A single-cell comparison of adult and fetal human epicardium defines the age-associated changes in epicardial activity

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.

Description

Acknowledgements: The authors would like to thank R. Barker at the University of Cambridge for assistance in obtaining the fetal tissue samples used in all analyses. Additionally, we are grateful for support from the Wellcome Sanger Cellular Generation and Phenotyping team and the Core DNA Pipelines team. This research was funded by the British Heart Foundation (BHF) Senior Fellowship (FS/18/46/33663)(S.S. and L.G.); the Oxbridge BHF Centre for Regenerative Medicine (RM/17/2/33380) (V.K.S.); and BHF grants PG/17/24/32886 (L.G.) and RG/17/5/32936 (H.D.). We also acknowledge core support from the Wellcome Trust, the Medical Research Council and the Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute. This research was funded, in whole or in part, by the Wellcome Trust (grant no. 203151/Z/16/Z). Finally, this project has been made possible, in part, by the Wellcome Trust (WT206194, S.A.T), the Wellcome Trust Clinical PhD Fellowship (J.C) and the Overseas Research Fellowship of the Takeda Science Foundation (K.K). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Funder: Takeda Science Foundation; doi: https://doi.org/10.13039/100007449

Funder: Wellcome Trust Clinical PhD Fellowship

Keywords

Resource, /631/443/592/2726, /631/532/7, /692/308/2171, /631/136/532/489, /631/208/514/1949, /38/91, /82, /45, /13/100, /14/1, /38, resource

Journal Title

Nature Cardiovascular Research

Journal ISSN

2731-0590

Volume Title

1

Publisher

Nature Publishing Group UK

Publisher DOI

https://doi.org/10.1038/s44161-022-00183-w

Rights

Attribution 4.0 International

Sponsorship

BHF Centre of Research Excellence, Oxford (BHF Centre of Research Excellence in Oxford) (RM/17/2/33380)
Wellcome Trust (Wellcome) (203151/Z/16/Z, 203151/Z/16/Z, 203151/Z/16/Z, 203151/Z/16/Z, 203151/Z/16/Z, WT206194, 203151/Z/16/Z)
British Heart Foundation (BHF) (RG/17/5/32936, FS/18/46/33663, PG/17/24/32886, FS/18/46/33663)
Wellcome Trust (Wellcome) (203151/Z/16/Z)

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