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Auxetic nuclei in embryonic stem cells exiting pluripotency

Abstract

Embryonic stem cells (ESCs) self-renew in a state of naïve pluripotency in which they are competent to generate all somatic cells. It has been hypothesized that, before irreversibly committing, ESCs pass through at least one metastable transition state. This transition would represent a gateway for differentiation and reprogramming of somatic cells. Here, we show that during the transition, the nuclei of ESCs are auxetic: they exhibit a cross-sectional expansion when stretched and a cross-sectional contraction when compressed, and their stiffness increases under compression. We also show that the auxetic phenotype of transition ESC nuclei is driven at least in part by global chromatin decondensation. Through the regulation of molecular turnover in the differentiating nucleus by external forces, auxeticity could be a key element in mechanotransduction. Our findings highlight the importance of nuclear structure in the regulation of differentiation and reprogramming.

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Figure 1: Atomic force microscopy measurements of ESCs.
Figure 2: Optofluidic assay.
Figure 3: Normal and auxetic nuclei.
Figure 4: Auxeticity and chromatin condensation states.

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Acknowledgements

This work was supported by the Royal Society, UK Medical Research Council and Wellcome Trust (G.W.W., C.L.F. and K.J.C.), a European Research Council starting grant (S.P. and U.F.K.), a Human Frontier in Science Program grant (R.J.M.F and C.R.M.), a Leverhulme and Newton Trust Early Career Fellowship (S.P.) and the UK Medical Research Council (Career Development Award to K.F.). We also thank T. Kalkan for providing cells and guidance, A. Ekpenyong for experimental support, D. Morrison for assistance with electron microscopy, E. Paluch for critical reading of the manuscript, and A. Brown, A. Smith and J. Nichols for helpful discussions.

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Authors

Contributions

K.J.C. developed the project; K.F., R.J.M.F., U.F.K. and K.J.C. designed the research; S.P., K.F., G.W.W., C.R.M., C.L.F. and K.J.C performed the experiments; S.P., K.F., C.R.M., A.J.K., U.F.K. and K.J.C. analysed and discussed the data; S.P., K.F. and K.J.C. wrote the paper.

Corresponding authors

Correspondence to Stefano Pagliara, Kristian Franze or Kevin J. Chalut.

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The authors declare no competing financial interests.

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Pagliara, S., Franze, K., McClain, C. et al. Auxetic nuclei in embryonic stem cells exiting pluripotency. Nature Mater 13, 638–644 (2014). https://doi.org/10.1038/nmat3943

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