Chinese Journal of Tissue Engineering Research ›› 2020, Vol. 24 ›› Issue (14): 2271-2276.doi: 10.3969/j.issn.2095-4344.2443
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Luo Xuanxiang1, 2, Feng Hu2, Jing Li1, 2, Pan Bin1
Received:
2019-07-12
Revised:
2019-07-24
Accepted:
2019-08-23
Online:
2020-05-18
Published:
2020-03-18
Contact:
Feng Hu, Master, Professor, Chief physician, Department of Spinal Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
About author:
Luo Xuanxiang, Master candidate, Department of Orthopedics, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China; Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
Supported by:
CLC Number:
Luo Xuanxiang, Feng Hu, Jing Li, Pan Bin. Important roles of non-coding RNA in peripheral nerve repair [J]. Chinese Journal of Tissue Engineering Research, 2020, 24(14): 2271-2276.
2.1 miRNA miRNA是一种小的非编码单链RNA,平均大小约为22个核苷酸。miRNA的合成始于细胞核。首先,RNA聚合酶II或III生成原始转录本,然后经过Drosha-DGCR8复合物调控,形成含有发卡结构的pre-miRNA。pre-miRNA在出核转运蛋白 Exportin 5的作用下与Ran-GTP和Exportin 5形成异三聚体,转移到达细胞质被释放。在细胞质内,pre-miRNA由Dicer酶剪切成为成熟的miRNA[10]。成熟的miRNA与靶基因配对结合,转录后调节靶基因的表达,并通过对靶基因翻译抑制,调控靶蛋白的表达量。 近年来,许多研究都对神经损伤后特异性miRNA表达与神经修复的关系感兴趣,随着基因测序技术的发展,越来越多的损伤特异性miRNA被发现并经RT-PCR证实。miR-21是此类miRNA的典型代表。编码该miRNA的基因位于染色体17q23.2,广泛表达于哺乳动物的各种组织和器官中。在周围神经系统中,miR-21在损伤后第7天明显上调。它调控Ras/Raf/细胞外调节蛋白激酶(ERK)信号通路,通过对SPRY2的负调控促进轴突生长。miR-21和miR-222还可以通过调节组织抑制物金属蛋白酶3来促进神经元的内在再生能力[11]。组织抑制物金属蛋白酶3具有广泛的抑制作用,可促进多种细胞类型的凋亡。组织抑制物金属蛋白酶家族作为一组基质金属蛋白酶抑制剂得到了越来越多的关注,并且最近被证明具有额外的生物学效应。miR-132是神经系统中最著名的miRNA之一,MENDOZA-VIVEROS等[12]曾报道,miR-132/212可以通过调节甲基CpG结合蛋白2 (MeCP2)和下游脑源性神经营养因子的表达以及雷帕霉素信号转导的哺乳动物靶蛋白的表达,调节小鼠和仓鼠的树突状突起密度和光周期适应。最近有研究表明,在周围神经中,miR-132可能作用于其他mRNA靶点,如Ras p21蛋白激活因子1(Rasa1)mRNA,这是miR-132的下游靶点,在背根神经节神经元发育过程中调控轴突生长[13]。 除了上述典型miRNA的外,许多其他的miRNA也被证明参与了周围神经损伤后的神经再生。坐骨神经损伤后,背根神经节中miR-144、145和214下调,跨膜受体Robo2升高。进一步的研究证实miR-145可能通过slit- Robo-srGAP通路抑制神经生长[14]。PTEN是雷帕霉素和磷酸肌醇3激酶通路的负调控因子,对中枢神经元系统的轴突生长具有重要作用。然而,在周围神经系统中,PTEN的抑制作用似乎增加了轴突的固有再生能力,PTEN在一定程度上对轴突的生长起到调节制动的作用[15]。miR-222、miR-29a和miR-29通过靶向PTEN促进轴突生长。miR-29a和miR-29c直接靶向PTEN mRNA的3’-UTR,从而下调PTEN。 在周围神经系统中,许旺细胞在周围神经的轴突周围形成髓鞘,为轴突提供支持和保护。周围神经损伤后,通常可观察到明显的快速再生反应。在此过程中,无论神经是高度髓鞘化还是无髓鞘化,许旺细胞均分化为功能性祖细胞。通过增殖和迁移,去分化的许旺细胞重建受损组织。支持轴突再生的Bungner条带是由增殖的许旺细胞形成的,这些去分化的许旺细胞还分泌轴突再生所需的各种神经营养因子[16]。miRNA被认为可以调节许旺细胞的凋亡、生长、增殖、分化和迁移。利用微阵列和RT-PCR技术鉴定了48种神经损伤后动态调控的miRNA,其中大部分参与了多基因修饰和增殖,从而增强了驱动许旺细胞重髓鞘化的转录程序。miR-34a和miR-140是这一类miRNA的代表;这些miRNA通过NOTCH1和细胞周期蛋白D1 (CCND1)以及转录因子Egr2影响神经损伤后许旺细胞的活性[17]。miR-221/222在周围神经损伤后上调,直接与LASS2基因的3’-非编码区结合,导致LASS2 mRNA和蛋白表达下调,miR-221/222通过这种方式促进许旺细胞的增殖和迁移[18]。miR-132在缺血周围神经损伤引起的缺氧中表达升高,并与蛋白激酶amp活化的非催化亚单位gamma 3 (PRKAG3)的3’-UTR结合,从而下调PRKAG3的表达,从而增加许旺细胞的增殖和迁移[19]。 同时许多miRNA也会抑制许旺细胞的增殖和迁移。miR-182直接靶向成纤维细胞生长因子9。miR-182对成纤维细胞生长因子9的抑制作用直接抑制许旺细胞的迁移和增殖[20]。miR-9抑制正常细胞和肿瘤细胞的迁移,其沉默促进周围神经损伤后许旺细胞的迁移。这是因为胶原三股螺旋重复蛋白1是miR-9的直接靶点,胶原三股螺旋重复蛋白1可使Rac1 GTP酶失活[21]。miR-146b是一种类Kruppel因子7靶向miRNA,抑制Kruppel因子7表达,可以减少许旺细胞增殖和迁移,Kruppel因子7是一种周围神经损伤后刺激许旺细胞增殖和轴突再生的转录因子,是一种潜在治疗神经损伤的候选药物[22]。miR-sc4通过靶向周期蛋白依赖性激酶5激活剂1发挥作用,周期蛋白依赖性激酶5激活剂1对许旺细胞活性具有抑制作用[23]。let-7 miRNA可以减少原代许旺细胞的迁移和增殖,let-7 miRNA下调可促进神经生长因子的合成和分泌,因此,神经损伤后let-7的表达下调为轴突再生创造了有利条件[24]。 2.2 circRNA circRNA是近年来发现的一类闭合环状结构非编码RNA,其特征是既不具有5'-3'极性,也没有多聚腺苷酸尾巴,大量存在于真核转录组,是目前神经科学领域的研究热点[25]。 circRNA通常来源于蛋白编码基因和完整的外显子,真核circRNA主要在剪接过程中产生,除了外显子反剪接环化形成circRNA外,根据不同的生物发生机制存在着不同类型的circRNA。circRNA在哺乳动物大脑中富集,在神经元分化过程中保守并动态表达。近年来,有报道称circRNA具有多种生物学功能,包括促进滚圈翻译、控制亲本基因转录、促进形成选择性剪接mRNA、充当miRNA海绵等。在这些功能中,越来越多的研究报道circRNA与miRNA发生海绵样作用,调节基因表达,在人类疾病的发病和诊断中发挥着重要的作用。在成年大鼠心室下区(SVZ),有一个SVZ特异性的circRNA 结合miR-138-5p作为神经干细胞增殖的潜在负调控因子。CircRNA CDR1as (ciRS-7)在脑组织中特异性高表达,在神经元组织中作为一种潜在的环状miR-7海绵。在人类脑组织中,ciRS-7随着miR-7表达的增加而降低,可以下调多种相关基因的表达,如泛素结合酶(UBE2A)蛋白。circRNA在神经系统的高稳定性、组织和时序高特异性等特征,使其在神经再生与修复的研究中越来越受到人们的关注[26]。 近年来,circRNA在神经损伤中的研究日益增多。已有多项研究通过微阵列和RNA-seq技术揭示了创伤性脑损伤和神经性疼痛模型中circRNA的表达模式。在大鼠脊髓中检测到188个表达差异的circRNA (68个表达上调,120个表达下调),表达时间为神经损伤后第14天。其中,circ_0006928可能通过结合miR-184调控神经元凋亡。circRNAs-Filipi11通过ago2依赖的方式结合剪接miRNA-1224负调控,在慢性炎症疼痛中升高,并通过靶向Ubr5调控痛感[27]。有研究表明,circRNA可以在体内和体外诱导神经元自噬,circRNA-2837的下调通过诱导神经元自噬减轻坐骨神经损伤;此外,荧光素酶检测显示circRNA-2837可以与miR-34家族结合,circRNA-2837的沉默直接靶向miR-34a诱导神经元自噬,其通过对miR-34家族发挥海绵作用,扮演着竞争性内源RNA(competing endogenous RNAs, ceRNA)的角色,竞争性抑制miRNA的转录调控,发挥相应的生物学功能[28]。 与线性RNA相比,circRNA不被RNA酶降解,具有更强的稳定性,且分离、鉴定和检测较为容易,但目前circRNA的具体生成机制仍不明确,涉及到的信号剪切及稳定性调控等还有待进一步研究,circRNA在发挥miRNA海绵样作用的吸附及释放过程中的信号调控尚不清楚,关于circRNA的生物信息学数据库尚未完全建立,因此导致circRNA的研究进展比较缓慢。 2.3 lncRNA lncRNA是指长度大于200个核苷酸的非编码RNA,是非编码RNA中最大的一类RNA。转录开始后,lncRNA由RNA聚合酶Ⅱ合成,经组蛋白修饰后产生。与编码蛋白质的mRNA相比,lncRNA具有更强的组织和细胞表达特异性。利用原位杂交技术,MERCER等[29]在小鼠脑组织中鉴定了大量的lncRNA,进一步分析得出这些lncRNA的表达水平与特定的神经解剖学位置、细胞类型和亚细胞位置相关。lncRNAs已被证实在几乎所有转录和翻译水平上调控基因表达,包括基因组印迹、染色质修饰和细胞质mRNA的翻译[30]。越来越多的研究数据表明,lncRNA在许多生物过程中都具有重要的调控功能。在神经生物学中,lncRNA已经被证实与神经发育障碍、神经系统退行性变和脑部肿瘤有关[31]。例如,linc-Brn1b基因的下调已经被证明会导致大脑中中间祖细胞的减少,这表明这种lncRNA可能在大脑皮质发育中发挥重要作用。 近年来研究发现,大量的lncRNA在周围神经损伤后发生差异性表达,在周围神经再生中发挥着重要作用。例如,坐骨神经损伤后,lncRNA uc.217在背根神经节神经元表达下调。敲除lncRNA uc.217能显著促进培养的背根神经节神经元生长[32]。有研究表明lncRNA BC089918的下调促进背根神经节中神经元的突起生长。基因共表达网络显示lncRNA BC089918的潜在靶点包括Fam57b、Kcns1和Cacng2。在这3个靶点中,Kcns1表达于感觉神经元,坐骨神经损伤后其蛋白水平显著下调,影响神经元的兴奋性[33]。 许旺细胞的增殖和迁移有助于周围神经损伤后轴突的生长和功能的恢复。研究发现,lncRNA在周围神经损伤后可作用于许旺细胞,在周围神经再生中起着重要作用[34]。周围神经损伤后,lncRNA富含核富集的转录物1(NEAT1)和核基质结合区蛋白1(Satb1)表达增加,miR-34a表达减少。富含核富集的转录物1的过表达促进了许旺细胞的增殖和迁移,富含核富集的转录物1通过与miR-34a发生海绵样作用调控核基质结合区蛋白1表达,是一种竞争性的内源性RNA。富含核富集的转录物1通过调节miR-34a和核基质结合区蛋白1的表达,促进背根神经节神经元轴突的生长[35]。坐骨神经损伤后,lncRNA TNXA-PS1表达下调,其下调可通过作用于miR-24-3p/miR-152-3p促进许旺细胞迁移,影响双特异性磷酸酶1表达[36]。在坐骨神经损伤模型中,lncRNA BC088327表达上调,沉默lncRNA BC088327可抑制许旺细胞的存活,诱导许旺细胞凋亡并抑制细胞增殖。使用微阵列技术检测非编码RNA表达谱与坐骨神经损伤的大鼠模型中神经修复的关系,同时通过在缺氧的许旺细胞模型中对细胞活力、细胞周期和细胞凋亡检测,进一步评估lncRNA Bc088327在周围神经损伤中的具体功能;研究表明,lncRNA的表达谱与heregulin-1β密切相关,在周围神经损伤中,heregulin-1β能够促进皮肤源性前体分化许旺细胞治疗去细胞异体神经再生,而lncRNA Bc088327可能与heregulin-1β通过协同作用修复周围神经损伤[37]。 近年有研究预测lncRNA-mRNA参与周围神经损伤后修复,通过进一步分析,发现lncRNA ENSMUSG00000087366顺式调控Jun,Jun是一种由癌基因编码的蛋白,与c-Fos结合形成AP-1转录因子。先前的一项研究表明Jun是许旺细胞对损伤的中枢调节因子。Jun基因的敲除已被证明会导致轴突的再生和修复功能严重受损[38]。NONMMUG042235和ENSMUSG00000097535靶向作用于细胞间黏附分子1 (Icam1)。最近已经证明细胞间黏附分子1与周围神经损伤后修复的炎性反应和细胞聚集,以及许旺细胞髓鞘形成有关[39]。lncRNA的靶向作用见表1。 "
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