Inhibitory effects of hypoxia on metabolic switch and osteogenic differentiation of human mesenchymal stem cells

Shu Han Hsu, Chien Tsun Chen, Yau Huei Wei*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

101 Scopus citations

Abstract

We previously demonstrated that metabolic switch and mitochondrial activation are required for osteogenic differentiation of human mesenchymal stem cells (hMSCs). However, stem cells in niches or transplanted into injured tissues constantly encounter hypoxic stress that hinders aerobic metabolism. Therefore, we investigated the effects of oxygen tension (1%vs. 21%) on metabolism and osteogenic differentiation of hMSCs. We found that hypoxia impaired osteogenic differentiation as indicated by attenuation of alkaline phosphatase activity and expression of osteogenic markers core binding factor a-1 and osteopontin. In addition, differentiationinduced mitochondrial activation was compromised as shown by the decrease in the expression of respiratory enzymes and oxygen consumption rate. On the contrary, anaerobic metabolism was augmented as revealed by the upregulation of glycolytic enzymes and increase of lactate production, rendering the cells to rely more on anaerobic glycolysis for energy supply. Moreover, administration of 2-deoxyglucose (a glycolytic inhibitor) but not antimycin A (a respiratory inhibitor) significantly decreased intracellular ATP levels of hMSCs differentiating under hypoxia. Treatment with cobalt chloride, a hypoxia-inducible factor-1α (HIF-1α) stabilizer, recapitulated the inhibitory effects of hypoxia, suggesting that HIF-1α is involved in the compromise of hMSCs differentiation. These results suggest that hypoxia inhibits metabolic switch and mitochondrial function and therefore suppresses osteogenic differentiation of hMSCs. Stem Cells.

Original languageEnglish
Pages (from-to)2779-2788
Number of pages10
JournalStem Cells
Volume31
Issue number12
DOIs
StatePublished - 12 2013
Externally publishedYes

Keywords

  • Hypoxia
  • Mesenchymal stem cells
  • Metabolic switch
  • Mitochondria
  • Osteogenic differentiation

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