Inhibition of miR-221-3p promotes axonal regeneration and repair of primary sensory neurons via regulating p27 expression.
Inhibition of miR-221-3p promotes axonal regeneration and repair of primary sensory neurons via regulating p27 expression.
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DOI：
10.1097/wnr.0000000000001912
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发表时间：
2023-06-07
期刊：
影响因子：
1.7
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中科院分区：
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本研究旨在探索在脊髓损伤后恶劣微环境中对轴突再生起重要作用的关键microRNA(MiRNA)。根据坐骨神经条件性损伤(SNCI)可促进背柱损伤修复的理论。根据微阵列筛选差异表达的miRNAs，发现47个已知的miRNAs在损伤后有差异表达，可能参与了神经再生。在47个miRNAs中，SNCI组miR-221-3p的表达明显低于单纯背柱损毁(SDCL)组。随后，通过荧光素酶报告基因检测，证实p27为miR-221-3p的目的基因。此外，我们发现抑制miR-221-3p的表达可以特异性地靶向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，从而促进背根神经节神经元轴突的再生。硫酸软骨素蛋白多糖(CSPGs)是胶质瘢痕的主要成分，可阻碍受损神经元轴突的伸展和生长。结果表明，抑制miR-221-3p的表达还可通过p27促进GAP-43、α-TAT1和α-微管蛋白的表达，并促进背根神经节神经元的轴突生长。因此，miR-221-3p可能通过特异性调控p27/CDK2/GAP-43和p27/α-TAT1/α-微管蛋白通路中的p27而促进背根节神经元的再生，即使在CSPGs的抑制环境中也是如此。
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.