中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 21 ›› Issue (5): 2060-2072.doi: 10.4103/NRR.NRR-D-25-00127

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

毛囊神经嵴干细胞来源细胞外小泡促进周神经细胞的增殖和迁移

  

  • 出版日期:2026-05-15 发布日期:2025-08-23

Small extracellular vesicles derived from hair follicle neural crest stem cells enhance perineurial cell proliferation and migration via the TGF-β/SMAD/HAS2 pathway

Yiming Huo1, #, Bing Xiao2, #, Haojie Yu3, #, Yang Xu1 , Jiachen Zheng1 , Chao Huang1 , Ling Wang1 , Haiyan Lin1 , Jiajun Xu1, *, Pengfei Yang4, *, Fang Liu1, *   

  1. 1 Department of Human Anatomy, Naval Medical University, Shanghai, China;  2 Department of Orthopedic Surgery, Affiliated Changzheng Hospital, Naval Medical University, Shanghai, China;  3 Department of Special Clinic, Affiliated Changhai Hospital, Naval Medical University, Shanghai, China;  4 Neurovascular Center, Affiliated Changhai Hospital, Naval Medical University, Shanghai, China
  • Online:2026-05-15 Published:2025-08-23
  • Contact: Fang Liu, MD, liu_fang403@163.com; Pengfei Yang, MD, chyangpf@163.com; Jiajun Xu, MD, xujiajunsmmu@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81571211 (to FL) and the Natural Science Foundation of Shanghai, No. 22ZR1476800 (to CH).

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摘要：

周围神经缺损修复是一个涉及多种细胞类型的复杂过程，其中神经周围细胞起着关键作用。毛囊神经嵴干细胞已被证明可通过旁分泌信号促进神经周围细胞的增殖和迁移；然而，其临床应用受到潜在风险的限制，如肿瘤发生和异种免疫排斥反应，这些风险与其他干细胞移植相关。因此，实验重点关注毛囊神经嵴干细胞来源的小细胞外囊泡，这种囊泡既保留了母细胞的生物活性特性，又避免了与移植相关的风险。在体外，毛囊神经嵴干细胞来源的小细胞外囊泡能显著增强周神经细胞的增殖、迁移、管形成和屏障功能，并随之上调紧密连接蛋白的表达。在用硅胶管桥接坐骨神经缺损的大鼠模型中，用毛囊神经嵴干细胞来源的小细胞外囊泡处理可增加周神经细胞中紧密连接蛋白的表达，促进神经组织再生。损伤后 10 周，接受毛囊神经嵴干细胞来源的小细胞外囊泡治疗的大鼠神经功能恢复得到改善，肌肉萎缩减少。转录组和miRNA分析表明，毛囊神经嵴干细胞来源的小细胞外囊泡可传递抑制Smad7表达的miR-21-5p，从而激活TGF-β/Smad信号通路并上调HAS2的表达，进一步增强紧密连接蛋白的表达。实验阐明了毛囊神经嵴干细胞来源的小细胞外囊泡对周神经细胞增殖、迁移和紧密连接蛋白形成的促进作用。它从周神经细胞的角度为周围神经再生提供了新的见解，并为临床治疗提供了一种新方法。

https://orcid.org/0000-0001-9709-4493 (Fang Liu)

关键词: 毛囊神经嵴干细胞, HAS2, 迁移, miR-21-5p, 会厌细胞, 增殖, 周围神经损伤, Smad7, 细胞外囊泡, TGF-β/Smad 信号通路

Abstract: Peripheral nerve defect repair is a complex process that involves multiple cell types; perineurial cells play a pivotal role. Hair follicle neural crest stem cells promote perineurial cell proliferation and migration via paracrine signaling; however, their clinical applications are limited by potential risks such as tumorigenesis and xenogeneic immune rejection, which are similar to the risks associated with other stem cell transplantations. The present study therefore focuses on small extracellular vesicles derived from hair follicle neural crest stem cells, which preserve the bioactive properties of the parent cells while avoiding the transplantation-associated risks. In vitro, small extracellular vesicles derived from hair follicle neural crest stem cells significantly enhanced the proliferation, migration, tube formation, and barrier function of perineurial cells, and subsequently upregulated the expression of tight junction proteins. Furthermore, in a rat model of sciatic nerve defects bridged with silicon tubes, treatment with small extracellular vesicles derived from hair follicle neural crest stem cells resulted in higher tight junction protein expression in perineurial cells, thus facilitating neural tissue regeneration. At 10 weeks post-surgery, rats treated with small extracellular vesicles derived from hair follicle neural crest stem cells exhibited improved nerve function recovery and reduced muscle atrophy. Transcriptomic and microRNA analyses revealed that small extracellular vesicles derived from hair follicle neural crest stem cells deliver miR-21-5p, which inhibits mothers against decapentaplegic homolog 7 expression, thereby activating the transforming growth factor-β/mothers against decapentaplegic homolog signaling pathway and upregulating hyaluronan synthase 2 expression, and further enhancing tight junction protein expression. Together, our findings indicate that small extracellular vesicles derived from hair follicle neural crest stem cells promote the proliferation, migration, and tight junction protein formation of perineurial cells. These results provide new insights into peripheral nerve regeneration from the perspective of perineurial cells, and present a novel approach for the clinical treatment of peripheral nerve defects.

Key words: hair follicle neural crest stem cells, HAS2, migration, miR-21-5p, perineurial cells, proliferation, peripheral nerve injury, Smad7, small extracellular vesicles, transforming growth factor-β/SMAD signaling pathway