中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (7): 1584-1590.doi: 10.4103/1673-5374.357914

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

Let-7a拮抗剂促进损伤周围神经再生

  

  • 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;江苏省高校自然科学基金;江苏省高等学校重点学科建设计划[PAPD];江苏省自然科学基金

Potential application of let-7a antagomir in injured peripheral nerve regeneration

Qian-Qian Chen1, 2 Qian-Yan Liu2, Pan Wang2, Tian-Mei Qian2, Xing-Hui Wang2, Sheng Yi2, Shi-Ying Li2, *   

  1. 1State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School, Nanjing University, Nanjing, Jiangsu Province, China; 2NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
  • Online:2023-07-15 Published:2023-01-12
  • Contact: Shi-Ying Li, PhD, lisy0379@ntu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 31970968 (to SYL), the Collegiate Natural Science Foundation of Jiangsu Province, No.16KJA310005 (to SYL), Priority Academic Program Development of Jiangsu Higher Education Institutions [PAPD] and the Natural Science Foundation of Jiangsu Province, No. BK20200976 (to XHW).

摘要:

作者所在课题组以往研究表明let-7可以靶向调控神经生长因子,同时let-7也是调控周围神经损伤修复和再生的核心和枢纽因子。为评估let-7a在周围神经损伤修复方面的潜在应用可能性,实验首先通过对内源性表达、调控关系和功能筛选的分析,确定抗let-7a为最合适的let-7家族分子。根据体内安全性评估结果,let-7a拮抗剂具有生物安全性,可以进入坐骨神经的主要细胞类型,包括许旺细胞、成纤维细胞和巨噬细胞,水凝胶可以有效实现let-7a拮抗剂的可控、定位和持续递送。最后,将let-7a拮抗剂与水凝胶混合,并整合进壳聚糖导管中构建了包含miRNA的壳聚糖-水凝胶支架组织工程神经移植,用以桥接离断的坐骨神经。由此产生的人工神经移植物实现了let-7a拮抗剂的可控长时间释放,显著促进了轴突生长及功能恢复。该研究为let-7a的潜在体内周围神经修复应用提供了重要的实验基础。

http://orcid.org/0000-0001-5150-7299 (Shi-Ying Li)

Abstract: Neurotrophic factors, particularly nerve growth factor, enhance neuronal regeneration. However, the in vivo applications of nerve growth factor are largely limited by its intrinsic disadvantages, such as its short biological half-life, its contribution to pain response, and its inability to cross the blood-brain barrier. Considering that let-7 (human miRNA) targets and regulates nerve growth factor, and that let-7 is a core regulator in peripheral nerve regeneration, we evaluated the possibilities of let-7 application in nerve repair. In this study, anti-let-7a was identified as the most suitable let-7 family molecule by analyses of endogenous expression and regulatory relationship, and functional screening. Let-7a antagomir demonstrated biosafety based on the results of in vivo safety assessments and it entered into the main cell types of the sciatic nerve, including Schwann cells, fibroblasts and macrophages. Use of hydrogel effectively achieved controlled, localized, and sustained delivery of let-7a antagomir. Finally, let-7a antagomir was integrated into chitosan conduit to construct a chitosan-hydrogel scaffold tissue-engineered nerve graft, which promoted nerve regeneration and functional recovery in a rat model of sciatic nerve transection. Our study provides an experimental basis for potential in vivo application of let-7a.

Key words: chitosan, chitosan-hydrogel scaffold, let-7, let-7a antagomir, miRNA, nerve graft, peripheral nerve injury, peripheral nerve regeneration, Schwann cells