The epicardium and its derivatives provide trophic and structural support for the developing and adult heart. Here we tested the ability of human embryonic stem cell (hESC)-derived epicardium to augment the structure and function of engineered heart tissue in vitro and to improve efficacy of hESC-cardiomyocyte grafts in infarcted athymic rat hearts. Epicardial cells markedly enhanced the contractility, myofibril structure and calcium handling of human engineered heart tissues, while reducing passive stiffness compared with mesenchymal stromal cells. Transplanted epicardial cells formed persistent fibroblast grafts in infarcted hearts. Cotransplantation of hESC-derived epicardial cells and cardiomyocytes doubled graft cardiomyocyte proliferation rates in vivo, resulting in 2.6-fold greater cardiac graft size and simultaneously augmenting graft and host vascularization. Notably, cotransplantation improved systolic function compared with hearts receiving either cardiomyocytes alone, epicardial cells alone or vehicle. The ability of epicardial cells to enhance cardiac graft size and function makes them a promising adjuvant therapeutic for cardiac repair.
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The raw data that support the findings of this study are available from the corresponding author upon reasonable request.
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This work was supported by the British Heart Foundation (BHF; grants nos. NH/11/1/28922, G1000847, FS/13/29/30024 and FS/18/46/33663), Oxford-Cambridge Centre for Regenerative Medicine (grant no. RM/13/3/30159), the UK Medical Research Council (MRC) and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre funding (S.S.), as well as National Institutes of Health grant nos. P01HL094374, P01GM081619 and R01HL128362 and a grant from the Fondation Leducq Transatlantic Network of Excellence (C.E.M.). J.B. was supported by a Cambridge National Institute for Health Research Biomedical Research Centre Cardiovascular Clinical Research Fellowship and, subsequently, by a BHF Studentship (grant no. FS/13/65/30441). D.I. received a University of Cambridge Commonwealth Scholarship. L.G. is supported by BHF Award RM/l3/3/30159 and L.P.O. is funded by a Wellcome Trust Fellowship (grant no. 203568/Z/16/Z). N.F. was supported by BHF grant no. RG/13/14/30314. N.L.N. was supported by the Biotechnology and Biological Sciences Research Council (Institute Strategic Programmes BBS/E/B/000C0419 and BBS/E/B/000C0434). S.S. and M.R.B. were supported by the BHF Centre for Cardiovascular Research Excellence. Core support was provided by the Wellcome-MRC Cambridge Stem Cell Institute (grant no. 203151/Z/16/Z). The authors thank Osiris for providing the primary mesenchymal stem cells47.
A patent has been filed on the cardiac application of epicardial cells, on which C.E.M., S.S. and J.B. are coinventors (WO2018170280A1). C.E.M. is a scientific founder and equity holder in Cytocardia.
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