Hypoxia induces re-entry of committed cells into pluripotency

Authors

  • Julie Mathieu,

    1. Department of Biochemistry, University of Washington, Seattle, Washington, USA
    2. Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, Washington, USA
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  • Zhan Zhang,

    1. Merck Research Laboratories, Seattle, Washington, USA
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  • Angelique Nelson,

    1. Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, Washington, USA
    2. Department of Comparative Medicine, University of Washington, Seattle, Washington, USA
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  • Deepak A. Lamba,

    1. Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, Washington, USA
    2. Department of Biological Structure, and University of Washington, Seattle, Washington, USA
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  • Thomas A. Reh,

    1. Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, Washington, USA
    2. Department of Biological Structure, and University of Washington, Seattle, Washington, USA
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  • Carol Ware,

    1. Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, Washington, USA
    2. Department of Comparative Medicine, University of Washington, Seattle, Washington, USA
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  • Hannele Ruohola-Baker

    Corresponding author
    1. Department of Biochemistry, University of Washington, Seattle, Washington, USA
    2. Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, Washington, USA
    • Correspondence: Hannele Ruohola-Baker, Ph.D., Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. Telephone: 1–206-543–8468; Fax: 1–206-685–1357; e-mail: hannele@u.washington.edu

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  • Author contributions: J.M.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; Z.Z.: data analysis and interpretation; A.N.: collection of data; D.A.L.: collection of data and data analysis and interpretation; T.A.R.: provision of study material; C.W.: conception and design and provision of study material; H.R.B: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript.

ABSTRACT

Adult stem cells reside in hypoxic niches, and embryonic stem cells (ESCs) are derived from a low oxygen environment. However, it is not clear whether hypoxia is critical for stem cell fate since for example human ESCs (hESCs) are able to self-renew in atmospheric oxygen concentrations as well. We now show that hypoxia can govern cell fate decisions since hypoxia alone can revert hESC- or iPSC-derived differentiated cells back to a stem cell-like state, as evidenced by re-activation of an Oct4-promoter reporter. Hypoxia-induced “de-differentiated” cells also mimic hESCs in their morphology, long-term self-renewal capacity, genome-wide mRNA and miRNA profiles, Oct4 promoter methylation state, cell surface markers TRA1–60 and SSEA4 expression, and capacity to form teratomas. These data demonstrate that hypoxia can influence cell fate decisions and could elucidate hypoxic niche function. Stem Cells 2013;31:1737-1748

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