Repair of Critical-Sized Rat Calvarial Defects Using Genetically Engineered Bone Marrow-Derived Mesenchymal Stem Cells Overexpressing Hypoxia-Inducible Factor-la
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 criticalsize bone defects. Enhancing their ability to undergo angiogenic and osteo-genic differentiation will enhance their potential use in bone regeneration. Hypoxia-inducible factor-la (HIF-la) has recently been identified as a major regulator of angiogenicosteogenic coupling. In this study, we tested the hypothesis that HIF-la gene therapy could be used to promote the repair of critical-sized bone defects. Using lentivirusmediated delivery of wild-type (HIF) or constitutively active HIF-la (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-la-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-la modified BMSCs in angiogenesis and osteogenesis in vitro and in vivo.
Hypoxia-inducible factor-la Bone marrow-derived mesenchymal stem cells Osteogenesis Gene therapy Bone regeneration
Duohong Zou CHAO ZHU JIAN ZHOU JIACAI HE Yuanyin Wang Feng Xu Yuanliang Huang Xinquan Jiang Zhiyuan Zhang Dongxia Ye Aifa Tang Lianfu Deng Wei Han JUN ZHAO SHUHONG WANG WENJIE ZHANG
School of Stomatology, Tongji University, Shanghai, China Department of Oral and Maxillofacial Surge Department of Oral and Maxillofacial Surgery, Ninth Peoples Hospital Affiliated with Shanghai Jiao Department of Oral and Maxillofacial Surgery, School of Stomatology, Stomatological Hospital, Anhui Department of Stomatology, Shanghai East Hospital Affiliated with Tongji University, Shanghai, China The Second Peoples Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University, China Department of Orthopaedics, Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hos Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Nanjing, China School of Stomatology, Tongji University, Shanghai, China