中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (7): 1591-1600.doi: 10.4103/1673-5374.355979

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

circ_0002538/miR-138-5p/纤溶蛋白轴可调节糖尿病周围神经病变中许旺细胞的迁移及髓鞘形成

  

  • 出版日期:2023-07-15 发布日期:2023-01-12
  • 基金资助:
    国家自然科学基金项目（81772094，81974289）；湖北省重点研发计划项目（2020BCB031）；湖北省自然科学基金（2020CFB433）

The circ_0002538/miR-138-5p/plasmolipin axis regulates Schwann cell migration and myelination in diabetic peripheral neuropathy

Yu-Tian Liu1, #, Zhao Xu1, #, Wei Liu2, Sen Ren1, He-Wei Xiong1, Tao Jiang1, Jing Chen1, Yu Kang1, Qian-Yun Li1, Zi-Han Wu1, Hans-GüNther Machens3, Xiao-Fan Yang1, *, Zhen-Bing Chen1, *#br#   

  1. 1Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; 2Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; 3Department of Plastic and Hand Surgery, Technical University of Munich, Munich, Germany
  • Online:2023-07-15 Published:2023-01-12
  • Contact: Zhen-Bing Chen, PhD, zbchen@hust.edu.cn; Xiao-Fan Yang, PhD, 2017xh0119@hust.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81772094 (to ZBC), 81974289 (to ZBC); the Key Research and Development Program of Hubei Province, No. 2020BCB031 (to ZBC); and Natural Science Foundation of Hubei Province, No. 2020CFB433 (to YTL).

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摘要：

研究表明，环状RNA在糖尿病及其并发症中发挥重要作用，但其在糖尿病周围神经病变许旺细胞中的表达和功能尚无研究。此次实验率先对糖尿病周围神经病变患者及对照者的腓肠神经进行环状RNA测序和蛋白质谱分析。蛋白质谱鉴定结果显示，存在265种差异表达的蛋白质，进一步GO分析发现，差异表达蛋白主要富集于髓鞘形成和线粒体氧化磷酸化等过程。实时PCR验证环状RNA测序结果得出11种差异表达的环状RNA，其中circ_0002538在糖尿病周围神经病变患者中显著稳定下调。进一步体外研究发现，过表达circ_0002538可通过上调纤溶蛋白表达来促进纤维细胞的迁移。而在链脲佐菌素诱导糖尿病周围神经病变小鼠模型的坐骨神经中，过表达circ_0002538可缓解糖尿病周围神经病变脱髓鞘病变并改善其坐骨神经功能。机制分析结果显示，circ_0002538可通过海绵吸附miR-138-5p以促进纤溶蛋白表达，而敲低circ_0002538会下调纤溶蛋白水平，从而抑制纤维细胞的迁移。提示circ_0002538/miR-138-5p/纤溶蛋白轴可促进糖尿病周围神经病变中许旺细胞的迁移，改善髓鞘结构和神经功能，这将为治疗糖尿病周围神经病变提供潜在干预 靶点。

https://orcid.org/0000-0003-2828-866X (Zhen-Bing Chen); https://orcid.org/0000-0002-0997-0973 (Xiao-Fan Yang)

关键词: 糖尿病周围神经病变, 脱髓鞘, 许旺细胞, 髓鞘形成, 环状RNA测序, 蛋白质分析, circ_0002538, miR-138-5p, 胞浆磷脂, 竞争性内源性 RNA

Abstract: Circular RNAs (circRNAs) play a vital role in diabetic peripheral neuropathy. However, their expression and function in Schwann cells in individuals with diabetic peripheral neuropathy remain poorly understood. Here, we performed protein profiling and circRNA sequencing of sural nerves in patients with diabetic peripheral neuropathy and controls. Protein profiling revealed 265 differentially expressed proteins in the diabetic peripheral neuropathy group. Gene Ontology indicated that differentially expressed proteins were mainly enriched in myelination and mitochondrial oxidative phosphorylation. A real-time polymerase chain reaction assay performed to validate the circRNA sequencing results yielded 11 differentially expressed circRNAs. circ_0002538 was markedly downregulated in patients with diabetic peripheral neuropathy. Further in vitro experiments showed that overexpression of circ_0002538 promoted the migration of Schwann cells by upregulating plasmolipin (PLLP) expression. Moreover, overexpression of circ_0002538 in the sciatic nerve in a streptozotocin-induced mouse model of diabetic peripheral neuropathy alleviated demyelination and improved sciatic nerve function. The results of a mechanistic experiment showed that circ_0002538 promotes PLLP expression by sponging miR-138-5p, while a lack of circ_0002538 led to a PLLP deficiency that further suppressed Schwann cell migration. These findings suggest that the circ_0002538/miR-138-5p/PLLP axis can promote the migration of Schwann cells in diabetic peripheral neuropathy patients, improving myelin sheath structure and nerve function. Thus, this axis is a potential target for therapeutic treatment of diabetic peripheral neuropathy.

Key words: circ_0002538, circRNA sequencing, competing endogenous RNAs, demyelination, diabetic peripheral neuropathy, miR-138-5, myelination, plasmolipin, protein profiling, Schwann cells