The effect of oxygen tension on the long-term osteogenic differentiation and MMP/TIMP expression of human mesenchymal stem cells

The use of mesenchymal stem cells in tissue engineering to augment the repair of a variety of tissues including bone is a rapidly growing and exciting field. Although oxygen tension is a powerful stimulus for cells both in vitro and in vivo, the oxygen environment in which such cells would undergo differentiation is commonly overlooked. We examined the effect of long-term (21-days) low oxygen tension (1, 2 and 5%) on the osteogenic differentiation and matrix metalloproteinase (MMP)/tissue inhibitor of MMP (TIMP) expression of human mesenchymal stem cells (MSCs). Our data suggest that MSCs undergo osteoblastic differentiation most rapidly under 21% oxygen while oxygen tensions below 5% have an inhibitory effect. Interestingly, there was not a statistically significant difference in osteogenic markers between 5 and 21% oxygen. In addition, our data suggest that oxygen tension affects the expression of individual MMP and TIMPs differently. Low oxygen tension has an inhibitory effect on MMP-13 and TIMP-1 expression, which are involved in extracellular matrix remodeling and potentially vascular invasion. In contrast, MMP-2, a metalloproteinase involved in cell migration was not affected by oxygen tension. This data suggests that 21% oxygen may be beneficial for rapid osteogenic differentiation as would be required for the production of individual patient ex vivo constructs. In addition, this has important in vivo implications relating to the importance of early vascularization of sites of orthopedic injury. By augmenting the neovascularization process, it may be possible to facilitate more rapid differentiation of progenitors and thus the repair process.