Epicardial cells derived from human embryonic stem cells augment cardiomyocyte-driven heart regeneration.

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Colzani, Maria 
Davaapil, Hongorzul 
Hofsteen, Peter 

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.

Animals, Chick Embryo, Gene Expression Regulation, Heart, Human Embryonic Stem Cells, Humans, Male, Myocardial Infarction, Myocytes, Cardiac, Rats, Rats, Nude, Rats, Sprague-Dawley, Regeneration, Tissue Engineering
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Nat Biotechnol
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Springer Science and Business Media LLC
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Wellcome Trust (203568/Z/16/Z)
Medical Research Council (MR/L016761/1)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Addenbrooke's Charitable Trust (ACT) (Minute 23/17 B (iii))
Medical Research Council (G1000847)
Wellcome Trust (203151/Z/16/Z)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (PG/17/24/32886)
British Heart Foundation (RG/17/5/32936)
Medical Research Council (MC_PC_12009)
British Heart Foundation (SP/15/7/31561)
British Heart Foundation (PG/16/11/32021)
British Heart Foundation (FS/18/46/33663)
Stroke Association (TSA 2016/02)
: This work was supported by the British Heart Foundation (BHF; Grants NH/11/1/28922, G1000847, FS/13/29/30024 and FS/18/46/33663), Oxford-Cambridge Centre for Regenerative Medicine (RM/13/3/30159), the UK Medical Research Council (MRC) and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre funding (SS), as well as National Institutes of Health Grants P01HL094374, P01GM081619, R01HL12836 and a grant from the Fondation Leducq Transatlantic Network of Excellence (CEM). 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 FS/13/65/30441). DI received a University of Cambridge Commonwealth Scholarship. LG is supported by BHF Award RM/l3/3/30159 and LPO is funded by a Wellcome Trust Fellowship (203568/Z/16/Z). NF was supported by BHF grants RG/13/14/30314. NL was supported by the Biotechnology and Biological Sciences Research Council (Institute Strategic Programmes BBS/E/B/000C0419 and BBS/E/B/000C0434). SS and MB were supported by the British Heart Foundation Centre for Cardiovascular Research Excellence. Core support was provided by the Wellcome-MRC Cambridge Stem Cell Institute (203151/Z/16/Z), The authors thank Osiris for provision of the primary mesenchymal stem cells (59)