Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (3): 671-682.doi: 10.4103/1673-5374.350214

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Sequential expression of miR-221-3p and miR-338-3p in Schwann cells as a therapeutic strategy to promote nerve regeneration and functional recovery

Li-Li Wen1, Tian-Hao Yu2, Yi-Zhan Ma1, Xiao-Yan Mao1, Tian-Rang Ao3, Rabia Javed1, Hirotomo Ten4, Akira Matsuno4, Qiang Ao1, 5, *   

  1. 1Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning Province, China; 2The VIP Department, School and Hospital of Stomatology, Liaoning Provincial Key Laboratory of Oral Diseases, China Medical University, Shenyang, Liaoning Province, China; 3Department of Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; 4Department of Neurosurgery, Teikyo University School of Medicine, Tokyo, Japan; 5NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterial & Institute of Regulatory Science for Medical Device & National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan Province, China
  • Online:2023-03-15 Published:2022-08-28
  • Contact: Qiang Ao, PhD, aoqiang@tsinghua.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81771351, the National Key R&D Program of China, No. 2017YFA0105802, the Joint Research Fund Liaoning-Shenyang National Laboratory for Materials Science, No. 2019JH3/30100022, and the National Science Foundation for Post-doctoral Scientists of China, No. 2018M641732 (all to QA and LLW).

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Abstract: The functional properties of endogenous Schwann cells (SCs) during nerve repair are dynamic. Optimizing the functional properties of SCs at different stages of nerve repair may have therapeutic benefit in improving the repair of damaged nerves. Previous studies showed that miR-221-3p promotes the proliferation and migration of SCs, and miR-338-3p promotes the myelination of SCs. In this study, we established rat models of sciatic nerve injury by bridging the transected sciatic nerve with a silicone tube. We injected a miR-221 lentiviral vector system together with a doxycycline-inducible Tet-On miR-338 lentiviral vector system into the cavity of nerve conduits of nerve stumps to sequentially regulate the biological function of endogenous SCs at different stages of nerve regeneration. We found that the biological function of SCs was sequentially regulated, the diameter and density of myelinated axons were increased, the expression levels of NF200 and myelin basic protein were increased, and the function of injured peripheral nerve was improved using this system. miRNA Target Prediction Database prediction, Nanopore whole transcriptome sequencing, quantitative PCR, and dual luciferase reporter gene assay results predicted and verified Cdkn1b and Nrp1 as target genes of miR-221-3p and miR-338-3p, respectively, and their regulatory effects on SCs were confirmed in vitro. In conclusion, here we established a new method to enhance nerve regeneration through sequential regulation of biological functions of endogenous SCs, which establishes a new concept and model for the treatment of peripheral nerve injury. The findings from this study will provide direct guiding significance for clinical treatment of sciatic nerve injury.

Key words: cdkn1b, miR-221, miR-338, miRNA, nerve regeneration, Nrp1, peripheral nerve injury, regulation, Schwann cells, sequential expression