HIF1α Modulates Cell Fate Reprogramming Through Early Glycolytic Shift and Upregulation of PDK1–3 and PKM2

Authors

  • Alessandro Prigione,

    Corresponding author
    1. Molecular Embryology and Ageing Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
    2. Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany
    • Correspondence: Alessandro Prigione, M.D., Ph.D., Robert-Roessle-Str. 10, D-13125 Berlin-Buch, Germany. Telephone: +49-30-9406-2871; Fax: +49-30-9406-3869; e-mail: alessandro.prigione@mdc-berlin.de.; or James Adjaye, Ph.D., Institute for Stem Cell Research and Regenerative Medicine, Medical faculty, Heinrich Heine University, Duesseldorf, Germany. Telephone: +49–211 81 08191; Fax: +49–211 81 19147; e-mail: James.Adjaye@med.uni-duesseldorf.de

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  • Nadine Rohwer,

    1. Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
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  • Sheila Hoffmann,

    1. Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany
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  • Barbara Mlody,

    1. Molecular Embryology and Ageing Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
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  • Katharina Drews,

    1. Molecular Embryology and Ageing Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
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  • Raul Bukowiecki,

    1. Molecular Embryology and Ageing Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
    2. Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany
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  • Katharina Blümlein,

    1. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
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  • Erich E. Wanker,

    1. Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany
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  • Markus Ralser,

    1. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
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  • Thorsten Cramer,

    1. Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
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  • James Adjaye

    1. Molecular Embryology and Ageing Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
    2. Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
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Abstract

Reprogramming somatic cells to a pluripotent state drastically reconfigures the cellular anabolic requirements, thus potentially inducing cancer-like metabolic transformation. Accordingly, we and others previously showed that somatic mitochondria and bioenergetics are extensively remodeled upon derivation of induced pluripotent stem cells (iPSCs), as the cells transit from oxidative to glycolytic metabolism. In the attempt to identify possible regulatory mechanisms underlying this metabolic restructuring, we investigated the contributing role of hypoxia-inducible factor one alpha (HIF1α), a master regulator of energy metabolism, in the induction and maintenance of pluripotency. We discovered that the ablation of HIF1α function in dermal fibroblasts dramatically hampers reprogramming efficiency, while small molecule-based activation of HIF1α significantly improves cell fate conversion. Transcriptional and bioenergetic analysis during reprogramming initiation indicated that the transduction of the four factors is sufficient to upregulate the HIF1α target pyruvate dehydrogenase kinase (PDK) one and set in motion the glycolytic shift. However, additional HIF1α activation appears critical in the early upregulation of other HIF1α-associated metabolic regulators, including PDK3 and pyruvate kinase (PK) isoform M2 (PKM2), resulting in increased glycolysis and enhanced reprogramming. Accordingly, elevated levels of PDK1, PDK3, and PKM2 and reduced PK activity could be observed in iPSCs and human embryonic stem cells in the undifferentiated state. Overall, the findings suggest that the early induction of HIF1α targets may be instrumental in iPSC derivation via the activation of a glycolytic program. These findings implicate the HIF1α pathway as an enabling regulator of cellular reprogramming. Stem Cells 2014;32:364–376

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