Abstract
Pluripotent stem cells exist in naive and primed states, epitomized by mouse embryonic stem cells (ESCs) and the developmentally more advanced epiblast stem cells (EpiSCs; ref. 1). In the naive state of ESCs, the genome has an unusual open conformation and possesses a minimum of repressive epigenetic marks2. In contrast, EpiSCs have activated the epigenetic machinery that supports differentiation towards the embryonic cell types3,4,5,6. The transition from naive to primed pluripotency therefore represents a pivotal event in cellular differentiation. But the signals that control this fundamental differentiation step remain unclear. We show here that paracrine and autocrine Wnt signals are essential self-renewal factors for ESCs, and are required to inhibit their differentiation into EpiSCs. Moreover, we find that Wnt proteins in combination with the cytokine LIF are sufficient to support ESC self-renewal in the absence of any undefined factors, and support the derivation of new ESC lines, including ones from non-permissive mouse strains. Our results not only demonstrate that Wnt signals regulate the naive-to-primed pluripotency transition, but also identify Wnt as an essential and limiting ESC self-renewal factor.
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Change history
07 October 2011
In the version of this article initially published online, the sequences of the primers used for Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a and Wnt5b listed in supplementary table 5 were incorrect.
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Acknowledgements
These studies were supported by the Howard Hughes Medical Institute, the Erasmus MC Stem Cell Institute and grants from the California Institute of Regenerative Medicine (RC1-00133-1), the National Institutes of Health (DK67834-01) and the European Union (FP7-PEOPLE-2009-RG-256560). We thank H. Zeng for technical advice, J. Kong-A-San for assistance with blastocyst injections and R. van der Linden for assistance with FACS. We are grateful for the use of the Cellavista imager and the assistance of V. Vincent and Roche Diagnostics.
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D.t.B., D.K. and T.B. designed and carried out experiments, analysed data and wrote the paper. W.K., A.M., R.S. and E.E. designed and carried out experiments and analysed data. R.N. designed experiments and wrote the paper.
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ten Berge, D., Kurek, D., Blauwkamp, T. et al. Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nat Cell Biol 13, 1070–1075 (2011). https://doi.org/10.1038/ncb2314
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DOI: https://doi.org/10.1038/ncb2314
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