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Direct reprogramming of fibroblasts into epiblast stem cells

Nature Cell Biology volume 13, pages 66–71 (2011)Cite this article

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Abstract

Epiblast stem cells (EpiSCs) derived from epiblast tissue of post-implantation embryos are pluripotent and can give rise to all three germ layers in teratoma assays1,2. Introduction of the four transcription factors Oct4, Sox2, Klf4 and c-Myc into somatic cells has been shown to generate induced pluripotent stem cells (iPSCs) that are very similar to embryonic stem cells (ESCs) in a number of characteristics3,4,5,6. However, generation of EpiSCs by the direct reprogramming of somatic cells using these transcription factors has not been shown to date. Here, we show that these transcription factors can be used to directly generate induced EpiSCs (iEpiSCs) under EpiSC culture conditions. iEpiSCs resemble EpiSCs in morphology, gene expression pattern, epigenetic status and chimaera-forming capability. This study demonstrates that the culture environment in transcription factor-mediated reprogramming determines the cell fate of the reprogrammed cell. We therefore hypothesize that it will eventually be possible to shape the identity of a directly reprogrammed cell simply by modulating culture conditions.

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Figure 1: Direct reprogramming of fibroblasts into iEpiSCs.
Figure 2: Characterization of iEpiSCs.
Figure 3: Induction of naive pluripotency in iEpiSCs.
Figure 4: Four factors induce a naive or primed pluripotent state in fibroblasts depending on culture conditions.

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Acknowledgements

We are indebted to all members of the Schöler laboratory for discussions on the results. We are especially grateful to P. Tesar for providing T9 EpiSCs and A. Malapetsas for editing the manuscript. We are also grateful to M. Sinn for technical assistance and I. M. Verma for providing the pBOB-CAG-iCRE-SD plasmid. This work was supported by funds of the Max Planck Society and the Federal Ministry of Education and Research (BMBF) (Grant 01GN0934).

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster, 48149, Germany

    Dong Wook Han, Boris Greber, Guangming Wu, Natalia Tapia, Marcos J. Araúzo-Bravo, Christof Bernemann, Martin Stehling & Hans R. Schöler

  2. Center for Stem Cell Research, Institute of Biomedical Sciences and Technology, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, 143-701, Republic of Korea

    Kinarm Ko

  3. Department of Neuroscience, School of Medicine, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, 143-701, Republic of Korea

    Kinarm Ko

  4. University of Münster, Medical Faculty, Domagkstrasse 3, Münster, 48149, Germany

    Hans R. Schöler

Authors
  1. Dong Wook Han
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  2. Boris Greber
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  3. Guangming Wu
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  4. Natalia Tapia
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  7. Christof Bernemann
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  8. Martin Stehling
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  9. Hans R. Schöler
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Contributions

D.W.H. designed and performed most experiments and wrote the manuscript. B.G. performed microarray experiments, analysed the data and edited the manuscript. M.J.A. analysed the microarray data. N.T. carried out lentivirus construction and infection. C.B. analysed the gene expression data. G.W. and K.K. performed morula aggregation and the teratoma assay, respectively. M.S. performed FACS analysis. H.S. conceived the experiments and edited the manuscript.

Corresponding author

Correspondence to Hans R. Schöler.

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The authors declare no competing financial interests.

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Han, D., Greber, B., Wu, G. et al. Direct reprogramming of fibroblasts into epiblast stem cells. Nat Cell Biol 13, 66–71 (2011). https://doi.org/10.1038/ncb2136

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