Neural Regeneration Research ›› 2022, Vol. 17 ›› Issue (8): 1814-1820.doi: 10.4103/1673-5374.330624

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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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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