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

Abstract

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.

GIP attenuates neuronal oxidative stress by regulating glucose uptake in spinal cord injury of rat

“…In addition, the results showed that more neuronal projections were presented in the injury sites after the treatment of GIP, which might be due to the stimulative effect on axon growth. These effects have been described in our previous study 9,10 . Then, we could speculate a promising approach for the application of GIP or GIPR agonist in spinal cord injury, which could combine the properties of neuronal protection and axon regeneration.…”

“…These effects have been described in our previous study. 9 , 10 Then, we could speculate a promising approach for the application of GIP or GIPR agonist in spinal cord injury, which could combine the properties of neuronal protection and axon regeneration. Moreover, GIP and GIPR agonists are feasible for crossing the blood–brain barrier, 42 , 43 which is another advantage for their potential application.…”

“…GIP and GIPR expression have also been detected in the nervous system 8 . In our previous study, we demonstrated that GIP/GIPR could significantly promote axon growth of cortical neuron 9 and facilitate Schwann cell migration after periphery injury 10 . Moreover, GIP was reported to show neuroprotective effects in animal models of neurodegenerative disease, 11,12 while the underlying mechanism is elusive yet.…”