MicroRNA dysregulation following spinal cord contusion: implications for neural plasticity and repair.
MicroRNA dysregulation following spinal cord contusion: implications for neural plasticity and repair.
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DOI：
10.1016/j.neuroscience.2011.03.063
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发表时间：
2011-07-14
期刊：
影响因子：
3.3
通讯作者：
Miranda RC
中科院分区：
文献类型：
--
作者：
Strickland ER;Hook MA;Balaraman S;Huie JR;Grau JW;Miranda RC
脊髓损伤（SCI）是医学和社会经济衰弱。目前，缺乏促进损伤部位再生的有效疗法，并且对可用于治疗性操纵脊髓可塑性的机制的理解有限。微小RNA（miRNAs）构成了治疗干预以促进修复和再生的新靶点。在SCI后4天和14天收集的挫伤和假手术大鼠脊髓损伤部位的微阵列比较显示，包括miR 124、miR 129和miR 1在内的32种miRNAs显著下调，而SNORD 2（一种抑制起始因子）被诱导。此外，包括miR 21在内的3种miRNAs被显著诱导，表明在损伤的脊髓中抗凋亡反应的适应性诱导。通过qRT-PCR和原位杂交分析验证miRNA表达，结果显示SCI对miRNA表达的影响持续长达14天，并且向前和向尾扩展超出病变部位。具体而言，miR 129 -2和miR 146 a表达的变化显著解释了初始损伤严重程度的变化，表明这些特异性miRNAs可作为SCI的生物标志物和治疗靶点。此外，miRNA的变化模式在空间和时间上与SOX 2、巢蛋白和REST免疫反应性的出现相吻合，这表明这些miRNA的异常表达不仅反映了干细胞龛的出现，而且还反映了存活神经元中前神经元表型的重新出现。最后，验证的miRNA靶向基因的生物信息学分析表明，miRNA失调可能解释与神经元身份丢失相关的凋亡易感性和异常细胞周期，这是继发性SCI发病机制的基础。
Spinal cord injury (SCI) is medically and socioeconomically debilitating. Currently, there is a paucity of effective therapies that promote regeneration at the injury site, and limited understanding of mechanisms that can be utilized to therapeutically manipulate spinal cord plasticity. MicroRNAs (miRNAs) constitute novel targets for therapeutic intervention to promote repair and regeneration. Microarray comparisons of the injury sites of contused and sham rat spinal cords, harvested 4 and 14 days following SCI, showed that 32 miRNAs, including miR124, miR129, and miR1, were significantly down-regulated, whereas SNORD2, a translation-initiation factor, was induced. Additionally, 3 miRNAs including miR21 were significantly induced, indicating adaptive induction of an anti-apoptotic response in the injured cord. Validation of miRNA expression by qRT-PCR and in situ hybridization assays revealed that the influence of SCI on miRNA expression persists up to 14 days and expands both anteriorly and caudally beyond the lesion site. Specifically, changes in miR129-2 and miR146a expression significantly explained the variability in initial injury severity, suggesting that these specific miRNAs may serve as biomarkers and therapeutic targets for SCI. Moreover, the pattern of miRNA changes coincided spatially and temporally with the appearance of SOX2, nestin, and REST immunoreactivity, suggesting that aberrant expression of these miRNAs may not only reflect the emergence of stem cell niches, but also the reemergence in surviving neurons of a pre-neuronal phenotype. Finally, bioinformatics analysis of validated miRNA-targeted genes indicates that miRNA dysregulation may explain apoptosis susceptibility and aberrant cell cycle associated with a loss of neuronal identity, which underlies the pathogenesis of secondary SCI.
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