中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (8): 1814-1820.doi: 10.4103/1673-5374.330624

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

抑制宿主醛糖还原酶活性可促进脊髓损伤区移植神经干细胞向神经元分化

  

  • 出版日期:2022-08-15 发布日期:2022-01-22
  • 基金资助:
    国家自然科学基金项目（81601056，81901252）；陕西省重点研发计划项目（2020SF-083）；深圳医药三明项目（SZSM201911011）；中国脊柱脊髓损伤修复与再生重点实验室（同济大学，教育部）项目

Reducing host aldose reductase activity promotes neuronal differentiation of transplanted neural stem cells at spinal cord injury sites and facilitates locomotion recovery

Kun Zhang1, 2, #, Wen-Can Lu3, #, Ming Zhang1, Qian Zhang4, Pan-Pan Xian1, Fang-Fang Liu1, Zhi-Yang Chen5, Chung Sookja Kim6, Sheng-Xi Wu1, Hui-Ren Tao3, *, Ya-Zhou Wang1, *   

  1. 1Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi Province, China; 2Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Tongji University, Shanghai, China; 3Department of Spine Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong Province, China; 4Department of Neurology, Hainan Hospital of Chinese PLA General Hospital, Sanya, Hainan Province, China; 5Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China; 6Faculty of Medicine, Macau University of Science and Technology, Macau Special Administrative Region, China
  • Online:2022-08-15 Published:2022-01-22
  • Contact: Ya-Zhou Wang, MD, yazhouw@fmmu.edu.cn; Hui-Ren Tao, MD, huiren_tao@163.com.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China, Nos. 81601056 (to KZ), 81901252 (to QZ); Shaanxi Key Research and Development Program of China, No. 2020SF-083 (to KZ); Sanming Project of Medicine in Shenzhen of China, No. SZSM201911011 (to SXW); and the Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University, Ministry of Education) of China (to KZ).

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摘要：

神经干细胞移植被认为是一种可用于补充脊髓损伤后缺失神经元的潜在策略，然而由于神经毒性炎症微环境的存在，移植神经干细胞的存活和分化情况通常很差。考虑到葡萄糖代谢在小胶质细胞/巨噬细胞的M1/M2型转换中起重要作用，实验假设调节葡萄糖代谢多元醇通路的核心酶醛糖还原酶活性改变小胶质细胞/巨噬细胞的表型，从而为神经干细胞移植提供有利的微环境。此次实验发现敲除宿主醛糖还原酶可促使脊髓损伤区的巨噬/小胶质细胞朝向M2极化。M2型巨噬细胞在体外可促进神经干细胞向神经元方向分化。向醛糖还原酶缺陷或给予了醛糖还原酶抑制剂sorbinil的脊髓损伤小鼠移植神经干细胞，可促进神经干细胞在脊髓损伤区的存活和神经元方向分化和运动功能恢复。表明抑制宿主醛糖还原酶活性有利于提高移植神经干细胞的存活和神经元分化能力，有应用于治疗脊髓损伤的潜力。

https://orcid.org/0000-0002-7116-2395 (Ya-Zhou Wang)

关键词: 脊髓损伤, 炎症, 功能恢复, 神经干细胞移植, 神经元分化, 醛糖还原酶, 小胶质细胞, 巨噬细胞, 极化

Abstract: Neural stem cell (NSC) transplantation is a promising strategy for replacing lost neurons following spinal cord injury. However, the survival and differentiation of transplanted NSCs is limited, possibly owing to the neurotoxic inflammatory microenvironment. Because of the important role of glucose metabolism in M1/M2 polarization of microglia/macrophages, we hypothesized that altering the phenotype of microglia/macrophages by regulating the activity of aldose reductase (AR), a key enzyme in the polyol pathway of glucose metabolism, would provide a more beneficial microenvironment for NSC survival and differentiation. Here, we reveal that inhibition of host AR promoted the polarization of microglia/macrophages toward the M2 phenotype in lesioned spinal cord injuries. M2 macrophages promoted the differentiation of NSCs into neurons in vitro. Transplantation of NSCs into injured spinal cords either deficient in AR or treated with the AR inhibitor sorbinil promoted the survival and neuronal differentiation of NSCs at the injured spinal cord site and contributed to locomotor functional recovery. Our findings suggest that inhibition of host AR activity is beneficial in enhancing the survival and neuronal differentiation of transplanted NSCs and shows potential as a treatment of spinal cord injury.

Key words: aldose reductase, functional recovery, inflammation, macrophage, microglia, neural stem cell transplantation, neuronal differentiation, polarization, spinal cord injury