Cellular biomechanisms of Wallerian degeneration in peripheral nerve axon injury

doi:10.12307/2025.709

Chinese Journal of Tissue Engineering Research ›› 2025, Vol. 29 ›› Issue (26): 5688-5694.doi: 10.12307/2025.709

Cellular biomechanisms of Wallerian degeneration in peripheral nerve axon injury

Shalayiding·Aierxiding1, 2, Aikebaierjiang·Aisaiti1,2, Kutiluke·Shoukeer1, 2, Gulimire·Yilihamu3, Aikeremujiang·Muheremu1, 2

1Department of Orthopedics, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi 830002, Xinjiang Uygur Autonomous Region, China; 2Key Laboratory of Orthopedic Regenerative Medicine, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi 830002, Xinjiang Uygur Autonomous Region, China; 3The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China

Received:2024-07-12 Accepted:2024-09-21 Online:2025-09-18 Published:2025-02-28
Contact: Aikeremujiang·Muheremu, MD, Chief physician, Associate professor, Master’s supervisor, Department of Orthopedics, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi 830002, Xinjiang Uygur Autonomous Region, China; Key Laboratory of Orthopedic Regenerative Medicine, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi 830002, Xinjiang Uygur Autonomous Region, China
About author:Shalayiding·Aierxiding, Master’s candidate, Department of Orthopedics, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi 830002, Xinjiang Uygur Autonomous Region, China; Key Laboratory of Orthopedic Regenerative Medicine, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi 830002, Xinjiang Uygur Autonomous Region, China
Supported by:
Natural Science Foundation of Xinjiang Uygur Autonomous Region (General Program), No. 2022D01C330 (to AM); National Natural Science Foundation of China (General Program), No. 82374487 (to AM); National Natural Science Foundation of China (Regional Program), No. 82260252 (to AM); Natural Science Foundation of Xinjiang Uygur Autonomous Region (General Program), 2022D01C331 (to AM [project participant]); Provincial-Ministerial Jointly-Built State Key Laboratory of Causes and Prevention of High Morbidity in Central Asia Open Topic Faceted Project, No. SKL-HIDCA-2022-16 (to AM); Key Scientific Research Program of Xinjiang Medical University, No. XYD2024ZX09 (to AM); “Tianchi Talent” Young Doctoral Project (to AM)

Abstract

Abstract: BACKGROUND: Successful regeneration of the peripheral nervous system relies on the damaged neuronal axons and non-neuronal cells, including Schwann cells and immune cells. The cellular processes that promote or limit axonal regeneration will be instructive in improving prognosis after peripheral nerve injury.
OBJECTIVE: To review the mechanisms and recent therapeutic advances in peripheral nerve axonal degeneration and regeneration during Wallerian degeneration.
METHODS: Utilizing computer-based searches, relevant articles published between 2004 and 2024 were retrieved from the Web of Science Core Collection, WanFang Database, and CNKI Database. The search terms included “peripheral nerve injury, axon injury, axon degeneration, Wallerian degeneration, cells, mechanism” in English and Chinese. Finally, 108 articles were included for review.
RESULTS AND CONCLUSION: Wallerian degeneration is a dynamic cellular process that is tightly regulated at the cellular and molecular levels. By unravelling the major roles and cellular molecular biological basis of Wallerian degeneration, it provides a useful framework for understanding Wallerian and Wallerian-like degeneration and lays the foundation for developing new therapeutic strategies to treat peripheral nerve injuries and neurodegenerative diseases.

Key words: peripheral nerves, Wallerian degeneration, axonal injury, axonal regeneration, Schwann cells, myelin, cellular biology, mechanism, review

CLC Number:

Shalayiding·Aierxiding, Aikebaierjiang·Aisaiti, Kutiluke·Shoukeer, Gulimire·Yilihamu, Aikeremujiang·Muheremu. Cellular biomechanisms of Wallerian degeneration in peripheral nerve axon injury[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(26): 5688-5694.

Figures/Tables 4

2.1.1 施万细胞对周围神经轴突损伤的反应在周围神经轴突损伤后的三四周内，轴突残端几乎所有的神经生长锥都没有核和髓鞘。但从第4周开始，有时甚至更早，带有细长细胞核的梭形细胞就会在纤维周围生长，这些细胞是由施万细胞增殖产生的[33-34]。施万细胞对正常神经功能和神经修复至关重要，占周围神经内有核细胞的90%[35]，为发育、成熟和再生的轴突提供营养支持。此外，施万细胞产生的基膜包围轴突，支持轴突生长。成人周围神经中有2种类型的施万细胞：髓鞘施万细胞和无髓鞘施万细胞[36]。髓鞘施万细胞在大口径轴突(运动或感觉)周围形成多层膜性髓鞘，与单个轴突的一段相关联，并沿轴突的纵向均匀分布[37]，绝缘的髓鞘结构使轴突能够比无髓鞘神经纤维轴突形成更快的动作电位。相反，无髓鞘施万细胞或Remak细胞松散地包裹多个小直径的无髓鞘轴突，其细胞质突起隔离并包围轴突。 (1)施万细胞是周围神经轴突损伤后前期最主要的吞噬细胞：外周神经损伤后不久，远端神经中的施万细胞开始去分化，这一过程依赖于泛素-蛋白酶体系统[38]。在轴突退化发生之前，与轴突相关的髓鞘施万细胞通过改变基因表达来对损伤做出反应[39-41]。在损伤的48 h内，这些施万细胞停止产生髓鞘蛋白[42-43]，上调再生相关基因(生长相关蛋白43、神经营养因子及其受体、神经调节蛋白及其受体)并开始增殖[44-47]。髓鞘施万细胞和Remak细胞均有分裂，在损伤后4 d左右达到增殖高峰，增殖的施万细胞被限制在基板管中，排列成Büngner带，为再生轴突提供支持底物和生长因子[48-49]。最近的研究揭示了施万细胞和免疫细胞最初感知附近轴突损伤的分子机制。其中，最重要的发现是Toll样受体，通过识别微生物病原体和激活天然免疫，在免疫稳态和抗病毒过程中发挥重要作用[50-53]，通过结合通常不存在于细胞外环境中的内源性配体(例如热休克蛋白[54]、mRNA[55]、降解的细胞外基质成分[56])来识别组织损伤。施万细胞表达多种Toll样受体，如Toll样受体1、Toll样受体3、Toll样受体4和Toll样受体7。Toll样受体1在轴突损伤后上调[57]。Toll样受体的表达模式表明，施万细胞在周围神经系统中起着前哨作用。髓鞘碎片是远端神经轴突再生的屏障，这些髓鞘碎片含有抑制轴突生长的分子，包括髓鞘相关糖蛋白和少突胶质细胞髓鞘磷脂糖蛋白[58-59]。施万细胞在早期清除髓鞘碎片方面发挥了重要作用，其中失神经施万细胞是损伤后前5 d的主要吞噬细胞[60]。轴突退化和消失后，施万细胞髓鞘纵向分裂，形成小的卵圆形结构[47]。施万细胞表达主要组织相容性复合体Ⅱ类分子，然而它们是否可以作为抗原提呈细胞尚不清楚[61-63]。 (2)施万细胞负责外周神经轴突损伤后的髓鞘初始降解：外周神经损伤后髓鞘的初始降解依赖于磷脂酶A2家族的激活[64]。施万细胞胞质内分泌形式的磷脂酶A2将磷脂酰胆碱水解为溶血磷脂酰胆碱(导致髓鞘分解)和花生四烯酸(可代谢为促炎二十烷类化合物)。炎症递质可能调控外周神经损伤后施万细胞中磷脂酶A2的激活[65-66]。值得注意的是，在损伤后几小时内，胞浆和分泌形式的磷脂酶A2在施万细胞和巨噬细胞中上调，并在2周内保持升高[66]，这一时间进程与外周神经损伤后的沃勒变性相关。外周神经损伤后3周恢复到基础磷脂酶A2水平，与轴突再生和重新髓鞘形成有关。Stirling等[66]还发现，阻断坐骨神经损伤远端磷脂酶A2的表达显著延长了变性髓鞘和轴突的清除时间。因此，施万细胞表达磷脂酶A2水平是外周神经损伤后髓鞘降解和沃勒变性进展所必需的。 (3)激活的施万细胞启动了细胞因子/趋化素级联反应：除外周神经损伤后的增殖和吞噬碎片外，施万细胞还释放能使免疫细胞招募到受损神经中的细胞因子和化学因子。招募的各种免疫细胞，特别是巨噬细胞，在沃勒变性的下一阶段碎片清除和生长因子产生方面发挥主要作用[67-68]。在小鼠坐骨神经切断后，施万细胞表达的白细胞介素6和白血病抑制因子mRNA在神经损伤后3 h内增加[68]，5 h内合成促炎细胞因子肿瘤坏死因子α和白细胞介素1α，而白细胞介素1β的产生延迟到24 h[69]。这些因子由施万细胞产生，是免疫细胞趋化所必需的[70]。肿瘤坏死因子α还诱导产生单核细胞趋化蛋白1[71]、基质金属蛋白酶9 [72]，两者都是切断轴突诱导巨噬细胞聚集所必需的。总而言之，这些研究表明，激活的施万细胞启动了细胞因子/趋化素级联反应，从而放大和微调外周神经损伤后的炎症反应。 (4)施万细胞通过分泌细胞外基质分子和营养因子促进轴突再生：受损神经残端的施万细胞分泌促进轴突生长的细胞外基质和营养因子。层粘连蛋白是外周神经系统中第二常见的细胞外基质成分(仅次于胶原蛋白)，支持轴突生长[73]，它们的表达在外周神经损伤后增加[74]。研究发现，施万细胞中层粘连蛋白γ1亚单位的条件性敲除，改变了施万细胞生理学，抑制了外周神经损伤后的轴突生长[75]。因此，层粘连蛋白对于维护和修复受损的外周神经系统是不可或缺的。施万细胞还分泌不同的营养因子，支持神经元的生存和生长。促炎症细胞因子白细胞介素6在外周神经损伤后的神经元和非神经元细胞中都升高[76-77]，通过其受体发出信号，增加神经元中再生相关基因的表达，促进轴突生长[78-79]。外周神经损伤会增加神经营养因子的释放，如神经生长因子，并可能促进轴突再生[80-83]。综上所述，外周神经系统轴突损伤后的施万细胞通过增殖、吞噬髓鞘碎片以及分泌营养因子和细胞因子来促进神经修复。 2.1.2 免疫细胞对周围神经损伤的反应免疫细胞对组织损伤和感染的反应在病理性外周神经系统中很大程度上是保守的，中性粒细胞和巨噬细胞在损伤后几小时或几天内到达，而远端损伤神经节段的淋巴细胞聚集延迟了1周或更长时间。此外，VOET等[84]研究表明，背根神经节损伤后神经元细胞周围的巨噬细胞激活可以促进轴突再生，这表明在远离原发损伤的区域(但仍在受影响细胞附近)通过损伤诱导的巨噬细胞激活也可以促进神经修复。因此，目前普遍认为外周神经系统轴突的再生依赖于快速而有效的免疫细胞反应。见表1。"

(1)中性粒细胞是第一个从循环中侵入受损组织的炎性白细胞：中性粒细胞作为髓系白细胞，是免疫系统的第一道防线，占体内所有循环白细胞的50%-70%[84]。中性粒细胞主要负责吞噬损伤细胞碎片，并在沃勒变性过程中调节其他白细胞(主要是单核细胞)的招募和激活[85]。虽然中性粒细胞在未损伤的大鼠神经中分布稀少，但其在损伤部位附近区域的密度在8 h内显著增加，并在24 h达到高峰(只有少数中性粒细胞渗透到远端残端的更远端区域)[86]。中性粒细胞在发生凋亡之前会短暂地吞噬损伤细胞碎片[87]。目前尚不清楚中性粒细胞如何影响外周神经损伤后轴突再生。 (2)外周神经轴突的再生依赖于快速而有效的巨噬细胞反应：巨噬细胞是另一个对外周神经损伤有反应的主要免疫细胞群。重要的是，它们在沃勒变性的后期阶段清除了髓鞘碎片。在未损伤的周围神经中，内膜巨噬细胞占有核细胞的29%[88]。巨噬细胞表达主要组织相容性复合体分子和补体受体3，这些表面分子分别赋予巨噬细胞抗原提呈和监视功能[89]。巨噬细胞通过增殖和吞噬髓鞘来对外周神经损伤做出反应[59]。血源性巨噬细胞对有效的髓鞘吞噬是必不可少的[90]，并产生激活施万细胞的细胞因子(例如白细胞介素1)和帮助轴突再生的营养因子(例如神经生长因子)。巨噬细胞还重建远端神经的细胞外基质，为再生轴突做准备[91]。巨噬细胞在神经中停留几天到几个月，之后它们一部分通过循环迁移到淋巴器官，一部分因细胞凋亡而死亡[64，92]。DAVID团队已经详细研究了巨噬细胞的迁移情况，发现巨噬细胞为了吞噬退化的髓鞘，穿透施万细胞基板管，接收信号并迁移到附近的血管[64]。 (3)单核细胞在组织中分化为巨噬细胞：外周神经系统中增殖的巨噬细胞在沃勒变性的早期阶段有重要作用。单核细胞是由施万细胞和巨噬细胞衍生的细胞因子和趋化因子从血液中招募。损伤后4 d，大量循环单核细胞在损伤神经内积累[93-94]，并且在组织中分化为巨噬细胞，局部趋化因子将巨噬细胞引导到不同的损伤区域。 (4)T淋巴细胞主要塑造沃勒变性后期的免疫反应：T淋巴细胞通过产生支持细胞免疫和体液免疫的促炎或抗炎细胞因子来调节免疫反应。1型辅助T(Th1)细胞分泌促炎细胞因子(例如肿瘤坏死因子α、γ-干扰素激活附近的巨噬细胞、中性粒细胞和自然杀伤细胞)，2型辅助T (Th2)细胞释放抗炎细胞因子(例如白细胞介素4、白细胞介素10)。两种辅助T细胞通过调节各种巨噬细胞的功能，调节细胞级联反应[95]。BEAHRS等[96]通过研究转基因小鼠发现，辅助T细胞反应能够保护面部运动神经元，使一小部分神经元在轴突损伤后仍存活，因此得出Th1和Th2细胞都是促进轴突再生所必需的结论。外周神经损伤后沃勒变性启动一种广泛的、涉及多种细胞类型的炎症反应，并持续数月。虽然施万细胞在沃勒变性的早期阶段调节髓鞘碎片的清除，但神经内膜和血源性巨噬细胞在外周神经损伤后1周内开始的碎片清除和神经修复中发挥关键作用[97]。见表2。 2.2 沃勒变性研究对周围神经损伤治疗研究的前景许多脊髓损伤、创伤性脑损伤或创伤性轴突损伤患者只有小部分轴突被完全切断、压碎或拉伸，但在损伤后仍与躯体相连的轴突以及在最初损伤中未受损的神经束内的轴突，最终都会与其他受损的轴突一起退化。因此，了解控制轴突沃勒变性过程中的细胞生物学机制可以保护这些轴突，并尽可能地保持受伤神经的生理功能。"

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Cellular biomechanisms of Wallerian degeneration in peripheral nerve axon injury

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