial outgrowth culture assay to assess epicardial-derived cells (EPDC) migration showed reduced invasion of the collagen gel by EPDCs in Ccbe1 KO epicardial explants. Ccbe1 KO hearts also displayed fewer nonmyocyte/nonendothelial cells intramyocardially with a reduced proliferation rate. Additionally, RNA-seq data and experimental validation by qRT-PCR showed a marked deregulation of EMT-related genes in developing Ccbe1 mutant hearts. Together, these findings indicate that the myocardium defects in Ccbe1 KO mice arise from disruption of epicardial development and function.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232012642