The activation of gastric inhibitory peptide/gastric inhibitory peptide receptor axis via sonic hedgehog signaling promotes the bridging of gapped nerves in sciatic nerve injury
The activation of gastric inhibitory peptide/gastric inhibitory peptide receptor axis via sonic hedgehog signaling promotes the bridging of gapped nerves in sciatic nerve injury
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DOI：
10.1111/jnc.15816
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发表时间：
2023-04-06
影响因子：
4.7
通讯作者：
Liu，Yan
中科院分区：
文献类型：
--
作者：
Guan，Tuchen;Guo，Beibei;Liu，Yan
雪旺细胞通过产生良好的微环境在周围神经再生中发挥重要作用。胃抑制肽/胃抑制肽受体(GIP/GIPR)轴缺陷导致坐骨神经修复失败。然而，潜在的机制仍然难以捉摸。在这项研究中，我们惊讶地发现，在大鼠坐骨神经损伤恢复过程中，GIP治疗显著增强了雪旺细胞的迁移和雪旺细胞索的形成。我们进一步发现，正常情况下雪旺细胞中GIP和GIPR的水平很低，而实时逆转录聚合酶链式反应(RT-PCR)和Western印迹显示损伤后雪旺细胞的GIP和GIPR水平显著升高。创面愈合和Transwell分析表明，GIP刺激和GIPR沉默可以影响雪旺细胞的迁移。基于干扰实验的体外和体内机制研究表明，GIP/GIPR可能促进雷帕霉素复合体2的机制靶点(MTORC2)活性，从而促进细胞迁移，Rap1的激活可能参与了这一过程。最后，我们检索了损伤后GIPR诱导的刺激因素。结果表明，sonic hedgehog(SHH)是一个潜在的候选基因，其表达随着损伤程度的增加而增加。荧光素酶和染色质免疫沉淀(ChIP)分析表明，SHH途径的靶转录因子Gli3显著增强GIPR的表达。此外，体内抑制SHH可有效降低坐骨神经损伤后GIPR的表达。总之，我们的研究揭示了GIP/GIPR信号在雪旺细胞迁移中的重要性，为周围神经损伤提供了一种治疗途径。
Schwann cells play an essential role in peripheral nerve regeneration by generating a favorable microenvironment. Gastric inhibitory peptide/gastric inhibitory peptide receptor (GIP/GIPR) axis deficiency leads to failure of sciatic nerve repair. However, the underlying mechanism remains elusive. In this study, we surprisingly found that GIP treatment significantly enhances the migration of Schwann cells and the formation of Schwann cell cords during recovery from sciatic nerve injury in rats. We further revealed that GIP and GIPR levels in Schwann cells were low under normal conditions, and significantly increased after injury demonstrated by real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) and Western blot. Wound healing and Transwell assays showed that GIP stimulation and GIPR silencing could affect Schwann cell migration. In vitro and in vivo mechanistic studies based on interference experiment revealed that GIP/GIPR might promote mechanistic target of rapamycin complex 2 (mTORC2) activity, thus facilitating cell migration; Rap1 activation might be involved in this process. Finally, we retrieved the stimulatory factors responsible for GIPR induction after injury. The results indicate that sonic hedgehog (SHH) is a potential candidate whose expression increased upon injury. Luciferase and chromatin immunoprecipitation (ChIP) assays showed that Gli3, the target transcription factor of the SHH pathway, dramatically augmented GIPR expression. Additionally, in vivo inhibition of SHH could effectively reduce GIPR expression after sciatic nerve injury. Collectively, our study reveals the importance of GIP/GIPR signaling in Schwann cell migration, providing a therapeutic avenue toward peripheral nerve injury.