Epicardial cells of human adults can undergo an epithelial-to-mesenchymal transition and obtain characteristics of smooth muscle cells in vitro.
Myocardial and coronary development are both critically dependent on epicardial cells. During cardiomorphogenesis, a subset of epicardial cells undergoes an epithelial-to-mesenchymal transition (EMT) and invades the myocardium to differentiate into various cell types, including coronary smooth muscle cells and perivascular and cardiac interstitial fibroblasts. Our current knowledge of epicardial EMT and the ensuing epicardium-derived cells (EPDCs) comes primarily from studies of chick and mouse embryonic development. Due to the absence of an in vitro culture system, very little is known about human EPDCs. Here, we report for the first time the establishment of cultures of primary epicardial cells from human adults and describe their immunophenotype, transcriptome, transducibility, and differentiation potential in vitro. Changes in morphology and beta-catenin staining pattern indicated that human epicardial cells spontaneously undergo EMT early during ex vivo culture. The surface antigen profile of the cells after EMT closely resembles that of subepithelial fibroblasts; however, only EPDCs express the cardiac marker genes GATA4 and cardiac troponin T. After infection with an adenovirus vector encoding the transcription factor myocardin or after treatment with transforming growth factor-beta1 or bone morphogenetic protein-2, EPDCs obtain characteristics of smooth muscle cells. Moreover, EPDCs can undergo osteogenesis but fail to form adipocytes or endothelial cells in vitro. Cultured epicardial cells from human adults recapitulate at least part of the differentiation potential of their embryonic counterparts and represent an excellent model system to explore the biological properties and therapeutic potential of these cells.
van Tuyn
John
J
Department of Cardiology, Leiden University Medical Center, Leiden, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Atsma
Douwe E
DE
Winter
Elizabeth M
EM
van der Velde-van Dijke
Ietje
I
Pijnappels
Daniel A
DA
Bax
Noortje A M
NA
Knaän-Shanzer
Shoshan
S
Gittenberger-de Groot
Adriana C
AC
Poelmann
Robert E
RE
van der Laarse
Arnoud
A
van der Wall
Ernst E
EE
Schalij
Martin J
MJ
de Vries
Antoine A F
AA
D000256:Adenoviridae; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002469:Cell Separation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D016130:Immunophenotyping; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis; D010496:Pericardium / Q000166:cytology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D000099251:Myocardin
D015415:Biomarkers; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D000099251:Myocardin