Bone defect regeneration is a complex process that involves the coordination of a variety of different type of cells. As bone tissues are innervated and rich in nerve fibers, the neuropeptides released from various never fibers could regulate bone development, metabolism, and remodeling. Among all the neuropeptides, vasoactive intestinal peptide (VIP) could modulate the functions of both osteoblasts and osteoclasts, and may play a vital role in bone marrow mesenchymal stem cell (BMSC) osteogenesis during bone repair. In this study, we investigated the role of VIP in bone formation and the mechanisms of VIP in mediating BMSC osteogenic differentiation, and its possibility in clinical application of bone defect reconstruction. Our in vitro study results indicated that VIP promoted BMSC osteogenic differentiation by activating Wnt/β-catenin signaling pathway in BMSCs. VIP could also stimulate tube formation of EA.hy926 endothelial cell and increase vascular endothelial growth factor (VEGF) expression in BMSCs. Furthermore, in the rat skull defect model, VIP-conjugated functionalized hydrogel significantly enhanced cranial bone defect repair compared with the control group, with increased bone formation and angiogenesis. Taken together, as a member of neuropeptides, VIP could promote the BMSCs osteogenesis and angiogenesis differentiation in vitro and stimulate bone repair in vivo by activating Wnt/β-catenin signaling pathway. The knowledge obtained from this study emphasized the close association between innervation and bone repair process, and VIP may be a potential therapeutic agent for augmenting bone repair.

中文翻译：

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血管活性肠肽通过激活Wnt /β-Catenin信号通路刺激骨髓间充质干细胞成骨分化并促进大鼠颅骨缺损修复。

骨缺陷再生是一个复杂的过程，涉及多种不同类型细胞的协调。由于骨骼组织被神经支配并且富含神经纤维，从各种永不纤维释放的神经肽可以调节骨骼的发育，新陈代谢和重塑。在所有的神经肽中，血管活性肠肽（VIP）可以调节成骨细胞和破骨细胞的功能，并且可能在骨骼修复过程中在骨髓间充质干细胞（BMSC）的成骨过程中发挥重要作用。在这项研究中，我们调查了VIP在骨形成中的作用以及VIP在介导BMSC成骨分化中的机制，及其在骨缺损重建的临床应用中的可能性。我们的体外研究结果表明，VIP通过激活BMSC中的Wnt /β-catenin信号传导途径促进BMSC成骨分化。VIP还可以刺激EA.hy926内皮细胞的管形成并增加BMSCs中血管内皮生长因子（VEGF）的表达。此外，在大鼠颅骨缺损模型中，与对照组相比，结合VIP的功能化水凝胶显着增强了颅骨缺损的修复，并增加了骨形成和血管生成。总之，作为神经肽的成员，VIP可以通过激活Wnt /β-catenin信号通路促进体外BMSCs的成骨和血管生成分化，并在体内刺激骨修复。从这项研究中获得的知识强调了神经支配与骨骼修复过程之间的紧密联系，