HIF-1α is upregulated in human mesenchymal stem cells

Authors

  • Sami Palomäki,

    1. Department of Anatomy and Cell Biology, Institute of Biomedicine, Biocenter Oulu and Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
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  • Mika Pietilä,

    1. Department of Anatomy and Cell Biology, Institute of Biomedicine, Biocenter Oulu and Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
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  • Saara Laitinen,

    1. Finnish Red Cross Blood Service, Helsinki, Finland
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  • Juha Pesälä,

    1. Department of Anatomy and Cell Biology, Institute of Biomedicine, Biocenter Oulu and Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
    2. Division of Surgery, Department of Surgery and Intensive Care, Institute of Clinical Medicine, University of Oulu and Clinical Research Centre, Oulu University Hospital, Oulu, Finland
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  • Raija Sormunen,

    1. Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Oulu, Finland
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  • Petri Lehenkari,

    1. Department of Anatomy and Cell Biology, Institute of Biomedicine, Biocenter Oulu and Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
    2. Division of Surgery, Department of Surgery and Intensive Care, Institute of Clinical Medicine, University of Oulu and Clinical Research Centre, Oulu University Hospital, Oulu, Finland
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  • Peppi Koivunen

    Corresponding author
    1. Department of Medical Biochemistry and Molecular Biology, Biocenter Oulu and Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
    • Correspondence: Peppi Koivunen, M.D., Ph.D., Department of Medical Biochemistry and Molecular Biology, Aapistie 7, P.O. Box 5000, University of Oulu, Oulu FIN-90014, Finland. Telephone: +358-8-5375822; Fax: +358-8-5375811; e-mail peppi.koivunen@oulu.fi

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  • Author contributions: S.P.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; M.P.: conception and design, collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; P.L. and P.K.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript, and contributed equally; S.L. and J.P.: provision of material or patients and final approval of manuscript; R.S.: collection and/or assembly of data and final approval of manuscript.

ABSTRACT

Human mesenchymal stem cells (hMSCs) are multipotent cells that have aroused great expectations in regenerative medicine. They are assumed to originate from hypoxic stem cell niches, especially in the bone marrow. This suggests that O2 is of importance in their regulation. In order to characterize regulation of the oxygen sensing pathway in these cells, we studied hMSCs isolated from three origins, adult and pediatric bone marrow and umbilical cord blood (UCB). Surprisingly, pediatric bone marrow and UCB MSCs showed normoxic stabilization of hypoxia-inducible factor-1α (HIF-1α) that is normally degraded completely by HIF prolyl 4-hydroxylases in the presence of oxygen. This was due to a high expression level of HIF-1α mRNA rather than inappropriate post-translational degradation of HIF-1α protein. HIF-1α mRNA was also induced in normoxic adult bone marrow MSCs, but 40% less than in the pediatric cells, and this was apparently not enough to stabilize the protein. The high normoxic HIF expression in all the hMSCs studied was accompanied by increased expression of a large number of glycolytic HIF target genes and increased glycolysis. Osteogenic differentiation of bone marrow-derived hMSCs reduced HIF-1α mRNA and protein expression and the expression of glycolytic mRNAs, resulting in decreased glycolysis and induction of oxidative metabolism. Induced mitochondrial biogenesis, changes in mitochondrial morphology and size indicative of increased oxidative phosphorylation, and induction of extracellular matrix synthesis were observed following osteogenic differentiation. Altogether, these data suggest that HIF-1α is a general regulator controlling the metabolic fate and multipotency of the hMSCs. Stem Cells 2013;31:1902-1909

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