Zhu Hui, Mu Li, Xu Xi, Huang Tianyi, Wang Ying, Xu Siyuan, Wang Yiting, Wang Wencong, Wang Zhiping, Wang Hongkui, Xue Chengbin
Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, China.
Medical School of Nantong University, Nantong, Jiangsu Province, China.
Neural Regen Res. 2025 Aug 1;20(8):2382-2394. doi: 10.4103/NRR.NRR-D-23-02040. Epub 2024 May 13.
JOURNAL/nrgr/04.03/01300535-202508000-00028/figure1/v/2024-09-30T120553Z/r/image-tiff Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury. Notably, the gene regulatory network of regenerated myelin differs from that of native myelin. Silencing of enhancer of zeste homolog 2 (EZH2) hinders the differentiation, maturation, and myelination of Schwann cells in vitro. To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury, conditional knockout mice lacking Ezh2 in Schwann cells (Ezh2fl/fl;Dhh-Cre and Ezh2fl/fl;Mpz-Cre) were generated. Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated. This highlights the crucial role of Ezh2 in initiating Schwann cell myelination. Furthermore, we observed that 21 days after inducing a sciatic nerve crush injury in these mice, most axons had remyelinated at the injury site in the control nerve, while Ezh2fl/fl;Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates. This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination. In conclusion, EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury. Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.
脱髓鞘和再髓鞘化一直是外周神经损伤后外周神经再生研究的主要焦点。值得注意的是，再生髓鞘的基因调控网络与天然髓鞘不同。zeste同源物2增强子（EZH2）的沉默会阻碍雪旺细胞在体外的分化、成熟和髓鞘形成。为了进一步确定EZH2在髓鞘形成和外周神经损伤后恢复中的作用，我们构建了雪旺细胞中缺乏Ezh2的条件性敲除小鼠（Ezh2fl/fl;Dhh-Cre和Ezh2fl/fl;Mpz-Cre）。我们的结果表明，EZH2缺失小鼠坐骨神经中相当一部分轴突仍未髓鞘化。这突出了Ezh2在启动雪旺细胞髓鞘形成中的关键作用。此外，我们观察到在这些小鼠中诱导坐骨神经挤压损伤21天后，对照神经损伤部位的大多数轴突已经再髓鞘化，而Ezh2fl/fl;Mpz-Cre小鼠与它们的野生型同窝小鼠相比，再髓鞘化的轴突明显更少。这表明雪旺细胞中EZH2的缺失会损害髓鞘形成和再髓鞘化。总之，EZH2已成为外周神经损伤后脱髓鞘和髓鞘再生过程中的关键调节因子。在这些过程中调节EZH2活性可能为外周神经损伤的治疗提供一个有前景的治疗靶点。
