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Advances in Clinical Medicine
Vol. 12  No. 11 ( 2022 ), Article ID: 58255 , 7 pages
10.12677/ACM.2022.12111525

外泌体对于缺血性脑卒中的保护作用机制研究进展

饶静¹，辛亮¹，魏亚囡¹，张禄露¹，徐瑞芬²

1西安医学院，陕西 西安

2陕西省人民医院，陕西 西安

收稿日期：2022年10月21日；录用日期：2022年11月15日；发布日期：2022年11月23日

摘要

外泌体作为近些年来发现的一种由体内多种细胞分泌的纳米级细胞外囊泡(EV)，可携带蛋白质、脂质、miRNA等分子物质参与细胞间的信息传递，靶向调控基因表达，并与生物体内多系统器官疾病的发展及预后密切相关。研究发现，外泌体在缺血性脑卒中的发病及预后均发挥了重要作用。并且基于其独特的性质，外泌体作为一种极具前景的药物递送载体引起了越来越多的关注。本文综述了外泌体在缺血性脑卒中的保护领域的最新研究进展。

关键词

外泌体，缺血性脑卒中，微小核糖核酸

Progress in the Mechanism of the Protective Effect of Exosomes on Ischemic Stroke

Jing Rao¹, Liang Xin¹, Yanan Wei¹, Lulu Zhang¹, Ruifen Xu²

1Xi’an Medical University, Xi’an Shaanxi

2Shaanxi Provincial People’s Hospital, Xi’an Shaanxi

Received: Oct. 21st, 2022; accepted: Nov. 15th, 2022; published: Nov. 23rd, 2022

ABSTRACT

Exosomes, as a kind of nanoscale extracellular vesicles (EVs) secreted by various cells in the body discovered in recent years, can carry proteins, lipids, miRNAs, and other molecular substances to participate in intercellular information transfer, targeting and regulating gene expression, and are closely related to the development and prognosis of multi-system organ diseases in living organisms. It has been found that exosomes play an important role in both the pathogenesis and prognosis of ischemic stroke. And based on their unique properties, exosomes have attracted increasing attention as a promising drug delivery vehicle. In this paper, we review the latest research progress in the field of exosome protection in ischemic stroke.

Keywords:Exosome, Ischemic Stroke, miRNA

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

脑卒中是全球第二大常见死因，也是导致残疾的主要原因。在脑卒中病例中缺血性卒中的发生占有很大比例。卒中后的脑损伤由一系列复杂的病理生理学过程引起，包括兴奋性毒性、氧化和硝化应激、炎症和细胞凋亡 [1]。目前临床上对于缺血性脑卒中的治疗方法仍然是非常有限的，主要使用的治疗方法包括通过药物治疗或手术实现快速再灌注，然而这两种治疗方法的治疗时间窗都比较短，使得多数患者不能得到及时有效的治疗而遗留不同程度的后遗症。外泌体作为一种由细胞主动分泌的生物囊泡，近年来越来越受到关注，成为医学领域的一大研究热点。而我们对外泌体的认知，从最初的“细胞垃圾桶”到如今转变为与疾病诊断有关的新型生物标志物和疾病治疗靶点 [2]。体内许多稳态调节过程中都有外泌体的参与，富含miR-126的缺氧MSC外泌体在骨再生中显示出有效的血管生成作用 [3]，阿尔茨海默病患者大脑星形胶质细胞释放含有促凋亡蛋白(例如前列腺凋亡反应4和神经酰胺)和tau蛋白的外泌体，并将这些蛋白质转移到受体细胞以诱导神经细胞死亡和神经变性 [4]，外泌体还可调节肠道屏障功能，炎症反应及肠道微生物群从而影响炎症的进展 [5]，间充质干细胞外泌体在皮肤伤口愈合中发挥重要作用，促进皮肤修复和再生 [6]。本文就外泌体对缺血性脑卒中的保护作用及其机制的最新研究进展进行总结。

2. 外泌体的生物学特征

外泌体，直径约为40~100 nm，是由细胞分泌的微小脂质双层囊泡，1983年首次发现于绵羊的网织红细胞中 [7]。外泌体的产生过程包含细胞质膜的两次内陷和多泡体(Multivesicular body, MVB)的形成 [8]。质膜第一次内陷形成内体(Early sorting exosome, ESE)，在内体转运复合体及相关蛋白的调控下，ESE膜再次内陷形成内含多个小囊泡(Intraluminal vesicles, ILV)的MVB，MVB可经由两条途径分解：在溶酶体或自噬体的作用下进行降解；或与细胞质膜融合并将ILV释放到细胞外环境中，即为外泌体 [8] [9]。在体内几乎所有类型的正常细胞都可以产生外泌体，如人脐静脉内皮细胞、间充质干细胞(MSC)、T细胞、B细胞、巨噬细胞、树突状细胞(DC)、自然杀伤细胞(NK)等 [10]。外泌体含有许多生物分子，包括蛋白质、脂质、代谢物、mRNA、线粒体DNA、microRNA (miRNA)和许多其他非编码RNA [11]，通过这些生物信息分子在细胞间的转运以调控细胞间的信号转导及基因表达，从而调节体内的多种疾病的发展及预后 [8]。

3. 外泌体的分离纯化

外泌体的分离纯化是外泌体在临床研究应用的首要解决问题。到目前为止，已经报道了六种外泌体分离方法，包括超速离心、超滤、免疫亲和捕获、基于电荷中和的聚合物沉淀、尺寸排阻色谱仪和微流体技术 [12]。目前认为超速离心是分离外泌体的“金标准”。根据外泌体与悬浮液中其他物质的密度及分子量的差异，通过施加不同的离心力及离心时间，悬浮液中的颗粒成分将依次进行沉淀，密度大的颗粒通常最先沉淀出来 [13]。虽然这种方法易于操作，然而其缺点是分离的沉淀物中仍然存在许多杂质，且高速离心可能会损害外泌体的完整性并造成其原有的生物活性的降低 [14]。密度梯度离心是一种基于超速离心而改进的分离技术，最常用的方法是两步分离方法，首先直接进行超速离心，然后进行30%蔗糖密度超速离心，通过去除蛋白质污染来提高外泌体的纯度 [15]。

4. 外泌体在脑缺血性损伤中的保护机制

4.1. 抑制炎症反应

神经炎症的进展过程与小胶质细胞的两种表型(M1/M2)密切相关。其中M2型小胶质细胞参与抗炎过程，其分泌的抗炎因子，如白细胞介素-4 (IL-4)、白细胞介素-10 (IL-10)、转化生长因子β (TGF-β)和一些神经营养因子，可促进脑功能恢复并改善中风的预后 [16] [17]。

脑缺血再灌注(I/R)损伤诱导的M1极化小胶质细胞可在骨髓间充质干细胞外泌体(BMSC-Exos)的作用下向M2表型转化，从而抑制炎症反应，部分缓解了神经元焦亡 [18]。Zhao等人研究证明BMSC-Exos通过上调miR-223-3p抑制半胱氨酸白三烯受体2 (CysLT2R)-ERK1/2介导的M1小胶质细胞极化，促进小胶质细胞转化为M2表型，增加抗炎分子的分泌，减少促炎细胞因子的产生，从而显著减轻大脑中动脉阻塞(MCAO)大鼠的缺血性脑损伤 [19] [20]。含有miR-138-5p的BMSC-Exos通过靶向下调脂质素2 (LCN2)不仅促进了星形胶质细胞增殖，还使炎症因子的表达减少，抑制缺血性卒中后星形胶质细胞的炎症反应 [21]。Giunti等发现MSC衍生的外泌体miRNA通过抑制其靶基因Map3k8和Mk2的表达来调节p38 MAPK信号通路，抑制了小胶质细胞的促炎表型，从而减轻了神经炎症 [22]。Tian等人将来自神经组细胞的外泌体与精氨酸–甘氨酸–天冬氨酸(RGD)-4C肽–乳胶粘蛋白结合(RGD-EV)经尾静脉注射到MCAO小鼠模型中，发现RGD-EV在静脉内给药后靶向脑的缺血性病变区域，并强烈抑制炎症反应，证明神经祖细胞衍生的外泌体具有内在的抗炎活性 [23]。而间充质干细胞衍生的外泌体miR-542-3p可降低脑梗死小鼠的梗死面积并减少变性神经元数量，抑制炎症因子表达和炎症细胞浸润，通过调控胶质细胞的Toll样受体4 (TLR4)抑制缺血性脑损伤 [24]。

4.2. 抑制神经细胞凋亡

研究证明，多种途径的细胞凋亡与缺血性卒中的发病机制密切相关 [25]。Chen等研究发现，从SHOC2基因转录的circSHOC2，在缺血处理的星形胶质细胞外泌体中的表达显著增加并作用于miR-7670-3p/SIRT1轴来抑制神经元凋亡 [26]。Cheng等人证明了MSCs-Exo过度表达miR-26a-5p靶向CDK6减弱了氧葡萄糖剥夺再灌注(OGD/R)模型中的小胶质细胞凋亡并有效地减少了脑I/R损伤小鼠的脑梗死面积 [27]。Song等人通过将M2小胶质细胞衍生的外泌体(M2 Mi-Exos)经静脉注射到大脑中动脉闭塞后的小鼠大脑中，在缺血性发作后3天检查小鼠脑梗塞体积、神经系统评分和神经元凋亡。发现小鼠脑梗塞体积显着减少且行为缺陷减轻，证明了来自M2 Mi-Exos的miR-124通过靶向泛素特异性蛋白酶14 (USP14)抑制神经元凋亡和减轻缺血性脑损伤 [28]。此外，他们还发现M2 Mi-Exos还通过miR-124减少神经胶质疤痕的形成并改善中风后脑功能的恢复 [29]。同样，来自小胶质细胞外泌体的miRNA-137可减轻体外OGD诱导的神经元的凋亡，并且减少了缺血性脑损伤小鼠的梗死体积，这可能与miRNA-137靶向抑制其下游基因Notch1有关 [30]。Li等人观察到，来源于BMSC外泌体的miR-150-5p抑制其下游靶基因Toll样受体5 (TLR5)减缓神经元凋亡并减少炎症因子的表达 [31]。

4.3. 促进神经元轴突生长

外泌体对脑损伤的保护作用还体现在促进神经元轴突的生长。Xin等人发现miR-133b在MCAO后在大鼠大脑中显着下调，并且MSC给药显着增加了缺血性脑组织中miR-133b水平，用这些外泌体处理原代培养的神经元和星形胶质细胞，发现神经元和星形胶质细胞中的miR-133b水平增加，这表明外泌体介导miR-133b从MSCs到神经元和星形胶质细胞的转移。并且证实MSCs的外泌体miR-133b显着增加了神经突分支数和总神经突长 [32] [33]。Hira等人证实，在脑卒中亚急性期信号蛋白3A (Sema3A)抑制剂处理星形胶质细胞抑制其活化，并通过增加前列腺素D2合成酶负调控As-Exos中miR-30c-2-3p和miR-326-5p，促进了MCAO大鼠的轴突生长和功能恢复 [34]。Zhang等人报道，缺血性和非缺血性脑内皮细胞分泌的外泌体通过调节miR-19a、miR-27a、miR-195和miR-298并靶向轴突抑制蛋白如Sema6A、磷酸酶和张力素同系物(phosphatase and tensin homolog deleted on chromosome ten, PTEN)以及受体神经元中的ras同系物家族成员A (ras homolog family member A, RhoA)来促进皮质神经元的轴突生长 [35]。

4.4. 促进神经血管生成

神经血管重塑是治疗神经系统疾病的可行办法，通过刺激血管生长可稳定脑血流灌注，同时促进神经元存活和神经功能恢复 [36]。在血管生成过程中外泌体可促进血管内皮的迁移和增殖、刺激新生血管形成，是血管生成过程中的重要介质 [37]。神经元通过分泌外泌体可以将miR-132易位给脑内皮细胞，通过靶向真核细胞延伸因子2激酶(eef2k)来调节血管连接蛋白Cdh5的表达，介导了神经元调节的脑血管完整性 [38]。创伤性脑损伤(TBI)小鼠静脉施用MSC外泌体，并用内皮屏障抗原(EBA)染色以识别TBI后大脑中成熟的脉管系统，与PBS组对比，外泌体治疗显着增加了受损皮层和齿状回区域的血管密度 [39]。Tian等人研究发现白介素4 (IL-4)极化小胶质细胞可能通过分泌含有miR-26a的外泌体促进血管生成来改善缺血性中风引起的损伤 [40]。

5. 脑缺血预处理(IPC)诱导血浆中外泌体含量升高

研究证明，IPC可使脑组织更容易耐受随后而发生的更严重的缺血缺氧。临床上，短暂性脑缺血发作(TIA)可视为一种原位IPC [41]。在脑卒中前曾有短暂性脑缺血发作的患者最终梗死体积显著减少，这表明脑 IPC 具有内源性脑保护作用 [42] [43]。反复的短暂肢体缺血，称为“远程缺血预处理(RIPC)”，也可以减轻远处器官(如大脑)的缺血性损伤，并且它避免了对重要器官的直接缺血/缺氧损伤 [44]。近年来，越来越多的研究人员发现，外泌体可能在缺血预处理介导的大脑保护中发挥重要作用。Li等人实验发现，脑-IPC小鼠相较于假手术组小鼠血浆中外泌体含量显著增多，并通过鉴定两组小鼠之间差异表达的miRNA，发现MiR-451a在IPC-外泌体中上调且通过抑制RAC1的总表达和NADPH氧化酶的形成介导神经保护作用 [45]。

6. 外泌体作为药物载体在治疗缺血性脑损伤中的应用

应用重组组织纤溶酶原激活剂(rt-PA)溶栓是目前临床上常用的治疗急性缺血性卒中的方法。然而，因为溶栓治疗的窗口期较短，只有少数的患者适用于此种治疗。药物治疗是减轻缺血性脑损伤的另一途径，但是由于其分子量高且穿透能力差，大多数药物难以穿过血脑屏障到达大脑缺血区域，从而使它们的临床应用受到很大程度的限制。因此需要一个有效的载体系统来参与药物的递送。

外泌体是由细胞分泌的小细胞外囊泡。因为它们具有低免疫原性、先天稳定性、高递送效率和穿过血脑屏障的能力等独特的性质，外泌体作为治疗缺血性脑损伤的内源性药物递送纳米系统具有很大的前景 [46]。并且有研究表明，不同的外泌体根据其起源和特征，具有特定的细胞趋向性，可用于将其靶向特定的组织或器官 [47]。黄芩素(BA)是一种强自由基清除剂，已被证明在缺血性卒中中发挥神经保护作用。然而，由于其无法靶向大脑且溶解性差，其临床应用受到限制 [48]。最初有研究证明，含负载抗炎小分子化合物BA的外泌体可以保护小鼠免受脂多糖诱导的脑部炎症。使用外泌体包封BA改善了其溶解度，增长了体内循环时间，保留了药物治疗活性，并改善了向大脑输送的速率 [48] [49]。Huang等人实验证实，负载BA的巨噬细胞衍生外泌体(Exo-BA)在瞬时中脑动脉闭塞/再灌注模型和永久性脑中动脉闭塞模型中表现出比游离BA更好的脑靶向能力，且与游离BA相比，Exo-BA显著降低了活性氧(ROS)的产生，激活了神经元中的Nrf2/HO-1通路，从而显著缓解了脑缺血性损伤 [50]。这表示外泌体作为药物载体在治疗中枢神经系统疾病中同样具有优势。

7. 不足与展望

综上研究表明，在研究缺血性脑卒中的治疗方法中，外泌体的应用具有重大意义。外泌体可以通过抑制神经元凋亡、缓解炎症反应、介导轴突重建和神经发生、促进血管再生等方式改善了脑组织缺血和缺氧，减弱了卒中后的脑组织损害，为缺血性脑卒中的治疗提供了新的思路。然而，目前我们对外泌体的认识仍处于初级阶段，在外泌体的临床应用中仍有许多难题有待解决。首先我们对外泌体生物发生的分子机制缺乏了解，目前还无法对外泌体的分泌进行调控；其次由于外泌体的分子量太小，要对其进行严格意义上的分离纯化仍需改进我们的技术；最后如何调节外泌体中分子物质及其负载药物的释放也是我们要面临的难题。因此外泌体介导的脑保护机制以及外泌体的临床应用还有待研究。

文章引用

饶 静,辛 亮,魏亚囡,张禄露,徐瑞芬. 外泌体对于缺血性脑卒中的保护作用机制研究进展
Progress in the Mechanism of the Protective Effect of Exosomes on Ischemic Stroke[J]. 临床医学进展, 2022, 12(11): 10591-10597. https://doi.org/10.12677/ACM.2022.12111525

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