Liu Jingmin, Ma Xinrui, Hu Xiaofang, Wen Jinkun, Zhang Haowen, Xu Jiawei, He Ye, Wang Xianghai, Guo Jiasong
Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Department of Spine Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Glia. 2023 Jul;71(7):1715-1728. doi: 10.1002/glia.24365. Epub 2023 Mar 27.
Our previous studies indicated that RhoA knockdown or inhibition could alleviate the proliferation, migration, and differentiation of Schwann cells. However, the role of RhoA in Schwann cells during nerve injury and repair is still unknown. Herein, we developed two lines of Schwann cells conditional RhoA knockout (cKO) mice by breeding RhoA mice with Plp or Dhh mice. Our results indicate that RhoA cKO in Schwann cells accelerates axonal regrowth and remyelination after sciatic nerve injury, which enhances the recovery of nerve conduction and hindlimb gait, and alleviates the amyotrophy in gastrocnemius muscle. Mechanistic studies in both in vivo and in vitro models revealed that RhoA cKO could facilitate Schwann cell dedifferentiation via JNK pathway. Schwann cell dedifferentiation subsequently promotes Wallerian degeneration by enhancing phagocytosis and myelinophagy, as well as stimulating the production of neurotrophins (NT-3, NGF, BDNF, and GDNF). These findings shed light on the role of RhoA in Schwann cells during nerve injury and repair, indicating that cell type-specific RhoA targeting could serve as a promising molecular therapeutic strategy for peripheral nerve injury.
我们之前的研究表明，RhoA基因敲低或抑制可减轻雪旺细胞的增殖、迁移和分化。然而，RhoA在神经损伤和修复过程中在雪旺细胞中的作用仍不清楚。在此，我们通过将RhoA小鼠与Plp或Dhh小鼠杂交，培育出了两株雪旺细胞条件性RhoA基因敲除（cKO）小鼠。我们的结果表明，雪旺细胞中的RhoA基因敲除可加速坐骨神经损伤后的轴突再生和髓鞘再生，从而促进神经传导和后肢步态的恢复，并减轻腓肠肌的肌萎缩。体内和体外模型的机制研究表明，RhoA基因敲除可通过JNK途径促进雪旺细胞去分化。雪旺细胞去分化随后通过增强吞噬作用和髓鞘吞噬作用以及刺激神经营养因子（NT-3、NGF、BDNF和GDNF）的产生来促进沃勒变性。这些发现揭示了RhoA在神经损伤和修复过程中在雪旺细胞中的作用，表明细胞类型特异性靶向RhoA可作为一种有前景的周围神经损伤分子治疗策略。
