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Development. 2019 Nov 25. pii: dev.174441. doi: 10.1242/dev.174441. [Epub ahead of print]

BNC1 regulates cell heterogeneity in human pluripotent stem cell derived-epicardium.

Author information

1
Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Department of Medicine, University of Cambridge, UK.
2
Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, UK.
3
The Babraham Institute, Cambridge, UK.
4
Department of Physiology, Anatomy and Genetics, University of Oxford, UK.
5
aSciStance Ltd, Cambridge, UK.
6
Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Department of Medicine, University of Cambridge, UK ss661@cam.ac.uk.

Abstract

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.

KEYWORDS:

BNC1; Epicardium; Heart development; Human pluripotent stem cells; Regenerative medicine; Single cell

PMID:
31767620
DOI:
10.1242/dev.174441

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