TGFβ signalling is required to maintain pluripotency of human naïve pluripotent stem cells
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Abstract
The signalling pathways that maintain primed human pluripotent stem cells (hPSCs) have been well characterised, revealing a critical role for TGFβ/Activin/Nodal signalling. In contrast, the signalling requirements of naive human pluripotency have not been fully established. Here, we demonstrate that TGFβ signalling is required to maintain naive hPSCs. The downstream effector proteins – SMAD2/3 – bind common sites in naive and primed hPSCs, including shared pluripotency genes. In naive hPSCs, SMAD2/3 additionally bind to active regulatory regions near to naive pluripotency genes. Inhibiting TGFβ signalling in naive hPSCs causes the downregulation of SMAD2/3-target genes and pluripotency exit. Single-cell analyses reveal that naive and primed hPSCs follow different transcriptional trajectories after inhibition of TGFβ signalling. Primed hPSCs differentiate into neuroectoderm cells, whereas naive hPSCs transition into trophectoderm. These results establish that there is a continuum for TGFβ pathway function in human pluripotency spanning a developmental window from naive to primed states.
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Funder: Gates Cambridge Trust; FundRef: http://dx.doi.org/10.13039/501100005370
Funder: Cambridge Hospitals National Institute for Health Research Biomedical Research Center
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Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0422)
Medical Research Council (MR/T011769/1)
Medical Research Council (MR/J003808/1)
European Research Council (New-Chol)
European Research Council (INTENS)
Japan Society for the Promotion of Science (201860446)
Japan Society for the Promotion of Science (16J08005)
Cancer Research UK (FC001120)
Medical Research Council (FC001120)
Wellcome Trust (FC001120)