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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. Cell therapy in a rat model of heart attack is enhanced by stem-cell-derived epicardium. [ABSTRACT FROM AUTHOR]

Re-activating quiescent adult epicardium represents a potential therapeutic approach for human cardiac regeneration. However, the exact molecular differences between inactive adult and active fetal epicardium are not known. In this study, we combined fetal and adult human hearts using single-cell and single-nuclei RNA sequencing and compared epicardial cells from both stages. We found that a migratory fibroblast-like epicardial population only in the fetal heart and fetal epicardium expressed angiogenic gene programs, whereas the adult epicardium was solely mesothelial and immune responsive. Furthermore, we predicted that adult hearts may still receive fetal epicardial paracrine communication, including WNT signaling with endocardium, reinforcing the validity of regenerative strategies that administer or reactivate epicardial cells in situ. Finally, we explained graft efficacy of our human embryonic stem-cell-derived epicardium model by noting its similarity to human fetal epicardium. Overall, our study defines epicardial programs of regenerative angiogenesis absent in adult hearts, contextualizes animal studies and defines epicardial states required for effective human heart regeneration., Competing Interests: Competing interests In the past 3 years, S.A.T. has consulted or been a member of scientific advisory boards at Roche, Genentech, Biogen, GlaxoSmithKline, Qiagen and ForeSite Labs and is an equity holder of Transition Bio. All other authors declare no competing interests.