Liu Li, Gao Zhigang, Niu Xueyuan, Yu Hong, Xin Xiaolong, Gu Yanlan, Ma Genghai, Gu Yan, Liu Yijun, Fang Sanhua, Marquardt Till, Wang Liang
Department of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
Department of General Surgery of Sir Run Run Shaw Hospital, Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Zhejiang University School of Medicine, Hangzhou, China.
Nat Commun. 2025 Jul 1;16(1):5433. doi: 10.1038/s41467-025-61318-8.
During peripheral nerve (PN) development, unmyelinated axons (nmAs) tightly fasciculate before being separated and enveloped by non-myelinating Schwann cells (nmSCs), glial cells essential for maintaining nmA integrity. How such a switch from axon-axon to axon-glia interactions is achieved remains poorly understood. Here, we find that inactivating SC-derived SEMA3B or its axonal receptor components in mice leads to incomplete nmA separation and envelopment by nmSCs, eliciting hyperalgesia and allodynia. Conversely, increasing SEMA3B levels in SCs accelerates nmA separation and envelopment. SEMA3B transiently promotes nmA defasciculation accompanied by cell adhesion molecule (CAM) endocytosis, subsequently facilitating nmA-nmSC association. Restoring SEMA3B expression following PN injury promotes nmA-nmSC re-association and alleviates hyperalgesia and allodynia. We propose that SEMA3B-induced CAM turnover facilitates a switch from axon-axon to axon-glia interactions promoting nmA envelopment by nmSCs, which may be exploitable for alleviating PN injury-induced pain by accelerating the restoration of nmA integrity.
在周围神经（PN）发育过程中，无髓鞘轴突（nmAs）在被非髓鞘施万细胞（nmSCs）分离并包裹之前紧密成束，nmSCs是维持nmA完整性所必需的神经胶质细胞。目前对于如何实现从轴突 - 轴突相互作用到轴突 - 神经胶质相互作用的这种转变仍知之甚少。在这里，我们发现，在小鼠中使施万细胞衍生的SEMA3B或其轴突受体成分失活会导致nmA分离不完全以及nmSCs对其包裹不完整，从而引发痛觉过敏和异常性疼痛。相反，提高施万细胞中SEMA3B的水平会加速nmA的分离和包裹。SEMA3B短暂促进nmA解束，并伴有细胞粘附分子（CAM）内吞作用，随后促进nmA与nmSC的结合。在PN损伤后恢复SEMA3B表达可促进nmA与nmSC重新结合，并减轻痛觉过敏和异常性疼痛。我们提出，SEMA3B诱导的CAM周转促进了从轴突 - 轴突相互作用到轴突 - 神经胶质相互作用的转变，从而促进nmSCs对nmA的包裹，这可能有助于通过加速nmA完整性的恢复来减轻PN损伤引起的疼痛。
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