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Repair of Critical‐Sized Rat Calvarial Defects Using Genetically Engineered Bone Marrow‐Derived Mesenchymal Stem Cells Overexpressing Hypoxia‐Inducible Factor‐1α

The processes of angiogenesis and bone formation are coupled both temporally and spatially during bone repair. Bone marrow‐derived mesenchymal stem cells (BMSCs) have been effectively used to heal critical‐size bone defects. Enhancing their ability to undergo angiogenic and osteogenic differentiation will enhance their potential use in bone regeneration. Hypoxia‐inducible factor‐1α (HIF‐1α) has recently been identified as a major regulator of angiogenic‐osteogenic coupling. In this study, we tested the hypothesis that HIF‐1α gene therapy could be used to promote the repair of critical‐sized bone defects. Using lentivirus‐mediated delivery of wild‐type (HIF) or constitutively active HIF‐1α (cHIF), we found that in cultured BMSCs in vitro, HIF and cHIF significantly enhanced osteogenic and angiogenic mRNA and protein expression when compared with the LacZ group. We found that HIF‐1α‐overexpressing BMSCs dramatically improved the repair of critical‐sized calvarial defects, including increased bone volume, bone mineral density, blood vessel number, and blood vessel area in vivo. These data confirm the essential role of HIF‐1α modified BMSCs in angiogenesis and osteogenesis in vitro and in vivo. STEM CELLS 2011;29:1380–1390