Neurotrophin-3 promotes peripheral nerve regeneration by maintaining a repair state of Schwann cells after chronic denervation via the TrkC/ERK/c-Jun pathway

作者：Xu Xiong, Lili Song, Yueying Li, Jin Guo, Shuo Huang, Shuang Du, Weizhen Li, Rangjuan Cao, Shusen Cui · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-04609-2 · 被引用次数：33 · 研究领域：Nerve injury and regeneration、Pain Mechanisms and Treatments、Facial Nerve Paralysis Treatment and Research

BACKGROUND: Maintaining the repair phenotype of denervated Schwann cells in the injured distal nerve is crucial for promoting peripheral nerve regeneration. However, when chronically denervated, the capacity of Schwann cells to support repair and regeneration deteriorates, leading to peripheral nerve regeneration and poor functional recovery. Herein, we investigated whether neurotrophin-3 (NT-3) could sustain the reparative phenotype of Schwann cells and promote peripheral nerve regeneration after chronic denervation and aimed to uncover its potential molecular mechanisms. METHODS: Western blot was employed to investigate the relationship between the expression of c-Jun and the reparative phenotype of Schwann cells. The inducible expression of c-Jun by NT-3 was examined both in vitro and in vivo with western blot and immunofluorescence staining. A chronic denervation model was established to study the role of NT-3 in peripheral nerve regeneration. The number of regenerated distal axons, myelination of regenerated axons, reinnervation of neuromuscular junctions, and muscle fiber diameters of target muscles were used to evaluate peripheral nerve regeneration by immunofluorescence staining, transmission electron microscopy (TEM), and hematoxylin and eosin (H&E) staining. Adeno-associated virus (AAV) 2/9 carrying shRNA, small molecule inhibitors, and siRNA were employed to investigate whether NT-3 could signal through the TrkC/ERK pathway to maintain c-Jun expression and promote ...