title: HIF-1α is upregulated in human mesenchymal stem cells.
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.
authors.affiliation: Department of Anatomy and Cell Biology, Institute of Biomedicine, Biocenter Oulu and Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Palomäki
authors.forename: Mika
authors.initials: M
authors.lastname: Pietilä
authors.forename: Saara
authors.initials: S
authors.lastname: Laitinen
authors.forename: Juha
authors.initials: J
authors.lastname: Pesälä
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.forename: Petri
authors.initials: P
authors.lastname: Lehenkari
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
mesh_terms: D000328:Adult; D000954:Antigens, Surface / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D048430:Cell Shape; D002648:Child; D006019:Glycolysis / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D008954:Models, Biological; D010012:Osteogenesis / Q000235:genetics; D016133:Polymerase Chain Reaction; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055153:Stem Cell Niche / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D000954:Antigens, Surface; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates; D012333:RNA, Messenger
keywords: Glycolysis; Hypoxia; Hypoxia-inducible factor; Mesenchymal stem cells; Metabolism; Osteogenic differentiation