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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2023 May 28;48(5):771–781. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.220379

外泌体在精神障碍中作用的研究进展

Research progress in role of exosomes exosomes in mental disorders

WU Jialing 1,2, LI Shansi 1, ZHANG Yi 1,2,3,✉
Editor: 田 朴
PMCID: PMC10930398  PMID: 37539580

Abstract

Exosomes are a class of extracellular vesicles with a structure of lipid bilayer-membrane. In the central nervous system (CNS), exosomes can be secreted from both neurons and glial cells. Exosomes released into the extracellular matrix can freely cross the blood-brain barrier and function as crucial carriers of cellular communication and substance exchange in the CNS. Exosomes play a key role in the pathological process of mental disorders such as schizophrenia, depression, and bipolar disorder, and they have the potential to be used as a targeted carrier of antipsychotic medications. Exosomes are likely to become a new tool in the future to aid in the early prevention, accurate diagnosis, and effective treatment for people with mental disorders.

Keywords: exosomes, extracellular vesicle, mental disorders, central nervous system

外泌体是一类直径为30~150 nm的具有脂质双层膜结构的细胞外囊泡(extracellular vesicle，EV)[1]，Johnstone等[2]于1987年在绵羊网织红细胞上清液中最先发现外泌体。外泌体被证实在肿瘤、心血管疾病等多种疾病的病理生理机制上发挥重要的作用[3-6]，在中枢神经系统中同样也扮演重要角色，是神经元和神经胶质细胞以及其他细胞之间局部交流或者远程通信的载体[7]，在精神障碍发生的病理生理过程及疾病的诊断与治疗中发挥重要的作用[8]。

1. 外泌体概述

外泌体是EV的一种亚型，几乎可以由所有的细胞分泌，并被释放到细胞外进入血液、乳汁、尿液、脑脊液、支气管肺泡灌洗液、胆汁等细胞外环境中[9-12]。外泌体的形成最初是由细胞膜向内出芽形成早期内体，早期内体成熟后转变成具有动态亚细胞结构的多泡体(multivesicular body，MVB)[13-14]，MVB又可分为分泌型MVB和降解型MVB，降解型MVB送至溶酶体中被降解，而分泌型MVB则与细胞膜融合后，被释放到细胞外基质形成外泌体[15-16]。尽管目前关于形成特定的MVB的调控机制尚不明确[14]，但有研究[17-18]发现外泌体的形成与内体分选转运复合物(endosomal sorting complex required for transport，ESCRT)有关，ESCRT参与分选被装入MVB中的内体蛋白，其中ESCRT-I、ESCRT-Ⅱ和ESCRT-Ⅲ与哺乳动物肝细胞受体酪氨酸激酶底物Hrs和囊泡分拣蛋白Vps27相互作用，将泛素化的内容物分类，并触发内容物进入MVB内。此外，Trajkovic等[19]发现髓磷脂髓鞘蛋白(myelin proteolipid protein，PLP)在少突胶质细胞前体细胞系Oli-neu来源外泌体内的膜运输依赖于中性鞘磷脂酶2(neutral sphingomyelinase 2，nSMase2)而非ESCRT，使用nSMase抑制剂GW4869处理Oli-neu后，其外泌体的释放明显减少。Guo等[20]发现在小鼠下丘脑神经元细胞系GT1-7中朊病毒蛋白(prion protein，PrP)的传递依赖于nSMase2介导的外泌体形成和释放的途径；寨卡病毒可通过增强小鼠皮层神经元中nSMase2的活性诱导外泌体释放并以外泌体为病毒RNA载体传播至其他神经元中，而GW4869干预后的外泌体中病毒载量明显减少[21]，提示在中枢神经系统中，外泌体的形成机制可能主要是nSMase2介导的非ESCRT依赖途径。

外泌体的双层膜上富含跨膜蛋白Tetraspanins(CD9、CD26、CD53、CD63、CD81和CD82)、细胞内源性蛋白(TSG101、Alix)、热休克蛋白(Hsp70、Hsp90)、网格蛋白、脂筏标记蛋白-1、细胞骨架元素(Ezrin、Tubulin和Annexins)、Rab蛋白、MHC分子、细胞间黏附分子1(intercellular cell adhesion molecule-1，ICAM-1)、共刺激T细胞分子(CD86)等特异性蛋白[22]，神经酰胺、磷脂酰乙醇胺、磷脂酰丝氨酸、二酰甘油酯、胆固醇和鞘磷脂等脂质也存在于外泌体膜上[23]，且外泌体内还携带DNA、mRNA、miRNA和其他非编码RNA等核酸物质[9]。Valadi等[24]于2007年在小鼠和人类肥大细胞系(MC/9和HMC-1)的体外实验中首次证明了mRNA、miRNA存在于外泌体，并发现它们能在受体细胞中翻译成蛋白质或参与受体细胞基因转录后调控。此外，Thakur等[25]发现外泌体中含有稳定的双链DNA结构，并可能成为癌症的诊断标志物。不同细胞来源的外泌体表面携带有CD9、CD63、CD81以及TSG101等相似的保守蛋白，而在外泌体内容物中则含有与其来源细胞相关的特异性生物活性物质[26]，如免疫细胞来源的外泌体含有与抗原结合和提呈相关的蛋白质[27]；心肌细胞分泌的外泌体中含有肌节蛋白、线粒体蛋白以及肿瘤坏死因子-α[28]；神经元来源的外泌体含有调节星形胶质细胞功能和谷氨酸转运体-1表达的特异性miRNAs[29]；少突胶质细胞来源的外泌体则含有能够维持轴突能量代谢的PLP、去乙酰化酶沉默信息调节因子2(silent information regulation 2，SIRT2)等特异性蛋白[30-31]；而小胶质细胞外泌体含有调节神经元功能和影响神经发生的miRNAs[32]。在生理和病理条件下，亲本细胞可以将特定的蛋白质、脂质和RNA装载进入外泌体，并靶向作用于受体细胞[33]。因此，外泌体内容物不仅能反映其来源细胞的类型，还能反映来源细胞的生理功能或病理状态，具有成为某些疾病的诊断标志物的潜力。

2. 中枢神经系统外泌体及其功能

在中枢神经系统中，神经元和神经胶质细胞均可分泌外泌体。Faure等[10]通过分离胎鼠大脑皮层并进行体外培养，首次发现神经元可分泌外泌体。神经元来源的外泌体主要分布在突触间隙，比在轴突处的外泌体浓度高50倍[34]，该特性提示外泌体的形成与释放可能发生自树突棘，从而调节突触的可塑性。此外，Potolicchio等[35]通过体外培养小鼠小胶质细胞系N9首次发现小胶质细胞可以分泌外泌体。随后研究[31, 36]发现星形胶质细胞和少突胶质细胞均可分泌外泌体。神经胶质细胞来源的外泌体其内容物与不同神经胶质细胞的特性相关，如静息状态下的小胶质细胞外泌体中，与小胶质细胞发挥免疫调控作用密切相关的MHC Ⅱ类分子表达较低，而在干扰素干预后的小胶质细胞外泌体中MHC Ⅱ类分子的表达水平升高，同时，仅在小胶质细胞来源的外泌体而非其他免疫细胞中发现可降解甲硫氨酸脑啡肽、亮氨酸脑啡肽等神经肽的CD13[35]。

外泌体在中枢神经系统中发挥信使或载体功能，通过与多种细胞进行物质交换或信号转导，形成紧密而有效的神经元-神经元、神经元-胶质细胞、神经胶质细胞-神经胶质细胞信号网络[37]。如神经元可以通过外泌体转移miR-124b到星形胶质细胞，并促进星形胶质细胞中谷氨酸转运体-1的表达，从而调节突触的可塑性[38]。Yuyama等[39]发现神经元分泌的外泌体能够改变β淀粉样蛋白的构象，形成淀粉样蛋白原纤维，促进小胶质细胞对β淀粉样蛋白的吸收，诱发神经系统病变。胶质细胞来源的外泌体也能影响神经元活动：星形胶质细胞来源的外泌体通过传递朊病毒蛋白，能够提高缺血缺氧条件下神经元的存活率[40]；感染了HIV的星形胶质细胞分泌的外泌体中miR-29b的表达水平增高，从而抑制受体神经元的血小板衍生生长因子的表达，导致神经元活性降低[41]；少突胶质细胞分泌的带有Nogo-66结构域的外泌体会抑制小鼠机械损伤后大脑皮层神经元的轴突再生[42]；在缺少营养支持和应激的情况下，少突胶质细胞来源的外泌体能够支持细胞应激条件下的神经元代谢，发挥神经保护作用，且因其分泌的外泌体内含有髓鞘蛋白，能够促进邻近轴突的髓鞘形成并维持神经元的完整性[43]；小胶质细胞来源的外泌体能够递送miR-146a-5p至海马神经元，通过调控KLF4/P-STAT3/CDKL5信号通路来调节神经发生[32]；小胶质细胞来源的外泌体还可以增强神经酰胺及鞘氨醇的代谢活动，从而改善突触活性[44]。此外，神经胶质细胞之间也可以通过外泌体进行相互调控，如小胶质细胞能摄取少突胶质细胞分泌的外泌体，降解清除过量的髓鞘膜蛋白，从而在髓鞘疾病中发挥调控作用[45]；星形胶质细胞来源的外泌体递送miR-873a-5p至小胶质细胞中，可促进小胶质细胞向M2型极化并发挥抗炎作用[46]；而小胶质细胞来源的外泌体可被星形胶质细胞摄取，并抑制星形胶质细胞的病理性增生和瘢痕形成，在脊髓损伤中发挥保护作用[47]。以上研究表明神经元和神经胶质细胞来源的外泌体在中枢神经系统生理和病理过程中具有双向调控作用，而外泌体的发现也在一定程度上解释了生物信号如何转化为神经发生、突触形成、突触可塑性的改变以及神经炎症等生理病理过程，从而导致特定大脑区域的改变以及认知、情感等心理生理的改变，为阐明精神障碍的病因和病理机制提供了新思路。

3. 外泌体与精神障碍

近年来，外泌体与精神障碍的相关研究逐渐增多，如外泌体通过介导神经炎症反应、影响突触形成和神经发生、改变神经元的可塑性、介导表观遗传的调节等方式[48-53]，参与精神分裂症(schizophrenia，SCZ)、抑郁障碍和双相情感障碍(bipolar disorder，BD)等精神障碍的发生、发展[54-56]。

3.1. 外泌体与SCZ

SCZ是以感知觉、思维、情感和行为的多方面障碍为主要表现的精神疾病，是最常见的重性精神障碍之一，目前缺乏特异性的生物指标和病理生理体征作为诊断依据。相关脑影像学研究提示SCZ患者的大脑结构和功能具有明显改变，同时大脑皮层的多巴胺和谷氨酸等神经递质也有变化[57]。

3.1.1. 外泌体参与SCZ发生的病理过程

Banigan等[56]以SCZ患者、BD患者以及健康对照者死亡后的脑组织为研究对象，发现不同组间前额叶皮层中外泌体源性miRNAs的表达具有显著的差异，其中SCZ患者的外泌体中miR-497表达上调，而BD患者的外泌体中miR-29c表达显著上调，但具体机制有待进一步研究。Amoah等[58]发现在SCZ患者以及BD患者外侧眶额叶皮质中外泌体miR-233表达增加，体外实验发现抗精神病药物能够特异性地调节小鼠的神经元以及星形胶质细胞中外泌体源性miR-233的表达。SCZ的发生、发展可能与线粒体功能障碍有关。Goetzl等[59]在SCZ早期患者血浆胞外囊泡中发现4种线粒体钙离子通道蛋白的表达水平显著低于正常组，而L型钙离子通道α1C亚基(calcium channel-voltage-dependent-L type-α1C subunit，CACNA1C)的表达水平则显著高于正常组；Khadimallah等[60]以SCZ、BD、重性抑郁障碍患者为研究对象，发现这些患者血浆外泌体源性miR-137的表达水平上升而细胞色素c氧化酶A2(cytochrome c oxidase ⅥA2，COX6A2)以及有丝分裂标志物的表达水平下降，通过建立氧化还原失调动物模型发现氧化应激诱导小鼠前额叶以及血浆外泌体源性miR-137的表达水平上升以及COX6A2和有丝分裂标志物的表达水平下降，受损的线粒体累积，最终加剧神经元损伤，而使用抗氧化剂MitoQ可抑制miR-137的表达从而逆转氧化应激以及大脑线粒体受损的情况，提示血浆外泌体中miR-137以及COX6A2的联合应用很可能反映了精神障碍患者中大脑线粒体功能受损的情况。Du等[61]将SCZ患者血浆来源外泌体自C57BL/6小鼠的尾静脉注射进小鼠体内，发现小鼠表现出前脉冲抑制(prepulse inhibition，PPI)水平降低、多动行为和焦虑水平增高以及社交障碍等SCZ样行为。在一项对49例首发未服药SCZ患者以及46例健康被试的血浆外泌体miRNAs进行全基因组分析的研究[62]中发现：血浆外泌体中hsa-miR-206表达显著上调，而脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)的蛋白质和mRNA表达水平均显著下调。Tan等[63]通过高通量测序首次比较SCZ患者与健康被试的血浆外泌体中circRNAs的差异，发现相较于健康被试组，SCZ患者中有38种circRNAs的表达水平上调，6种circRNAs下调；Guo等[64]发现SCZ患者血浆外泌体中2种lncRNAs的表达水平发生变化。以上研究提示外泌体及其特异性内容物如miRNAs、circRNAs、lncRNAs以及蛋白质在SCZ的发生、发展过程中起重要作用，并能在一定程度上反映其生理病理过程的变化。

3.1.2. 外泌体在SCZ药物治疗中的潜力

药物治疗是SCZ患者的主要治疗方法，但有三分之一的患者对抗精神病药物治疗反应不佳[65]，其原因可能或至少部分是血脑屏障限制了物质运输和细胞迁移。血脑屏障是位于中枢神经系统的特殊微血管系统，也是调节外周循环与中枢神经系统之间的通道。血脑屏障可防止外周血中有害物质进入大脑，但也使抗精神病药物难以到达治疗靶点，从而增加SCZ等精神障碍的治疗难度[66-67]。研究[68]证实外泌体能够自由穿过血脑屏障，具有低免疫原性以及保护内源性生物活性物质不被降解的能力，而目前的技术可通过一定的修饰来赋予外泌体靶向输送的能力，提示外泌体具有靶向输送抗精神病药物的潜力。Tsivion-Visbord等[69]将N-甲基-D-天冬氨酸受体拮抗剂苯环己哌啶(phencyclidine，PCP)皮下注射进C57BL/6小鼠体内，建立SCZ动物模型，并在小鼠鼻腔内给予间充质干细胞来源细胞外囊泡(mesenchymal stem cell-derived-extracellular visicles，MSC-EVs)来治疗PCP小鼠，发现MSC-EVs鼻内给药能够定位到大脑内损伤部位，改善PCP小鼠的SCZ样行为，MSC-EVs鼻腔给药的方式具有侵入性小、能够穿越血脑屏障靶向治疗的特点，具有很大的临床应用潜力。

早期检测和有效干预可以有效改善SCZ的临床症状和预后。然而，由于SCZ的异质性大，在遗传学、病理生理学和临床现象学层面进行研究仍然面临挑战。SCZ患者外泌体源性生物标志物在一定程度上反映了其大脑内神经递质失调、氧化应激、线粒体功能障碍等生理病理过程，但目前的研究结果还存在较大的不一致性，且外泌体作为抗精神病药物载体的相关研究较少，因此还需要更进一步的研究，探讨外泌体作为SCZ生物标志物的可靠性和稳定性，以及挖掘外泌体应用于SCZ患者个性化治疗的潜力。

3.2. 外泌体与抑郁障碍

抑郁障碍是指由多种原因引起的以心境低落、兴趣减退以及快感缺失为核心症状的一种精神障碍，具有高发病率、高复发率、高致残率和高自杀率等特征。根据世界卫生组织数据统计，抑郁障碍的全球发病率约为11%，且有逐年上升的趋势，10%~15%的患者以自杀为最终结局，已成为导致死亡的全球第二大疾病[70]。

3.2.1. 外泌体参与抑郁障碍发生的病理过程

外泌体可能参与抑郁障碍的发生、发展。Liang等[71]通过对重性抑郁障碍(major depressive disorder，MDD)患者血清外泌体miRNAs进行全基因组分析，发现MDD患者血清中外泌体miR-139-5p的表达水平明显上调，通过动物实验进一步发现鼻腔给予miR-139-5p拮抗剂能够有效缓解慢性不可预知性温和应激诱导小鼠出现的抑郁样行为以及调节小鼠的神经发生[72]，提示外周血外泌体可能反映抑郁发生的病理过程。Nasca等[55]对69例MDD患者和29例健康被试血浆中神经元来源的外泌体进行分析，发现MDD患者血浆中神经元来源的L1CAM+外泌体数量以及外泌体中胰岛素受体底物-1(insulin receptor substrate-1，IRS-1)的表达水平都有所增高，且与自杀风险和快感缺失水平相关。此外，外泌体所携带的相关蛋白的改变可能是反映疾病严重程度、药物疗效以及临床预后的指标。如Goetzl等[73]以20例抑郁障碍患者为研究对象，分别在接受8周选择性5-羟色胺再摄取抑制剂(selective serotonin reuptake inhibitors，SSRIs)药物治疗前后比较其血浆神经元来源的外泌体中的线粒体相关蛋白的表达水平，结果显示：部分线粒体相关蛋白表达水平低于同龄健康对照组，经SSRIs类药物有效治疗8周后，线粒体相关蛋白表达恢复至正常水平，治疗无效者则没有恢复，说明抑郁障碍患者病程和药物疗效均可能与线粒体功能障碍有关；Gelle等[74]研究发现MDD患者血清及外泌体中BDNF表达水平降低而前体BDNF(Pro-BDNF)表达升高，经药物治疗后则逆转了这一变化，然而尚未发现血清以及外泌体中BDNF和Pro-BDNF表达水平与抑郁严重程度和临床症状的改善具有相关性。一项动物研究[75]也发现：表现出抑郁样行为的小鼠血浆外泌体中富含神经酰胺，而将抗神经酰胺抗体或神经酰胺酶预处理后的血浆外泌体注射进小鼠体内可预防应激小鼠出现抑郁样行为。尽管外泌体与抑郁障碍发生的病理机制研究相对较少，但现有的研究均提示抑郁个体存在外泌体及其内容物的异常，且异常的外泌体在抑郁障碍发生、病程的维持和疾病严重程度等多维度发挥重要作用。

3.2.2. 外泌体在抑郁障碍药物治疗中的潜力

目前，临床上常用的抗抑郁药物具有起效较慢、疗效较差、复发率较高以及不良反应多的缺陷，SSRIs类药物是MDD的一线治疗药物，但约一半的MDD患者经SSRIs类药物治疗无效[76]。其原因一方面源于抑郁症的发病机制尚不清楚，新的抗抑郁药亟待开发；另一方面目前临床抗抑郁药与其他抗精神病药也一致存在血脑屏障的限制，难以到达治疗靶点。Alvarez-Erviti等[53]通过向小鼠大脑注射包含siRNA的具有靶向性的树突状细胞来源的外泌体，发现被赋予靶向性的外泌体能够将siRNA准确传递到目标区域，不仅不会诱发机体的免疫应答，而且多次重复给药也不会降低传递效率。环状RNA DYM(circular RNA DYM，circDYM)在MDD患者的血浆以及抑郁症小鼠模型的海马组织和血浆中的表达水平均明显下降[77-78]，而Yu等[79]发现经基因修饰后的RVG-circDYM-EVs的全身给药能够将circDYM递送至大脑，circDYM通过抑制小胶质细胞的激活，可减少血脑屏障渗漏和外周炎症因子浸润，显著减轻神经炎症反应，有效缓解慢性应激小鼠的抑郁样行为。干细胞是一类具有自我复制能力的多向分化潜能细胞，体外细胞实验[80]发现：干细胞来源的外泌体能够发挥神经保护的作用，来自乳牙牙髓干细胞的外泌体可缓解6-羟基多巴胺诱导的多巴胺能神经元的凋亡。脂肪干细胞来源的EV能够通过抑制内质网应激来逆转皮质酮诱导的神经元凋亡的现象[81]。动物实验[82-83]进一步揭示了干细胞来源的外泌体到达中枢神经系统发挥抗抑郁的作用。Guo等[82]发现骨髓间充质干细胞来源的外泌体通过上调miR-26a的表达水平，抑制抑郁大鼠海马神经元的凋亡，从而改善大鼠的抑郁样行为。Li等[83]发现自然杀伤(natural killer，NK)细胞来源的外泌体同样具有抗抑郁的作用，NK细胞来源外泌体通过递送miR-207至星形胶质细胞内与Toll样受体4(Toll-like receptor 4，TRL4)靶向结合，并抑制NF-κB的信号转导与炎症因子的释放，从而发挥抗抑郁的作用。以上研究表明外泌体具有成为抗抑郁药物靶向载体的潜力。

抑郁障碍患者外周血中脑源性外泌体及其内容物可以作为“大脑的窗口”，反映中枢神经系统神经递质失衡、胰岛素抵抗、线粒体功能障碍以及神经发生等生理病理过程，为了解抑郁障碍的病理生理机制以及临床病程变化提供了新视角。此外，基于外泌体的抗抑郁药物递送有望成为一种更为高效的抑郁障碍治疗方式，但由于伦理原因，外泌体作为药物载体参与到精神障碍治疗的研究还仅限于动物实验和细胞实验，其安全性尚未得到验证，因此，还需要进一步的研究来探讨外泌体的临床用药安全性和有效性。

3.3. 外泌体与BD

BD是一类由神经生化因素、遗传因素和心理社会因素等引起的既有躁狂发作又有抑郁发作的心境障碍[84]。目前，外泌体在BD中的研究主要集中于探讨中枢神经系统以及外周血中外泌体miRNAs、代谢物等作为BD生物标志物的可能性。Choi等[85]发现BD患者死亡后脑组织前扣带回皮层中外泌体miR-149的表达水平显著升高。Ceylan等[86]以69例BD患者(15例抑郁状态，27例躁狂状态，27例稳定状态)以及49例健康被试为研究对象，发现BD患者血浆外泌体中miR-484、miR-652-3p、miR-142-3p表达水平下调，miR-185-5p表达水平上调，且在不同临床状态BD患者中的表达水平差异无统计学意义，这4种miRNAs联合应用于BD的诊断具有较高的敏感性与中等的特异性。一项有关BD患者血清外泌体代谢组学的研究[87]中使用高效液相色谱-串联质谱法对32例BD患者、42例SCZ患者、31例MDD患者以及40例健康被试血清外泌体中差异表达的代谢物进行分析，发现共15种代谢物在区分BD患者与其他精神障碍患者和健康被试中表现出良好的准确性，且生信分析提示BD致病机制可能与糖代谢紊乱有关。研究[88]发现：BD患者外周血的外泌体中发现33种miRNAs的差异具有统计学意义，路径分析提示这些变化与神经突起生长导向因子Netrin的轴突导向作用以及5-羟色胺受体途径有关。但这些研究结果因外周血外泌体组织特异性较差不足以代表中枢神经系统的特异性变化。以上研究提示有关外泌体与BD的研究还只是观察性研究，外泌体参与其发病的机制还有待进一步探讨。

3.4. 外泌体与其他精神障碍

物质相关性障碍又称物质成瘾，主要包括阿片类物质、可卡因、苯丙胺兴奋剂以及酒精等物质成瘾，其中以酒精成瘾最为普遍[89]。研究[90]发现：与健康被试相比，海洛因滥用者和甲基苯丙胺滥用者血清外泌体中分别有34个和19个miRNAs的表达水平发生了明显改变。Liu等[91]对酒精成瘾患者的血清外泌体中的circRNAs进行高通量测序，发现有149种circRNAs表达上调以及105种circRNAs表达下调，其中hsa_circ_0004771的表达水平与酒精依赖程度有关，可能是酒精成瘾敏感的生物标志物。音猬因子(sonic hedgehog，SHH)是一种分泌型信号蛋白，SHH信号通路在吗啡诱导的痛觉减退和耐受中起关键作用[92]。研究[93]发现在吗啡耐受小鼠模型脑中星形胶质细胞以及吗啡干预的体外培养星形胶质细胞中所分离出来的外泌体中，SHH信号通路被激活且SHH的蛋白质表达水平明显上调，然而在经GW4869处理的小鼠中，SHH的蛋白质表达水平下调且吗啡未能诱发耐受性。以上研究提示外泌体有望为物质成瘾机制的研究以及物质戒断诊疗方案的制定提供新的视角，但还需要对物质成瘾引起的外泌体分泌及其内容物变化进行全面分析。

孤独症谱系障碍(autism spectrum disorder，ASD)是一种终生性的神经发育障碍，其核心症状是社会交往和交流能力异常、兴趣狭窄和行为刻板[94]。研究[95]发现与健康对照组相比，ASD患儿血清中外泌体的标志蛋白CD81和CD9的表达水平增高，体外实验结果显示ASD患儿血清外泌体会刺激人类小胶质细胞SV40分泌促炎因子白细胞介素-1β。ASD的治疗以康复训练和心理治疗为主，目前尚未发现可有效逆转或改善ASD核心症状的治疗药物[96]。研究[97-98]发现BTBR T+tf/J(BTBR)自闭症模型小鼠以及Shank3B基因敲除小鼠会出现社交互动行为减少、沟通交流行为减少和重复性行为增加等ASD样行为，而在小鼠鼻腔内给予间充质干细胞来源的外泌体(mesenchymal stem cell-derived-exosomes，MSC-exos)能够改善小鼠的ASD样行为，提示MSC-exos具有成为治疗ASD候选药物的潜力。同时，Pretes等[99]利用体内外泌体成像技术观察到在健康小鼠脑中MSC-exos表现为弥散性迁移模式，且MSC-exos在24 h内被清除，而在病理状态(脑卒中、ASD、阿尔茨海默症以及帕金森症)的小鼠脑内，MSC-exos穿过血脑屏障后能够特异性地迁移到病理损伤区域，在BTBR模型小鼠中MSC-exos靶向迁移至前额叶皮层以及小脑，提示外泌体具有靶向递送的能力。

此外，外泌体可能与焦虑症的发生也存在关联。如盐酸异丙肾上腺素能够导致SD大鼠心率加快并诱发焦虑样行为，而EV可能作为信使参与焦虑样行为的发生[100]；Yoon等[101]发现经过4周自主跑轮运动后，小鼠的血清外泌体中有46种miRNAs表达上调和36种miRNAs表达下调，研究者将从自主跑轮运动小鼠血清中分离出来的外泌体立体定位注射进束缚应激致焦虑样行为的小鼠侧脑室内，发现小鼠的焦虑样行为明显改善，提示外泌体可能与自主跑轮运动中抗焦虑作用有关。目前有关外泌体与焦虑症的研究主要以探讨动物焦虑样行为为主，缺乏以焦虑症患者为研究对象的研究，因此外泌体在焦虑症的发病、诊断和治疗中的作用还有待进一步研究。

4. 结 语

外泌体作为一种细胞间物质交换和信息交流的重要载体，是将生物学和精神病理症状联系起来的重要纽带。探究外泌体及其特异性内容物在不同精神障碍中的分子图谱，并对复杂的多组学信息进行整合，有望突破现有诊断方法的限制而捕捉到精神障碍病理生理过程的全貌，实现精神障碍的精准诊断。外泌体具有自然运输特性、良好的生物相容性和靶向能力，通过递送核酸、蛋白质以及基因治疗剂等抗精神病药物，未来可实现精神障碍的精准治疗以及个性化治疗。因此，外泌体有望帮助我们突破目前精神障碍的研究瓶颈，更加深入地研究精神障碍的病理生理机制，为未来精神障碍的早期预防、精确诊断和有效治疗提供客观支持。

目前关于外泌体在精神障碍中的研究尚处于初步阶段，还存在诸多问题亟待解决：1)多数研究仍停留在整个外泌体囊泡层面，对其特异性的内容物缺乏进一步的研究，因此多数研究中主要以外泌体及外泌体miRNAs为主，有关其他外泌体源性非编码RNA、脂质和蛋白质在精神障碍中的研究有限，这也是未来研究的方向之一。2)现有关于外泌体与精神障碍的研究结果异质性较大，可能与外泌体分离纯化方法和miRNA检测方法的不一致有关。3)在诊断过程中的敏感性和特异性尚未被充分验证。如何将大脑病理生理过程与生物标志物的水平联系起来仍然是一个亟待解决的难题，且精神障碍呈现出较高的异质性[102-103]，加大了将生物标志物应用于精神障碍诊断的困难程度。因此，外泌体提取的稳定性也有待改善，如有必要可分选出某种外泌体亚群或细胞来进行研究，并通过大样本的研究来证实某些蛋白质、非编码RNA在精神障碍中的诊断效能。4)在临床治疗过程中的应用潜力还有待进一步开发。血脑屏障的存在使得抗精神病药物难以到达靶点发挥作用，而外泌体可自由通过血脑屏障的特点正好弥补了以往药物难以发挥疗效的不足，将来或许可考虑以外泌体为靶向载体转导miRNAs和circRNAs等进行基因治疗，目前已有的研究仍主要集中在临床前研究，还需进一步的临床转化研究和临床试验验证其实用性和安全性。随着对外泌体的深入研究，外泌体有望成为协助精神障碍患者的早期预防、精准诊断与个性化治疗的一种新型工具。

基金资助

国家自然科学基金(81701333)；湖南省自然科学基金(2022JJ70146)；湖南省研究生科研创新项目(CX20220365)。

This work was supported by the National Natural Science Foundation (81701333), the Natural Science Foundation of Hunan Province (2022JJ70146), and the Hunan Provincial Innovation Foundation for Postgraduate (CX20220365), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

吴佳玲 文献收集与文章撰写；李善斯 文章修改；张逸 写作指导及文章校对。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202305771.pdf

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