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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.<\/jats:p>","DOI":"10.3390\/ijms232012642","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T22:49:46Z","timestamp":1666306186000},"page":"12642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["CCBE1 Is Essential for Epicardial Function during Myocardium Development"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9855-8173","authenticated-orcid":false,"given":"Fernando","family":"Bonet","sequence":"first","affiliation":[{"name":"Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"},{"name":"Medicine Department, School of Medicine, University of C\u00e1diz (UCA), 11003 C\u00e1diz, Spain"}]},{"given":"Sabrina Brito","family":"A\u00f1ez","sequence":"additional","affiliation":[{"name":"Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9790-8335","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"In\u00e1cio","sequence":"additional","affiliation":[{"name":"Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6245-8071","authenticated-orcid":false,"given":"Matthias E.","family":"Futschik","sequence":"additional","affiliation":[{"name":"MRC London Institute of Medical Sciences (LMS), Faculty of Medicine, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7384-0949","authenticated-orcid":false,"given":"Jos\u00e9 Antonio","family":"Belo","sequence":"additional","affiliation":[{"name":"Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/(SICI)1097-0185(20000401)258:4<319::AID-AR1>3.0.CO;2-O","article-title":"Developmental Patterning of the Myocardium","volume":"258","author":"Sedmera","year":"2000","journal-title":"Anat. 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