Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors (original) (raw)

Nature volume 454, pages 646–650 (2008)Cite this article

Abstract

Reprogramming of somatic cells is a valuable tool to understand the mechanisms of regaining pluripotency and further opens up the possibility of generating patient-specific pluripotent stem cells. Reprogramming of mouse and human somatic cells into pluripotent stem cells, designated as induced pluripotent stem (iPS) cells, has been possible with the expression of the transcription factor quartet Oct4 (also known as Pou5f1), Sox2, c-Myc and Klf4 (refs 1–11). Considering that ectopic expression of c-Myc causes tumorigenicity in offspring2 and that retroviruses themselves can cause insertional mutagenesis, the generation of iPS cells with a minimal number of factors may hasten the clinical application of this approach. Here we show that adult mouse neural stem cells express higher endogenous levels of Sox2 and c-Myc than embryonic stem cells, and that exogenous Oct4 together with either Klf4 or c-Myc is sufficient to generate iPS cells from neural stem cells. These two-factor iPS cells are similar to embryonic stem cells at the molecular level, contribute to development of the germ line, and form chimaeras. We propose that, in inducing pluripotency, the number of reprogramming factors can be reduced when using somatic cells that endogenously express appropriate levels of complementing factors.

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Gene Expression Omnibus

Data deposits

The microarray data sets are available from the GEO (Gene Expression Omnibus) website under accession number GSE10806.

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Acknowledgements

We thank J. Müller-Keuker for critically reviewing the manuscript, M. Stehling for fluorescence-activated cell sorting analysis, C. Ortmeier for real-time PCR analysis, B. Schäfer for histology, C. Becker, B. Kratz and B. Denicke for probe processing and array hybridization, and T. Kitamura for the pMX retroviral vector. J.B.K. was supported by the Interdepartmental Graduate-Programme for Experimental Life Sciences (iGEL) at the University of Münster. The microarray analyses were funded in part by a grant from the Deutsche Forschungsgemeinschaft DFG SPP1109.

Author Contributions J.B.K. (project design, generation and characterization of iPS cells and NSCs, and preparation of manuscript), H.Z. (project design, generation of iPS cells, and preparation of manuscript), G.W., L.G., V.S., K.K. and D.W.H. (characterization of iPS cells), M.J.A.-B., D.R., M.Z. (microarray and bioinformatics) and H.R.S. (project design, and preparation of manuscript).

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Author notes

  1. Jeong Beom Kim and Holm Zaehres: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, NRW, Germany,
    Jeong Beom Kim, Holm Zaehres, Guangming Wu, Luca Gentile, Kinarm Ko, Vittorio Sebastiano, Marcos J. Araúzo-Bravo, Dong Wook Han & Hans R. Schöler
  2. Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Pauwelsstrasse 30, 52074 Aachen, NRW, Germany,
    David Ruau & Martin Zenke

Authors

  1. Jeong Beom Kim
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  2. Holm Zaehres
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  3. Guangming Wu
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  4. Luca Gentile
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  5. Kinarm Ko
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  6. Vittorio Sebastiano
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  7. Marcos J. Araúzo-Bravo
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  8. David Ruau
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  9. Dong Wook Han
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  10. Martin Zenke
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  11. Hans R. Schöler
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Corresponding author

Correspondence toHans R. Schöler.

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Kim, J., Zaehres, H., Wu, G. et al. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors.Nature 454, 646–650 (2008). https://doi.org/10.1038/nature07061

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