title: Repair of critical-sized rat calvarial defects using genetically engineered bone marrow-derived mesenchymal stem cells overexpressing hypoxia-inducible factor-1α.
abstract: 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.
authors.affiliation: School of Stomatology, Tongji University, Shanghai, China.
authors.forename: Duohong
authors.initials: D
authors.lastname: Zou
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Dongxia
authors.initials: D
authors.lastname: Ye
authors.forename: Aifa
authors.initials: A
authors.lastname: Tang
authors.forename: Lianfu
authors.initials: L
authors.lastname: Deng
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Shuhong
authors.initials: S
authors.lastname: Wang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Zhu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Jiacai
authors.initials: J
authors.lastname: He
authors.forename: Yuanyin
authors.initials: Y
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Yuanliang
authors.initials: Y
authors.lastname: Huang
authors.forename: Xinquan
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001861:Bone Regeneration / Q000502:physiology; D001930:Brain Injuries / Q000628:therapy*; D048708:Cell Growth Processes / Q000502:physiology; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D018919:Neovascularization, Physiologic; D010012:Osteogenesis; D051381:Rats; D011916:Rats, Inbred F344; D023822:Tissue Engineering / Q000379:methods; D014161:Transduction, Genetic
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit