• Open Access

HIF-2α Suppresses p53 to Enhance the Stemness and Regenerative Potential of Human Embryonic Stem Cells§

Authors

  • Bikul Das,

    Corresponding author
    1. Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, California, USA
    2. Division of Hematology and Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    3. Developmental Biology and Stem Cell Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    4. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    • Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
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    • Telephone: (650) 724-6467; Fax: (650) 725-1420

  • Reza Bayat-Mokhtari,

    1. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    2. Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan
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  • Micky Tsui,

    1. Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan
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  • Shamim Lotfi,

    1. Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan
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  • Rika Tsuchida,

    1. Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan
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  • Dean W. Felsher,

    1. Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, California, USA
    2. Division of Hematology and Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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  • Herman Yeger

    1. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    2. Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan
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  • Author contributions: B.D.: conceived the idea, initiated the study, designed the experimental strategies, and wrote the manuscript; B.D., R.B.M., M.T., and S.L.: performed the in vitro and in vivo experiments; B.D., R.T., D.W.F., and H.Y.: analyzed the data and participated in manuscript revision.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS June 11, 2012; available online without subscription through the open access option.

Abstract

Human embryonic stem cells (hESCs) have been reported to exert cytoprotective activity in the area of tissue injury. However, hypoxia/oxidative stress prevailing in the area of injury could activate p53, leading to death and differentiation of hESCs. Here we report that when exposed to hypoxia/oxidative stress, a small fraction of hESCs, namely the SSEA3+/ABCG2+ fraction undergoes a transient state of reprogramming to a low p53 and high hypoxia inducible factor (HIF)-2α state of transcriptional activity. This state can be sustained for a period of 2 weeks and is associated with enhanced transcriptional activity of Oct-4 and Nanog, concomitant with high teratomagenic potential. Conditioned medium obtained from the post-hypoxia SSEA3+/ABCG2+ hESCs showed cytoprotection both in vitro and in vivo. We termed this phenotype as the “enhanced stemness” state. We then demonstrated that the underlying molecular mechanism of this transient phenotype of enhanced stemness involved high Bcl-2, fibroblast growth factor (FGF)-2, and MDM2 expression and an altered state of the p53/MDM2 oscillation system. Specific silencing of HIF-2α and p53 resisted the reprogramming of SSEA3+/ABCG2+ to the enhanced stemness phenotype. Thus, our studies have uncovered a unique transient reprogramming activity in hESCs, the enhanced stemness reprogramming where a highly cytoprotective and undifferentiated state is achieved by transiently suppressing p53 activity. We suggest that this transient reprogramming is a form of stem cell altruism that benefits the surrounding tissues during the process of tissue regeneration. STEM CELLS2012;30:1685–1695

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