TGFβ signalling is required to maintain pluripotency of human naïve pluripotent stem cells.

eLife 2021 Aug 31

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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. © 2021, Osnato et al.

Citation

Anna Osnato, Stephanie Brown, Christel Krueger, Simon Andrews, Amanda J Collier, Shota Nakanoh, Mariana Quiroga Londoño, Brandon T Wesley, Daniele Muraro, A Sophie Brumm, Kathy K Niakan, Ludovic Vallier, Daniel Ortmann, Peter J Rugg-Gunn. TGFβ signalling is required to maintain pluripotency of human naïve pluripotent stem cells. eLife. 2021 Aug 31;10