Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200030 People's Republic of China.
Biomater Sci. 2018 Dec 18;7(1):362-372. doi: 10.1039/c8bm00846a.
Biomaterials are widely used for bone regeneration and fracture repair. The migration of bone marrow mesenchymal stem cells (BMSCs) into bone defect sites or material implantation sites, and their differentiation into osteoblasts, is central to the fracture healing process, and the directional migration of BMSCs depends on cytokines or chemokines at the defect site. BMP-2 can stimulate the migration of a variety of cells, but it remains unclear whether BMSC migration can be induced. To provide evidence for BMP-2-induced BMSC migration, we tested the cytoskeletal changes and migration ability of BMSCs after treatment with recombinant human BMP-2 (rhBMP-2). We also explored the recruitment of BMSCs from the circulatory system using a collagen sponge incorporating rhBMP-2 that was implanted in vivo. Furthermore, to understand the mechanism underlying this migration, we investigated the effect of rhBMP-2 on migration-related signal pathways. Here, we found that, rhBMP-2 treatment significantly increased the migration of BMSCs in vitro via activation of the CDC42/PAK1/LIMK1 pathway, and that this migration could be blocked by silencing CDC42. In vivo, collagen sponge material loaded with rhBMP-2 could recruit BMSCs injected into the circulatory system. Moreover, inhibition using the small interfering RNA for CDC42 led to a significant decrease in the number of BMSCs within the material. In conclusion, our data prove that rhBMP-2 can accelerate BMSC migration via the CDC42/PAK1/LIMK1 pathway both in vivo and in vitro, and therefore provides a foundation for further understanding and application of rhBMP-2-incorporated materials by enhancing BMSC recruitment.
生物材料广泛用于骨再生和骨折修复。骨髓间充质干细胞（BMSCs）向骨缺损部位或材料植入部位的迁移及其向成骨细胞的分化是骨折愈合过程的核心，BMSCs 的定向迁移取决于缺损部位的细胞因子或趋化因子。BMP-2 可以刺激多种细胞的迁移，但尚不清楚 BMSC 的迁移是否可以被诱导。为了为 BMP-2 诱导的 BMSC 迁移提供证据，我们测试了重组人 BMP-2（rhBMP-2）处理后 BMSCs 的细胞骨架变化和迁移能力。我们还探索了通过将含有 rhBMP-2 的胶原海绵植入体内来招募来自循环系统的 BMSCs。此外，为了了解这种迁移的机制，我们研究了 rhBMP-2 对迁移相关信号通路的影响。在这里，我们发现 rhBMP-2 处理通过激活 CDC42/PAK1/LIMK1 通路显著增加了 BMSCs 的体外迁移，并且这种迁移可以通过沉默 CDC42 来阻断。在体内，负载 rhBMP-2 的胶原海绵材料可以招募注入循环系统的 BMSCs。此外，使用针对 CDC42 的小干扰 RNA 的抑制作用导致材料内的 BMSCs 数量显著减少。总之，我们的数据证明 rhBMP-2 可以通过体内和体外的 CDC42/PAK1/LIMK1 通路加速 BMSC 迁移，从而为进一步理解和应用 rhBMP-2 结合材料通过增强 BMSC 募集提供了基础。
