提高间充质干细胞(MSCs)的迁移能力，增加迁移到损伤部位移植细胞的数量对提高疗效至关重要，然而调控MSCs迁移的分子机制并未完全阐明。我们的研究结果证明Wnt3a通过激活Wnt/β-catenin信号促进MSCs迁移，抑制该信号则抑制MSCs迁移。然而，出乎我们意料的是，作为Wnt/β-catenin信号通路的特异抑制剂，一定浓度范围的DKK1不仅没有抑制、反而促进了MSCs的迁移。进一步研究发现，低浓度DKK1可以促进β-catenin入核，启动下游基因表达，上调AKT和JNK的磷酸化水平，提示DKK1不仅可以从受体水平，也可以通过下游调控β-catenin信号。本项目将在前期工作基础上，探讨不同浓度的DKK1是否通过以及如何通过Wnt/β-catenin、CKAP4-PI3K/AKT或JNK通路调控MSCs迁移，最终阐明DKK1对MSCs迁移的促进或抑制作用及分子机制。

Increasing the migration ability of mesenchymal stem cells (MSCs) and increasing the number of transplanted cells to the injured site are essential for improving the efficacy. However, the cellular and molecular mechanisms that influence and control the migration of MSCs are not fully elucidated. Our results demonstrate that Wnt3a promotes migration of MSCs by activating Wnt/β-catenin signaling, and inhibition of this signaling pathway inhibits migration of MSCs; PI3K/AKT and MAPKs are involved in the regulation of Wnt/β-catenin signaling and MSCs migration. However, to our surprise, as a specific inhibitor of the Wnt/β-catenin signaling pathway, a certain concentration range of DKK1 did not inhibited, but promoted the migration of MSCs. Further studies found that low concentration of DKK1 can promote β-catenin nuclear translocation, initiate downstream gene expression, and up-regulate the phosphorylation levels of AKT and JNK, suggesting that DKK1 can regulate Wnt/β-catenin signaling not only from the receptor level, but also through downstream levels. Based on our previous work, by using various mutants, this project will detect the binding of DKK1 to its receptors LRP5/6, CKAP4, etc., the expression and distribution of these receptors on the cell membrane, endocytosis, and further, LRP5/6 phosphorylation, β-catenin expression and nuclear import, downstream target gene expression, CKAP4-PI3/AKT or JNK signaling, and finally clarify how DKK1 regulates Wnt/β-catenin signaling, CKAP4-PI3/AKT or JNK signaling and promotes or inhibits the migration of MSCs. Results of this project have important significance and broad application value for the effective utilization of MSCs in the treatment of diseases, and make possible to improve the curative effect by improving the migration ability of MSCs and increasing the number of transplanted cells that migrate to the injured site.