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Nanog promotes transfer of pluripotency after cell fusion

Nature volume 441, pages 9971001 (22 June 2006) | Download Citation

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Abstract

Through cell fusion, embryonic stem (ES) cells can erase the developmental programming of differentiated cell nuclei and impose pluripotency1,2. Molecules that mediate this conversion should be identifiable in ES cells. One candidate is the variant homeodomain protein Nanog, which has the capacity to entrain undifferentiated ES cell propagation3,4. Here we report that in fusions between ES cells and neural stem (NS) cells, increased levels of Nanog stimulate pluripotent gene activation from the somatic cell genome and enable an up to 200-fold increase in the recovery of hybrid colonies, all of which show ES cell characteristics. Nanog also improves hybrid yield when thymocytes or fibroblasts are fused to ES cells; however, fewer colonies are obtained than from ES × NS cell fusions, consistent with a hierarchical susceptibility to reprogramming among somatic cell types. Notably, for NS × ES cell fusions elevated Nanog enables primary hybrids to develop into ES cell colonies with identical frequency to homotypic ES × ES fusion products. This means that in hybrids, increased Nanog is sufficient for the NS cell epigenome to be reset completely to a state of pluripotency. We conclude that Nanog can orchestrate ES cell machinery to instate pluripotency with an efficiency of up to 100% depending on the differentiation status of the somatic cell.

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Acknowledgements

We thank J. Vrana for assistance with FACS and Y. Costa for critical reading of the manuscript. This research was supported by the Biotechnological and Biological Sciences Research Council and the Medical Research Council of the United Kingdom, the Wellcome Trust, and by an EMBO Long-term Fellowship (J.S.). Author Contributions J.S. designed and executed experiments, analysed data, and drafted the paper; I.C. and S.P. generated reagents and contributed to experimental design; and A.S. designed experiments and wrote the paper.

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Affiliations

  1. Centre Development in Stem Cell Biology, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, EH9 3JQ, UK

    • José Silva
    • , Ian Chambers
    • , Steven Pollard
    •  & Austin Smith
  2. Institute for Stem Cell Biology University of Cambridge, Cambridge, CB2 1QT, UK

    • Austin Smith

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Competing interests

The University of Edinburgh has filed a patent application related to this work and has licensed this patent to Stem Cell Sciences, PLC. A.S. is a scientific consultant to Stem Cell Sciences, PLC.

Corresponding author

Correspondence to Austin Smith.

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    Supplementary Notes

    This file contains Supplementary Methods, Supplementary Figure Legends, Supplementary Figures 1–8 and additional references.

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https://doi.org/10.1038/nature04914

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