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Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells.



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Iyer, Dharini 
Gambardella, Laure 
Bernard, William G 
Serrano, Felipe 
Mascetti, Victoria L 


The epicardium has emerged as a multipotent cardiovascular progenitor source with therapeutic potential for coronary smooth muscle cell, cardiac fibroblast (CF) and cardiomyocyte regeneration, owing to its fundamental role in heart development and its potential ability to initiate myocardial repair in injured adult tissues. Here, we describe a chemically defined method for generating epicardium and epicardium-derived smooth muscle cells (EPI-SMCs) and CFs from human pluripotent stem cells (HPSCs) through an intermediate lateral plate mesoderm (LM) stage. HPSCs were initially differentiated to LM in the presence of FGF2 and high levels of BMP4. The LM was robustly differentiated to an epicardial lineage by activation of WNT, BMP and retinoic acid signalling pathways. HPSC-derived epicardium displayed enhanced expression of epithelial- and epicardium-specific markers, exhibited morphological features comparable with human foetal epicardial explants and engrafted in the subepicardial space in vivo. The in vitro-derived epicardial cells underwent an epithelial-to-mesenchymal transition when treated with PDGF-BB and TGFβ1, resulting in vascular SMCs that displayed contractile ability in response to vasoconstrictors. Furthermore, the EPI-SMCs displayed low density lipoprotein uptake and effective lowering of lipoprotein levels upon treatment with statins, similar to primary human coronary artery SMCs. Cumulatively, these findings suggest that HPSC-derived epicardium and EPI-SMCs could serve as important tools for studying human cardiogenesis, and as a platform for vascular disease modelling and drug screening.



Epicardium, Human pluripotent stem cells, Vascular smooth muscle cells, Blotting, Western, Cell Differentiation, Cells, Cultured, Flow Cytometry, Humans, Immunohistochemistry, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Pericardium, Pluripotent Stem Cells, Real-Time Polymerase Chain Reaction

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The Company of Biologists
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
Medical Research Council (G1000847)
Medical Research Council (G0800784)
Medical Research Council (G0600275)
Wellcome Trust (097922/Z/11/B)
This work was supported by the British Heart Foundation (BHF) [NH/11/1/28922], by the UK Medical Research Council and BHF [G1000847 to S.S. and R.A.P.), and by Cambridge Hospitals National Institute for Health Research Biomedical Research Centre funding (S.S. and R.A.P.). D.I. is on a University of Cambridge Commonwealth Scholarship. S.S. and F.S. are supported by the BHF [FS/13/29/ 30024]. L.G. is supported by the BHF [RM/l3/3/30159]. W.G.B. and V.L.M. are supported by BHF PhD studentships [FS/11/77/29327 and FS/10/48/28674].