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TISSUE-SPECIFIC STEM CELLS

Coordinated Changes of Mitochondrial Biogenesis and Antioxidant Enzymes During Osteogenic Differentiation of Human Mesenchymal Stem Cells

Institutes of ^aBiochemistry and Molecular Biology,
^bBiopharmaceutical Sciences, and
^cClinical Medicine, National Yang-Ming University, Taipei, Taiwan;
^dDepartment of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan

Key Words. Mesenchymal stem cells • Osteogenic differentiation • Mitochondria • Metabolic switch • Antioxidant enzymes

Correspondence: Yau-Huei Wei, Ph.D., 155 Li-Nong Street, Section 2, Peitou, Taipei 112, Taiwan. Telephone: 886-2-28267118; Fax: 886-2-28264843; e-mail: joeman{at}ym.edu.tw; or Oscar K. Lee, M.D., Ph.D., 201 Shi-Pai Road, Section 2, Taipei 112, Taiwan. Telephone: 886-2-28757557; Fax: 886-2-28757557; e-mail: kslee{at}vghtpe.gov.tw

Received July 2, 2007; accepted for publication January 4, 2008.
First published online in STEM CELLS EXPRESS   January 24, 2008.



The multidifferentiation ability of mesenchymal stem cells holds great promise for cell therapy. Numerous studies have focused on the establishment of differentiation protocols, whereas little attention has been paid to the metabolic changes during the differentiation process. Mitochondria, the powerhouse of mammalian cells, vary in their number and function in different cell types with different energy demands, but how these variations are associated with cell differentiation remains elusive. In this study, we investigated the changes of mitochondrial biogenesis and bioenergetic function using human mesenchymal stem cells (hMSCs) because of their well-defined differentiation potentials. Upon osteogenic induction, the copy number of mitochondrial DNA, protein subunits of the respiratory enzymes, oxygen consumption rate, and intracellular ATP content were increased, indicating the upregulation of aerobic mitochondrial metabolism. On the other hand, undifferentiated hMSCs showed higher levels of glycolytic enzymes and lactate production rate, suggesting that hMSCs rely more on glycolysis for energy supply in comparison with hMSC-differentiated osteoblasts. In addition, we observed a dramatic decrease of intracellular reactive oxygen species (ROS) as a consequence of upregulation of two antioxidant enzymes, manganese-dependent superoxide dismutase and catalase. Finally, we found that exogenous H₂O₂ and mitochondrial inhibitors could retard the osteogenic differentiation. These findings suggested an energy production transition from glycolysis to oxidative phosphorylation in hMSCs upon osteogenic induction. Meanwhile, antioxidant enzymes were concurrently upregulated to prevent the accumulation of intracellular ROS. Together, our findings suggest that coordinated regulation of mitochondrial biogenesis and antioxidant enzymes occurs synergistically during osteogenic differentiation of hMSCs.

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