title: Generation of the epicardial lineage from human pluripotent stem cells.
abstract: The epicardium supports cardiomyocyte proliferation early in development and provides fibroblasts and vascular smooth muscle cells to the developing heart. The epicardium has been shown to play an important role during tissue remodeling after cardiac injury, making access to this cell lineage necessary for the study of regenerative medicine. Here we describe the generation of epicardial lineage cells from human pluripotent stem cells by stage-specific activation of the BMP and WNT signaling pathways. These cells display morphological characteristics and express markers of the epicardial lineage, including the transcription factors WT1 and TBX18 and the retinoic acid-producing enzyme ALDH1A2. When induced to undergo epithelial-to-mesenchymal transition, the cells give rise to populations that display characteristics of the fibroblast and vascular smooth muscle lineages. These findings identify BMP and WNT as key regulators of the epicardial lineage in vitro and provide a model for investigating epicardial function in human development and disease.
authors.affiliation: 1] McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alec D
authors.initials: AD
authors.lastname: Witty
authors.affiliation: 1] McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. [2] Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada. [3] Toronto General Research Institute, Toronto, Ontario, Canada. [4] Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anton
authors.initials: A
authors.lastname: Mihic
authors.affiliation: 1] The Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada. [2] Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada. [3] Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Roger Y
authors.initials: RY
authors.lastname: Tam
authors.affiliation: 1] The Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada. [2] Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada. [3] Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Fisher
authors.affiliation: McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mikryukov
authors.affiliation: 1] McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. [2] The Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada. [3] Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada. [4] Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. [5] Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
authors.affiliation: 1] McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. [2] Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada. [3] Toronto General Research Institute, Toronto, Ontario, Canada. [4] Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.affiliation: McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kattman
authors.affiliation: 1] McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [3] Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Keller
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D019070:Cell Lineage / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology; D010496:Pericardium / Q000166:cytology*; D039904:Pluripotent Stem Cells / Q000166:cytology*; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: D055415:Bone Morphogenetic Protein 4; D000444:Aldehyde Dehydrogenase