BNC1 regulates cell heterogeneity in human pluripotent stem cell derived-epicardium
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Gambardella, L., McManus, S., Moignard, V., Bernard, W., Gottgens, B., & Sinha, S. BNC1 regulates cell heterogeneity in human pluripotent stem cell derived-epicardium. Development, 1-16. https://doi.org/10.17863/CAM.46306
The murine developing epicardium heterogeneously expresses the transcription factors TCF21 and WT1. Here, we show that this cell heterogeneity is conserved in human epicardium, regulated by BNC1 and associated with cell fate and function. Single cell RNAseq of epicardium derived from human pluripotent stem cells (hPSC-epi) revealed that distinct epicardial sub-populations are defined by high levels of expression for the transcription factors BNC1 or TCF21. WT1+ cells are included in the BNC1+ population, which was confirmed in human foetal hearts. THY1 emerged as a membrane marker of the TCF21 population. We show that THY1+ cells can differentiate into cardiac fibroblast (CF) and smooth muscle cells (SMC), while THY1-cells were predominantly restricted to SMC. Knocking down BNC1 during the establishment of the epicardial populations resulted in a homogeneous, predominantly, TCF21high population. Network inference methods using transcriptomic data from the different cell lineages derived from the hPSC-epi, delivered a core transcriptional network organized around WT1, TCF21 and BNC1. This study is a step towards engineering sub-populations of epicardial cells with selective biological activities and unveils a list of epicardial regulators.
This work was supported by the British Heart Foundation Oxbridge Centre for Regenerative Medicine RM/13/3/30159 and RM/17/2/33380 (LG, SS) and BHF grants FS/14/59/31282 (SAM), FS/13/29/30024 and FS/18/46/33663 (SS). SS was also 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) and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre funding (SS). VM was supported by a Wellcome PhD studentship as part of the Stem Cell Institute PhD programme. Research in the Gottgens group is supported by programmatic funding from Wellcome, CRUK and Bloodwise. Single cell experiments were supported through an MRC Clinical Research Infrastructure award. NL was supported by the Biotechnology and Biological Sciences Research Council (Institute Strategic Programmes BBS/E/B/000C0419 and BBS/E/B/000C0434). DS was supported by an ERASMUS+ internship. WGB was supported from the Stroke Association (TSA 2016/02 PP11_Sinha).
MEDICAL RESEARCH COUNCIL (MR/M008975/1)
British Heart Foundation (FS/13/29/30024)
British Heart Foundation (FS/14/59/31282)
British Heart Foundation (PG/17/24/32886)
Wellcome Trust (203151/Z/16/Z)
British Heart Foundation (BHF-FS/18/46/33663)
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This record's DOI: https://doi.org/10.17863/CAM.46306
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299241
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/