Epicardial Cells of Human Adults Can Undergo an Epithelial-to-Mesenchymal Transition and Obtain Characteristics of Smooth Muscle Cells In Vitro

Authors

  • John van Tuyn,

    1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
    2. Virus and Stem Cell Biology Laboratory, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
    3. Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
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  • Douwe E. Atsma M.D., Ph.D.,

    Corresponding author
    1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
    • Department of Cardiology, Leiden University Medical Center, Leiden, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Telephone: +31715269245; Fax: +31715268270
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  • Elizabeth M. Winter,

    1. Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
    2. Department of Anatomy, Leiden University Medical Center, Leiden, The Netherlands
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  • Ietje van der Velde-van Dijke,

    1. Virus and Stem Cell Biology Laboratory, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
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  • Daniel A. Pijnappels,

    1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
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  • Noortje A.M. Bax,

    1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
    2. Department of Anatomy, Leiden University Medical Center, Leiden, The Netherlands
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  • Shoshan Knaän-Shanzer,

    1. Virus and Stem Cell Biology Laboratory, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
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  • Adriana C. Gittenberger-de Groot,

    1. Department of Anatomy, Leiden University Medical Center, Leiden, The Netherlands
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  • Robert E. Poelmann,

    1. Department of Anatomy, Leiden University Medical Center, Leiden, The Netherlands
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  • Arnoud van der Laarse,

    1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
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  • Ernst E. van der Wall,

    1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
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  • Martin J. Schalij,

    1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
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  • Antoine A.F. de Vries

    1. Virus and Stem Cell Biology Laboratory, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
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Abstract

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 β-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-β1 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.

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