仿颅颌面骨再生相关基因调控的实验研究
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摘要
因肿瘤、外伤、放射性骨坏死、骨髓炎、牙周炎或先天疾病等导致的颅颌面骨缺损直接影响口腔颌面部修复，颌骨缺损修复时新骨形成的质量、速度和长期稳定性与种植义齿修复息息相关。多年来，临床医师和研究者们尝试利用自体或异体骨移植、人工骨移植、细胞或／和生长因子介导的组织工程技术、屏障膜及骨牵张等临床技术，在修复颌骨或牙槽骨缺损方面取得了一定的成效。近年来，骨缺损修复的理念更倾向于——结合细胞及活性分子的骨支架材料植入机体后能引导及促进机体自身组织的再生修复，因此，设计模仿骨再生生理机制的骨缺损修复方案至关重要。根据颅颌面膜内成骨的特点，我们选择了在骨缺损修复初期能促进血管再生的碱性成纤维细胞生长因子(bFGF)，和在骨缺损修复中后期能调控其下游信号通路促进新骨再生的信号分子SonicHedgehog(Shh)，目的是通过对这两种关键因子的调控，模拟机体骨缺损修复过程，探寻理想的促颌骨缺损修复方案。方法是利用腺相关病毒高效稳定的感染效率及四环素调控系统对外源基因的开关作用，构建重组病毒rAAV2-Shh及rAAV2-tet-off-bFGF；将两种病毒共同感染原代培养的大鼠骨髓间充质干细胞；继而将这种转基因细胞与β-磷酸三钙复合形成可调控的基因增强型组织工程骨；并通过在四环素衍生物Dox的调控下，体外检测双因子时序表达和三维培养对细胞生物学性状、胞内成骨因子水平的影响；最后将这种可调控的基因增强型组织工程骨移植到大鼠颅骨缺损区，通过Dox调控使骨缺损修复初期bFGF过表达，中后期以Shh表达为主，组织学观察双因子时序调控对缺损区骨组织再生修复的影响，形态学检测新骨形成面积及新生血管密度。结果显示，bFGF协同Shh的分阶段治疗能促进大鼠颅骨缺损区血管再生及新骨形成，新生血管的密度与新骨面积有显著相关性。说明这种双因子时序调控的基因增强型组织工程技术，可以模拟机体自身骨修复不同阶段的生理过程，能更好的促进大鼠颅骨缺损再生修复。
Craniofacial bone defects resulting from tumor, trauma, osteoradionecrosis, osteomyelitis, periodontitis or congenital deformities present a challenge to prosthetic reconstruction. The quality, speed and biomechanical stability of new bone formation in repair of craniofacial bone defects are closely related to dental implantation. Various methods such as allografting. xenographic bone graft, artificial bone graft, cells- or/and growth factors-based tissue engineering, guided bone regeneration and distraction osteogenesis, are applied for craniofacial bone and alveolar bone reconstruction, and achieve satisfactory effects. Recently, the concepts of bone reconstruction involve the combination of a scaffold with cells and/or biomolecules that promotes the repair and/or regeneration of tissues. Therefore, it is very important to mimic the natural environment in which bone cells grow. Bone regeneration is complexly regulated processes that involve a plethora of different growth and transcription factors which coordinate the interaction of cells and matrix in response to external or internal stimuli. Basic fibroblast growth factor (bFGF) induces angiogenesis, and stimulates mitogenesis of mesenchymal cells and osteoblasts in the early phase of bone defects repair. Sonic hedgehog (Shh) is involved in osteoblast differentiation by a mechanism involving BMPs, and may play an important role in bone formation, especially at later stages of skeletogenesis and fracture repair. In this study, bFGF and Shh were used to mimic natural bone repair processes through artificial regulation, and an optimal osteo-inductive approach for craniofacial bone regeneration was discussed.
In this study, recombinant viruses rAAV2-Shh and rAAV2-tet-off-bFGF that were controlled by tetracycline regulation system were reconstructed. Rat bone marrow-derived mesenchymal stem cells (BMSCs) were routinely isolated from bone marrow, and co-infected with above two recombinant viruses in vitro. The expression of bFGF was controlled through doxycycline (Dox, a tetracycline analogue) administration, and thus sequential expression of bFGF and Shh was induced. Thereafter, the co-infected BMSCs regulated by sequential delivery factors were seeded on the biodegradable scaffold (β-tricalcium phosphate), and this gene-enhanced tissue engineering bone was cultured in a three-dimensional (3D) in vitro culture system. Cell morphology, viability, and differentiation were studied at different sequential expression periods. Osteogenic potential of BMSCs was evaluated according to the concentration of alkaline Phosphatase and the mRNA expression of osteogenic marker genes. Finally, this regulated gene-enhanced tissue engineering bone was introduced into rat critical sized calvarial defects (8 mm). The sequential expression of angiogenic and osteogenic genes, which mimics the intramembranous bone repair, was regulated through Dox administration. Histological slides, obtained from defect sites at the 2nd, 4th and 8th week, were digitized, and the total two-dimensional amount of new bone area and vascular density in defects were quantitated. It was shown that the increased bone formation accompanied with angiogenesis was induced by sequential key factors delivery in vivo, and a positive correlation between new bone area and blood vessel density was found. This study suggests that stage treatment for craniofacial bone regeneration plays a significant role in enhancing bone regeneration through sequential delivery of osteogenic and angiogenic genes.
Craniofacial bone defects resulting from tumor, trauma, osteoradionecrosis, osteomyelitis, periodontitis or congenital deformities present a challenge to prosthetic reconstruction. The quality, speed and biomechanical stability of new bone formation in repair of craniofacial bone defects are closely related to dental implantation. Various methods such as allografting. xenographic bone graft, artificial bone graft, cells- or/and growth factors-based tissue engineering, guided bone regeneration and distraction osteogenesis, are applied for craniofacial bone and alveolar bone reconstruction, and achieve satisfactory effects. Recently, the concepts of bone reconstruction involve the combination of a scaffold with cells and/or biomolecules that promotes the repair and/or regeneration of tissues. Therefore, it is very important to mimic the natural environment in which bone cells grow. Bone regeneration is complexly regulated processes that involve a plethora of different growth and transcription factors which coordinate the interaction of cells and matrix in response to external or internal stimuli. Basic fibroblast growth factor (bFGF) induces angiogenesis, and stimulates mitogenesis of mesenchymal cells and osteoblasts in the early phase of bone defects repair. Sonic hedgehog (Shh) is involved in osteoblast differentiation by a mechanism involving BMPs, and may play an important role in bone formation, especially at later stages of skeletogenesis and fracture repair. In this study, bFGF and Shh were used to mimic natural bone repair processes through artificial regulation, and an optimal osteo-inductive approach for craniofacial bone regeneration was discussed.
In this study, recombinant viruses rAAV2-Shh and rAAV2-tet-off-bFGF that were controlled by tetracycline regulation system were reconstructed. Rat bone marrow-derived mesenchymal stem cells (BMSCs) were routinely isolated from bone marrow, and co-infected with above two recombinant viruses in vitro. The expression of bFGF was controlled through doxycycline (Dox, a tetracycline analogue) administration, and thus sequential expression of bFGF and Shh was induced. Thereafter, the co-infected BMSCs regulated by sequential delivery factors were seeded on the biodegradable scaffold (β-tricalcium phosphate), and this gene-enhanced tissue engineering bone was cultured in a three-dimensional (3D) in vitro culture system. Cell morphology, viability, and differentiation were studied at different sequential expression periods. Osteogenic potential of BMSCs was evaluated according to the concentration of alkaline Phosphatase and the mRNA expression of osteogenic marker genes. Finally, this regulated gene-enhanced tissue engineering bone was introduced into rat critical sized calvarial defects (8 mm). The sequential expression of angiogenic and osteogenic genes, which mimics the intramembranous bone repair, was regulated through Dox administration. Histological slides, obtained from defect sites at the 2nd, 4th and 8th week, were digitized, and the total two-dimensional amount of new bone area and vascular density in defects were quantitated. It was shown that the increased bone formation accompanied with angiogenesis was induced by sequential key factors delivery in vivo, and a positive correlation between new bone area and blood vessel density was found. This study suggests that stage treatment for craniofacial bone regeneration plays a significant role in enhancing bone regeneration through sequential delivery of osteogenic and angiogenic genes.
引文
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