Department of Orthopedic Surgery, General Hospital of Ningxia Medical University.
School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region.
Neuroreport. 2023 Jun 7;34(9):471-484. doi: 10.1097/WNR.0000000000001912. Epub 2023 Apr 28.
This study aimed to explore the key microRNA (miRNA) playing a vital role in axonal regeneration with a hostile microenvironment after spinal cord injury. Based on the theory that sciatic nerve conditioning injury (SNCI) could promote the repair of the injured dorsal column. Differentially expressed miRNAs were screened according to the microarray, revealing that 47 known miRNAs were differentially expressed after injury and perhaps involved in nerve regeneration. Among the 47 miRNAs, the expression of miR-221-3p decreased sharply in the SNCI group compared with the simple dorsal column lesion (SDCL) group. Subsequently, it was confirmed that p27 was the target gene of miR-221-3p from luciferase reporter assay. Further, we found that inhibition of miR-221-3p expression could specifically target p27 to upregulate the expression of growth-associated protein 43 (GAP-43), α-tubulin acetyltransferase (α-TAT1) together with α-tubulin, and advance the regeneration of dorsal root ganglion (DRG) neuronal axons. Chondroitin sulfate proteoglycans (CSPGs) are the main components of glial scar, which can hinder the extension and growth of damaged neuronal axons. After CSPGs were used in this study, the results demonstrated that restrained miR-221-3p expression also via p27 promoted the upregulation of GAP-43, α-TAT1, and α-tubulin and enhanced the axonal growth of DRG neurons. Hence, miR-221-3p could contribute significantly to the regeneration of DRG neurons by specifically regulating p27 in the p27/CDK2/GAP-43 and p27/α-TAT1/α-tubulin pathways even in the inhibitory environment with CSPGs.
本研究旨在探讨在脊髓损伤后的轴突再生中起关键作用的微小 RNA（miRNA）。基于坐骨神经条件性损伤（SNCI）可促进损伤背柱修复的理论。根据微阵列筛选出差异表达的 miRNAs，结果显示，损伤后有 47 种已知的 miRNAs 表达差异，可能参与神经再生。在这 47 个 miRNA 中，miR-221-3p 在 SNCI 组中的表达明显低于单纯背柱损伤（SDCL）组。随后，通过荧光素酶报告基因检测证实了 p27 是 miR-221-3p 的靶基因。进一步发现，抑制 miR-221-3p 的表达可以特异性靶向 p27，上调生长相关蛋白 43（GAP-43）、α-微管蛋白乙酰转移酶（α-TAT1）和α-微管蛋白的表达，促进背根神经节（DRG）神经元轴突的再生。软骨素硫酸盐蛋白聚糖（CSPGs）是胶质瘢痕的主要成分，可阻碍受损神经元轴突的延伸和生长。在本研究中使用 CSPGs 后，结果表明，通过 p27 抑制 miR-221-3p 的表达也促进了 GAP-43、α-TAT1 和α-微管蛋白的上调，增强了 DRG 神经元的轴突生长。因此，miR-221-3p 可以通过在 p27/CDK2/GAP-43 和 p27/α-TAT1/α-tubulin 通路中特异性调节 p27，对 DRG 神经元的再生做出重大贡献，即使在有 CSPGs 的抑制环境中也是如此。
