Blood vessel formation in the tissue-engineered bone with the constitutively active form of HIF-1¦Á mediated BMSCs

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• 作者：Duohong Zou^a ; ^b ; ^c ; Zhiyuan Zhang^b ; Jiacai He^c ; Kai Zhang^d ; Dongxia Ye^b ; Wei Han^e ; Jian Zhou^c ; Yuanyin Wang^c ; Quanli Li^c ; Xin Liu^c ; Xin Zhang^a ; Shaoyi Wang^b ; Jingzhou Hu^b ; Chao Zhu^b ; Wenjie Zhang^b ; Yong zhou^b ; Honghai Fu^b ; Yuanliang Huang^f ; ^{Yuanlianghuangyx@126.com} ; Xinquan Jiang^b ; ^{xinquanj@yahoo.cn}
• 关键词：HIF-1a ; Angiogenesis ; The tissue-engineered bone ; Gene therapy
• 刊名：Biomaterials
• 出版年：2012
• 出版时间：March 2012
• 年：2012
• 卷：33
• 期：7
• 页码：2097-2108
• 全文大小：2503 K

文摘

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-1¦Á (HIF-1¦Á) 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-1¦Á mediated stem cells, in this study, we systematically evaluated the function of HIF-1¦Á in enhancing BMSCs angiogenesis in?vitro and in?vivo. A constitutively active form of HIF-1¦Á (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-1¦Á overexpression compared to the in?vitro control group. In addition, HIF-1¦Á-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-1¦Á 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.