SIRT7修饰的BMSCs促进血管生成的作用机制研究及复合生物支架在修复大段骨缺损中的应用

The repair of large bone defect need new treatments, of which the key were bone formation and rapid angiogenesis. Our previous study found that Knockdown of SIRT7 enhanced osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) via activation of the Wnt/β-catenin signaling pathway. We also found that knockdown of SIRT7 promoted the paracrine effect of BMSCs to produce vascular endothelial growth factor-A (VEGF-A) and angiopoietin-1 (Ang1) and enhanced endothelial differentiation of BMSCs. Therefore, we supposed that SIRT7 promoted the paracrine production of VEGF-A and Ang1 via HIF1 and/or FoxO-1 signaling pathway and enhanced endothelial differentiation of BMSCs to accelerate angiogenesis of bone healing. In this study, we will explore the role and mechanism underlying of SIRT7 in angiogenesis of BMSCs by using in vitro cell culture and tissue engineering, and evaluate the effect of SIRT7-modified BMSCs combined with nano-hydroxyapatite/chitosan scaffold in rat large femoral defect model. The present study will provide a new theoretical and practical basis for the repair of large bone defect by bone vascularized tissue engineering.

大段骨缺损的修复疗效不佳而亟需新的治疗手段，其中缺损区域的骨形成和快速血管化是成功修复的关键。我们前期的研究发现，敲降SIRT7通过激活Wnt/β-catenin信号增强骨髓间充质干细胞（BMSCs）的成骨分化；同时，我们也发现敲降SIRT7增强BMSCs旁分泌产生血管内皮生长因子-A（VEGF-A）和血管生成素-1（Ang1）以及BMSCs向内皮分化。因此，我们推测SIRT7可能通过HIF1和/或FoxO-1信号促进旁分泌产生VEGF-A和Ang1，同时促进BMSCs向内皮细胞分化进而促进血管生成。为此，本项目利用体外细胞模型以及SIRT7修饰的组织工程化BMSCs探索SIRT7修饰的BMSCs促进血管生成的作用和分子机制，并进一步评价SIRT7修饰的BMSCs复合纳米羟基磷灰石/壳聚糖支架高效地修复大段骨缺损的可能。通过本研究以期为骨血管化组织工程修复大段骨缺损提供新的理论和实践依据。

大段骨缺损的修复疗效不佳而亟需新的治疗手段，其中缺损区域的骨形成和快速血管化是 成功修复的关键。本研究通过体内外实验验证了敲降内源性SIRT7可以促进BMSCs分泌Ang1和VEGF-A等成血管相关因子。同时通过条件培养基方式验证了在BMSCs中敲降SIRT7可以通过旁分泌作用增强HUVECs的成血管能力。我们创新性地采用SIRT7修饰的BMSCs和HUVECs构成的三层夹心细胞膜片治疗小鼠股骨骨缺损，同样取得了良好疗效。上述结果说明敲降SIRT7可以促进BMSCs分泌成血管相关因子并促进骨缺损的修复，为临床上大段骨缺损的治疗提供新的靶点。