Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.67259
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Funding
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0421, BBS/E/B/000C0422]
- Medical Research Council [MR/T011769/1, MR/J003808/1, FC001120]
- European Research Council
- Gates Cambridge Trust
- Japan Society for the Promotion of Science [201860446, 16J08005]
- Cancer Research UK [FC001120]
- Wellcome Trust [FC001120]
- Cambridge Hospitals National Institute for Health Research Biomedical Research Center
- Grants-in-Aid for Scientific Research [16J08005] Funding Source: KAKEN
- BBSRC [BBS/E/B/000C0422, BBS/E/B/000C0421] Funding Source: UKRI
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TGF beta signaling is essential for maintaining naive human pluripotent stem cells, with downstream effector proteins SMAD2/3 binding to common sites in both naive and primed cells. Inhibition of TGF beta signaling leads to downregulation of target genes and differentiation of pluripotent cells, with different transcriptional trajectories observed between naive and primed cells. These findings indicate a continuum of TGF beta pathway function in human pluripotency.
The signalling pathways that maintain primed human pluripotent stem cells (hPSCs) have been well characterised, revealing a critical role for TGF beta/Activin/Nodal signalling. In contrast, the signalling requirements of naive human pluripotency have not been fully established. Here, we demonstrate that TGF beta 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 TGF beta 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 TGF beta signalling. Primed hPSCs differentiate into neuroectoderm cells, whereas naive hPSCs transition into trophectoderm. These results establish that there is a continuum for TGF beta pathway function in human pluripotency spanning a developmental window from naive to primed states.
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