title: Blood vessel formation in the tissue-engineered bone with the constitutively active form of HIF-1α mediated BMSCs.
abstract: The successful clinical outcome of the implanted tissue-engineered bone is dependent on the establishment of a functional vascular network. A gene-enhanced tissue engineering represents a promising approach for vascularization. Our previous study indicated that hypoxia-inducible factor-1α (HIF-1α) can up-regulate the expression of vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (SDF-1) in bone mesenchymal stem cells (BMSCs). The angiogenesis is a co-ordinated process that requires the participation of multiple angiogenic factors. To further explore the angiogenic effect of HIF-1α mediated stem cells, in this study, we systematically evaluated the function of HIF-1α in enhancing BMSCs angiogenesis in vitro and in vivo. A constitutively active form of HIF-1α (CA5) was inserted into a lentivirus vector and transduced into BMSCs, and its effect on vascularization and vascular remodeling was further evaluated in a rat critical-sized calvarial defects model with a gelatin sponge (GS) scaffold. The expression of the key angiogenic factors including VEGF, SDF-1, basic fibroblast growth factor (bFGF), placental growth factor (PLGF), angiopoietin 1 (ANGPT1), and stem cell factor (SCF) at both mRNAs and proteins levels in BMSCs were significantly enhanced by HIF-1α overexpression compared to the in vitro control group. In addition, HIF-1α-over expressing BMSCs showed dramatically improved blood vessel formation in the tissue-engineered bone as analyzed by photography of specimen, micro-CT, and histology. These data confirm the important role of HIF-1α in angiogenesis in tissue-engineered bone. Improved understanding of the mechanisms of angiogenesis may offer exciting therapeutic opportunities for vascularization, vascular remodeling, and bone defect repair using tissue engineering strategies in the future.
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Stomatology, Tongji University, Shanghai 200072, China.
authors.forename: Duohong
authors.initials: D
authors.lastname: Zou
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jiacai
authors.initials: J
authors.lastname: He
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: Dongxia
authors.initials: D
authors.lastname: Ye
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Yuanyin
authors.initials: Y
authors.lastname: Wang
authors.forename: Quanli
authors.initials: Q
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Wang
authors.forename: Jingzhou
authors.initials: J
authors.lastname: Hu
authors.forename: Chao
authors.initials: C
authors.lastname: Zhu
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: zhou
authors.forename: Honghai
authors.initials: H
authors.lastname: Fu
authors.forename: Yuanliang
authors.initials: Y
authors.lastname: Huang
authors.forename: Xinquan
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D001842:Bone and Bones / Q000098:blood supply* / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D023822:Tissue Engineering / Q000379:methods*; D014161:Transduction, Genetic; D055114:X-Ray Microtomography
chemical_list: D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit