Repair of Critical-Sized Mandible Defects in Aged Rat Using Hypoxia Preconditioned BMSCs with Up-regulation of Hif-1α.

The repair of bone defects in the geriatric population remains a challenge for modern medicine. Transplantation of bone marrow mesenchymal stem cells (BMSCs) combined with or without biomaterials has been a promising approach to bone restoration and regeneration. Typically, the transplanted BMSCs are cultured under normoxic conditions (21% O2 and 10% serum medium) in vitro. However, the micro-environment of bone defect area is much more severe, in which lower physiological oxygen tension (<1%) and tissue ischemia were present. Therefore, how to improve the survival rate and osteogenesis of transplanted BMSCs at the low oxygenic and ischemic region in vivo is critical. Hypoxia inducible factor-1α (HIF-1α) plays an important role in the tolerance, angiogenesis and osteogenesis of BMSCs during bone regeneration after transplantation. Previous studies have demonstrated that Dimethyloxaloylglycine (DMOG) improves the angiogenic activity of BMSCs. Typically, angiogenesis and osteogenesis are coupled with each other. Therefore, we detected that hypoxia preconditioned BMSCs with the combined treatment of 1% O2 and 0.5mM DMOG showing up-regulation of Hif-1α could enhance the survival rate of BMSCs under severe condition (serum-free medium and 1% O2) in vitro and enhances the angiogenesis and osteogenesis potential of BMSCs under 1% O2 microenvironment in vitro. The hypoxia preconditioned BMSCs were transplanted into critical-sized mandible defects in aged SD rats to test the effectiveness of hypoxic preconditioning approach. We found that hypoxia preconditioned BMSCs improved the repair of critical-sized mandible defects in vivo. These data showed that hypoxia preconditioned BMSCs with the up-regulation of Hif-1α have the potential of enhancing the bone healing process in geriatric individuals.