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第59卷 第1期 厦门大学学报(自然科学版) Vol59 No1
2020年1月 JournalofXiamenUniversity(NaturalScience) Jan2020
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doi106043jissn0438-0479201907016
middot特约综述middot
细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
江 珊吕 鹏林忠宁刘 刚
(厦门大学公共卫生学院分子疫苗学和分子诊断学国家重点实验室福建 厦门361102)
摘要肝脏是机体代谢外源因素的主要功能性器官其具有独特的血窦结构和丰富的细胞组成而细胞的功能改变是造
成肝毒性损伤的主要原因细胞外囊泡(EVs)是由脂质双分子层所形成的纳米级球形囊泡几乎源自各类细胞用于负载
特定的内容物并可作为载体介导相邻或远处细胞间的信息交流该文综述了外源因素暴露下EVs介导肝毒性损伤进程
中的细胞间通信并探讨靶向干预EVs的具体途径为预防和控制肝毒性损伤提供指导与参考关键词细胞外囊泡细胞间通信肝毒性损伤外源因素靶向干预
中图分类号R543 文献标志码A 文章编号0438-0479(2020)01-0010-09
收稿日期2019-07-13 录用日期2019-10-17 基金项目国家重点研发计划项目(2017YFA0205201)国家自然科学基金(8142202351273165U1705281U1505221)教育部新世纪优秀人
才支持计划项目(ncet-13-0502)通信作者gangliucmitmxmueducn引文格式江珊吕鹏林忠宁等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展[J]厦门大学学报(自然科学
版)202059(1)10-18 CitationJIANGSLVPLINZNetalResearchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinduced
byexogenousfactors[J]JXiamenUnivNatSci202059(1)10-18(inChinese)
肝脏是人体最大的实质性器官承载着物质的合
成分解生物代谢与转化等多种功能外源因素暴露所
致的毒性损伤是大多数肝脏疾病的起始可发展成为肝
硬化肝癌等严重危害公众健康其中肝实质细胞对外
源因素的代谢是肝毒性损伤的始动因素而后通过细胞
间的通信机制将信息传递到非实质细胞进一步加剧肝
毒性损伤细胞外囊泡(extracellularvesiclesEVs)早期
仅被当作细胞运输代谢废物出胞的载体但近年来它们参与细胞间组分交换以达成细胞间信息交流的功能
引起了研究者们的广泛关注并已成为一种参与细胞间
通信的新媒介尤其是在肝脏的病理进程中发挥着重要
的作用[1-3]本文系统阐述了在药物酒精肝炎病毒及
高脂几类外源因素暴露下细胞经诱导产生肝毒性损伤
相关EVs的机制以及潜在的干预靶点以期为外源因
素诱导肝毒性损伤的干预提供理论依据
1 EVs的分类形成和功能
11 EVs的分类
EVs是一组脂质双分子层包绕形成的纳米级球
状膜性囊泡无功能性细胞核是细胞自发或在一定
条件下释放出的一种亚细胞成分主要包括源于内体
(endosome)系统的外泌体(exosome)膜出芽的微囊
泡(microvesicle)和细胞凋亡产生的膜囊泡即凋亡小
体(apoptoticbody)3类[3-7]近年来的研究又发现一个
新的EVs亚群称为癌小体(largeoncosomeLO)[8]LOs由肿瘤细胞膜出芽形成依赖于细胞内蛋白激酶
AKT1和表皮生长因子受体(EGFR)信号通路的激
活[9-10]并与肿瘤的侵袭性直接相关[9-11]根据EVs产
生途径的差异可用独特的标志物分子来区分不同的
亚群(表1)目前关于外泌体和微囊泡的功能研究居
多本文亦着重关注这两个亚群
12 EVs的形成
几乎所有细胞都能够分泌负载丰富内容物的
EVs该过程在从细菌到人类和植物的整个进化过程
中均保守[12-14]其中微囊泡由细胞膜直接出芽形成是磷脂再分布和细胞骨架蛋白收缩之间动态互作的
结果该过程受到胞内钙离子浓度的调控[7]而外泌
体发生需要通过内体途径形成过程相对繁杂需要
借助一系列蛋白质的相互作用以调节EVs内容物的装
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
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表1 EVs分类及标志物
Tab1 ClassificationandmarkersofEVs
分类 来源 直径nm 密度(gmiddotmL-1) 标志物
外泌体 内体 30~150 113~118 四跨膜蛋白Alix微囊泡 膜出芽 150~1000 116~119 整合素CD40凋亡小体 凋亡细胞膜出芽 gt1000 116~128 磷脂酰丝氨酸基因组DNA癌小体 癌细胞膜出芽 1000~10000 110~115 角蛋白CK18
载最后经多囊泡晚期内吞体即多泡体(multivesicularbodyMVB)与质膜融合释放外泌体[15-17](图1)
图1 EVs的形成及释放
Fig1 BiogenesisandsecretionofEVs
13 EVs的内容物组成及功能
细胞产生的EVs可携带大量的生物信息物质包括mRNA非编码RNADNA脂质和蛋白质等目前
Vesiclepedia数据库 (http∥wwwmicrovesiclesorg)中记录了来自于41个物种的共计1254份研究
数据(2018年8月前收录)统计分析出EVs中含有
349988 种蛋白质27646种 mRNAs10520种
miRNAs和639种脂质EVs主要存在于细胞生存的微环境以及生物体
液(血液淋巴液唾液尿液精液及乳汁等)中参与
多种病理进程[3]研究表明肝细胞通过释放EVs调
节肝脏与其他组织间的信息传递同时血液循环中大
量存在的其他细胞来源的EVs也能够将信息运载到
肝组织内[18]EVs将其携带的生物信息运输到周边靶
细胞或经血液循环及体液运输至远处以实现信息
传递[19]一旦附着至靶细胞EVs可触发受体与配体
的结合反应诱导下游信号通路的激活或通过胞吞
或膜融合作用等方式将内容物转移至靶细胞由此改
变靶细胞的生理状态及功能或对靶细胞遗传组进行
重新编排使靶细胞获得新功能或失去某种功能甚至
死亡进而影响疾病的发生及发展[20-21]
2 外源因素经由EVs诱导肝毒性损伤
肝脏血液供应丰富细胞组成亦丰富几乎所有
的肝脏细胞包括肝上皮细胞(即肝细胞和胆管细
胞)天然杀伤(naturalkillerNK)T细胞肝星状细
胞巨噬细胞成体肝干细胞和肝窦内皮细胞均可释
放EVs也可作为EVs的靶细胞[22-26]不同类型细胞
的共存需要建立细胞间通信网络以维持肝脏稳
态[27]大量研究表明EVs与肝脏疾病的发生及发展
相关在药物病毒酒精及脂毒性物质等外源因素刺
激下肝脏内各细胞响应刺激并分泌负载非编码
RNA脂质和蛋白质等内容物的EVs通过细胞间通
信调控靶细胞的信号通路共同导致肝脏毒性损伤因此EVs可作为肝脏疾病诊断及预后判断的潜在新
型生物标志物[28]
21 药 物
肝脏作为药物代谢的核心器官药物代谢产生异
生物质诱导的损伤即为药物性肝损伤(drug-inducedliverinjuryDILI)DILI是一种严重的全球性健康问
题占急性肝功能衰竭病因的50以上[29]例如含有对乙酰氨基酚(acetaminophenAPAP)的化合物是
最常用的处方药APAP蛋白质加合物的形成是
APAP肝毒性的关键特征[30]也是引起DILI最常见
的原因[31]在APAP所致的DILI中已有研究显示
肝脏血清EVs的数量增加且这些EVs中miR-122和白蛋白 mRNA的含量显著增加[32]当 APAP以
300mgkg暴露剂量经腹腔注射入小鼠24h后观察
发现BALBc小鼠肝脏小叶中心坏死并同步检测到
循环EVs数量的增加且其中肝脏特异性标志物
miR-122miR-192和miR-155的含量明显增加[33]双氯芬酸(diclofenacDCF)以400μmolL暴露于肝细
胞36h可改变EVs的释放量及内容物的组成经蛋
白质组学方法筛选发现存在25种特异性差异蛋白这
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些差异蛋白可作为DCF诱导肝损伤的关键因子[30]在D-氨基半乳糖胺(D-galactatosamineGalN)诱导的肝
损伤模型中18h后观察到EVs中AlbGnb2l和Rbp4等肝损伤指标的mRNA水平上调[3034]同时研究发
现源自小鼠肝细胞的EVs含有具活性的异生素代谢
酶如细胞色素P450尿苷-5-二磷酸葡糖醛酸基转移
酶和谷胱甘肽S-转移酶等药物代谢蛋白家族的几个
成员提示EVs可能参与靶细胞中药物和内源性有毒
物质的解毒过程[24]且与DILI密切相关[30]
22 酒 精
长期过量摄入酒精会导致酒精性肝损伤即酒精
性肝病(alcoholicliverdiseaseALD)并可能发展为
酒精性肝炎肝纤维化肝硬化肝癌等[35]ALD最显
著的特征是炎性单核细胞和巨噬细胞群的募集以及
库普夫细胞(KupffercellKC)的激活[36]多项研究
表明酒精性肝炎患者和慢性酒精喂养或急性酒精暴
露小鼠的循环血液中EVs的数量均显著增加[37-40]Verma等[41]的研究表明酒精通过肿瘤坏死因子
(TNF)相关诱导配体(TRAIL)受体-caspase3依赖性
途径诱导肝细胞释放携带CD40L的EVs进而诱导
巨噬细胞的浸润及激活而促炎细胞因子的释放进一
步促进ALD的发生酒精也可以通过诱导源细胞释
放携带miRNA的外泌体介导与其他肝脏细胞的通
信如诱导Huh75细胞释放携带miR-122的外泌体通过抑制HO-1途径并促进单核巨噬细胞对脂多糖
(LPS)刺激的响应上调促炎细胞因子TNF-αIL-1β和NOX2的水平[38]进而介导 ALD的发展提取
ALD小鼠血清EVs并经静脉滴注入未经酒精暴露的
小鼠体内结果显示肝细胞中单核细胞趋化蛋白1(MCP1)表达增强体内KCs(CD11b+F480+)数量增加其中M1型KCs(TNF-α+IL-1223+)百分
比增加M2型KCs(CD163+CD206+)百分比降低同时通过酒精暴露小鼠中循环EVs的蛋白质组学分
析发现EVs携带的热休克蛋白90(HSP90)也可作
为酒精暴露小鼠活化巨噬细胞群的介质[3642]
23 肝炎病毒
在病毒性肝炎的病理过程中EVs参与病毒的播
散宿主免疫抑制以及局部免疫微环境的维持导致
细胞持续感染分离慢性乙型肝炎患者血清中的
EVs发现其负载乙型肝炎病毒(HBV)的核酸和蛋
白同时分离患者的NK细胞也发现存在HBV的核
酸和蛋白表明EVs被NK细胞摄取而 HBV的核
酸可抑制NK细胞表面的模式识别受体表达特别是
视黄酸诱导基因Ⅰ (RIG-Ⅰ)的表达导致核因子κB(NF-κB)和有丝分裂原活化蛋白激酶p38途径的抑
制最终导致NK细胞的免疫功能障碍[43]HBV感染
状态下肝细胞释放 包 裹 具 有 免 疫 调 节 功 能 的
miRNA的EVs并传递至肝脏巨噬细胞抑制巨噬细
胞中IL-12和p35的mRNA表达介导病毒免疫逃逸
的发生[44]Devhare等[45]的研究表明丙型肝炎病毒
(HCV)感染肝细胞释放的外泌体携带miR-19a靶向
肝星状细胞(hepaticstellatecellHSC)经SOCS3-STAT3信号途径激活转化生长因子β(TGF-β)信号
传导诱导肝脏纤维化Cobb等[46]发现HCV感染肝
细胞释放含有TGF-β的外泌体通过扩增生发中心的
T滤泡调节(TfollicularregulatoryTfr)细胞抑制
T滤泡辅助(TfollicularhelperTfh)细胞最终导致
HCV患者中CD4+ T细胞功能失调同时抑制B细
胞产生高亲和力抗体引起抗病毒免疫失调此外Bukong等[47]发现慢性 HCV感染者血清中分离的
EVs包含HCV的RNA可以调节HCV通过非受体
依赖的方式转运到人原代正常肝细胞中
24 高 脂
研究表明脂毒性诱导肝实质细胞释放EVs其作
用于肝非实质细胞如KC和HSC等可促进非酒精性
脂肪性肝病(nonalcoholicfattyliverdiseaseNAFLD)进程[48-49]Hirsova等[50]研究证实在饱和脂肪酸刺激下
肝实质细胞死亡受体(DR5)被激活进而介导caspase8caspase3以及Rho关联含卷曲螺旋结合蛋白激酶1(ROCK1)的依次激活释放携带TRAIL的EVs随后被骨髓来源的巨噬细胞内吞进一步通过激活受体
相互作用蛋白1(RIP1)Fas相关死亡域蛋白(FADD)TNF相关死亡域蛋白(TRADD)和 NF-κB信号通
路上调促炎因子IL-6和IL-1β的表达介导巨噬细
胞炎症反应的发生棕榈酸酯或溶血磷脂酰胆碱可
通过混合谱系激酶3(MLK3)诱导肝细胞释放携带趋
化因子CXCL10的EVs从而诱导单核细胞巨噬细胞
对肝脏的趋化性引起KC的激活以及对外周血淋巴细
胞的招募反应促进非酒精性脂肪性肝炎(nonalcoholicsteatohepatitisNASH)的发生及发展[51-53]Kakazu等[54]发现棕榈酸酯激活内质网应激通过IRE1α-XBP1信号途经介导携带神经酰胺的EVs释放神经
酰胺形成的鞘氨醇-1-磷酸(S1P)再激活巨噬细胞的趋
化性该过程是脂毒性条件下肝脏募集巨噬细胞的潜
在机制脂质过载诱导肝细胞释放包含miR-128-3p的
EVsHSC内化后通过靶向调控过氧化物酶体增殖物
激活受体-γ(PPAR-γ)信号通路促使HSC中胶原蛋
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白α-SMA和TIMP-2等促纤维化因子的mRNA水
平显著上调并分泌细胞外基质及多种细胞因子在肝纤维化进程中起重要作用[3455-56]高脂饮食喂养的
小鼠血清中存在高水平的EVs可被KC吞噬而介导
细胞间通信其中内容物线粒体DNA(mtDNA)可经
干扰素(IFN)调节因子核转录因子激活蛋白1和
NF-κB等信号通路激活KC促进肝炎的发生[57]而富
含TRAIL的EVs有助于巨噬细胞活化导致在营养
过剩的NASH小鼠模型中观察到无菌性炎症反应共同参与肝细胞炎症反应的发生[50]
综上肝实质细胞在药物病毒酒精及脂毒性物
质等多种外源因素刺激下经细胞内相应信号通路诱
导负载miRNA蛋白质病毒核酸等内容物的EVs释
放通过受体-配体相互作用或直接与靶细胞膜融合的
方式释放内容物作用于巨噬细胞HSCNK细胞等
非实质细胞诱导促炎促纤维化相关信号通路的激
活并上调促炎因子IL-6IL-1βTNF-α和促纤维化
相关因子α-SMATGF-β的表达从而介导巨噬细胞
炎症反应及纤维化的发生引起NK细胞免疫功能障
碍最终导致肝脏毒性损伤(图2)
图2 外源因素经EVs诱导肝毒性损伤的相关机制
Fig2 EVs-relatedmechanismsofhepatotoxicdamageinducedbyexogenousfactors
3 EVs的靶向干预及功能化改造策略
细胞间通信是机体实现生理功能的方式也是诸
多病理过程的发生机制[58]近年来EVs作为参与细
胞间通信的新型介质引起了科研界的探索热潮随着肝脏毒理学机制越来越受到关注更深入地了解
EVs参与的细胞间通信对减轻或逆转肝损伤具有重
要意义同时基于EVs的高生物相容性低免疫原性
及高效递送等生物学特性建立起另一套功能化膜囊
泡体系用于小分子多肽及药物的靶向递送也为治疗
策略提供了新方向
31 干预EVs的内容物组成释放及摄取
APAP诱导细胞氧化损伤释放EVs对于其介导
的药物性肝损伤使用抗氧化剂 N-乙酰半胱氨酸
(NAC)或谷胱甘肽(GSH)联合APAP处理小鼠可
使EVs中蛋白质及miR-122等恢复至正常水平一定
程度上预防了肝毒性的发展[37]酒精通过TRAIL受
体-caspase3依赖性途径诱导肝细胞释放携带CD40L的EVs进而诱导巨噬细胞的浸润及激活而caspase3抑制剂IDN-7314可抑制EVs的释放减轻酒精诱导
的肝脏炎症反应[41]HBV感染的肝细胞释放负载病
毒核酸的EVs经过游走可被正常肝细胞摄取加剧
病毒的感染提示阻断EVs的释放可阻止病毒的播
散[4359]饱和脂肪酸刺激可诱导携带TRAIL的EVs释放募集巨噬细胞并激活其促炎性转化导致
NASH的发生及发展使用盐酸法舒地尔(fasudil)抑制ROCK1依赖性EVs释放可减轻饱和脂肪酸诱导
的肝脏炎症反应对NASH模型小鼠施用ROCK1依
赖性EVs释放抑制剂可有效降低循环EVs的数量这与谷丙转氨酶(ALT)谷草转氨酶(AST)等肝脏损
伤血清学指标以及IL-1β等炎性因子水平的降低呈现
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显著相关性减轻了纤维化的发展可据此开发治疗
NASH的策略[50]EVs的释放也依赖于胞内一系列蛋白的作用
Ras相关GTP结合蛋白(RAB)是EVs中常见的胞质
成分也是介导MVB与质膜融合的关键分子通过敲
除RAB基因的表达而抑制其GTPase活性能有效减
少EVs释放[60]此外棕榈酸酯通过MLK3诱导脂毒
性肝细胞释放携带趋化因子CXCL10的EVs诱导单
核细胞或巨噬细胞对肝脏的趋化性而促进炎症的发
展抑制MLK3活性则可以有效降低EVs中CXCL10的蛋白含量从而减少巨噬细胞的活化降低炎性因
子的表达[53]脂质过载诱导包含miR-128-3p的EVs靶向调控HSC中的PPAR-γ促进肝纤维化进程而靶向HSC的miR-128-3p功能化抑制可以逆转脂质诱
导的肝纤维化进程[56]CD40--小鼠经酒精暴露后炎症
反应明显减弱提示阻断EVs与靶细胞的受体-配体
结合可降低EVs介导的损伤[41]将组 装 有 表 皮 生 长 因 子 受 体 Ⅷ(EGFRⅧ)
mRNA的胶质瘤衍生EVs与肝素一起温育可以减
少受体细胞对EVs的摄取抑制促瘤信号向受体细胞
的转移因此肝素可能为研究EV功能提供独特的工
具并作为靶向EVs发挥作用的治疗药物[61]近期的
一项研究显示富含泛酰巯基乙胺酶1(Vanin-1)的EVs在NASH小鼠模型中介导内皮细胞迁移和体外
血管以及新血管形成用针对Vanin-1的中和抗体处
理会明显减少受体细胞对EVs的摄取[62]综上抑制EVs释放调控EVs内容物组成以及
阻断受体细胞对EVs的摄取为基于外源因素暴露下
靶向干预EVs介导的细胞间通信的治疗策略提供了
新契机
32 EVs衍生的功能化囊泡用于靶向递送治疗
EVs的磷脂双分子层稳定结构及纳米级的微小
尺寸能够保护其携带的活性物质免遭巨噬细胞或相
关补体的清除及破坏进而延长循环半衰期增强自
身生物活性因此成为具有高生物相容性低免疫原
性及高效递送的非常有前景的药物递送载体[63]采用纳米工程学方法将EVs作为靶向治疗的天
然载 体装 载 紫 杉 醇(paclitaxel)[64]和 多 柔 比 星
(doxorubicinDox)[65]等化疗药物可提高药物的靶
向性同时也能减少药物在靶点以外部位的聚集从而降低脏器毒性Zhang等[66]研发出一种新型病毒模
拟纳米囊泡(virus-mimeticnanovesicleVMV)由源
自哺乳动物细胞质膜的磷脂通过信号肽分选途径将
重组蛋白锚定至细胞膜并能够控制VMV大小和强
度的表面活性剂组成且VMV能够有效诱导针对活
包膜病毒的抗体产生经VMV接种的小鼠在H1N1病毒(H)致死剂量暴露后仍能存活该研究团队进而
设计了具有靶向配体的生物工程细胞膜纳米囊泡包
封溶瘤病毒(OABCMNs)结果显示OABCMNs可显著抑制针对溶瘤病毒的先天性和适应性免疫应
答且其表面的前S1蛋白(preS1)修饰增强了多种异
种移植肿瘤模型中的靶向递送能力可实现有效的抗
病毒免疫屏蔽并增强溶瘤病毒疗法的靶向性[67]此外将HBV特异性受体人类牛磺胆酸钠共转运多肽
(hNTCP)定向锚定表达至膜囊泡(hNTCP-MVs)可迅速阻断细胞模型的HBV感染从而有效预防HBV感染的人肝嵌合小鼠模型中的病毒感染传播和复
制[68]采用上述定向表达技术Liu等[69]设计了可以
展示全长单克隆抗体(mAb)的新型细胞膜衍生纳米
囊泡(nanovesicleNV)选择性将细胞毒性剂递送至
肿瘤细胞并发挥有效的抑制作用调节肿瘤免疫微环
境上述研究为推动囊泡的功能化设计研发做出了积
极探索对于解决目前棘手的公共卫生学问题具有理
论意义和潜在应用价值尽管目前已有大量研究表明EVs在药物装载及靶
向递送领域具有广阔的应用前景但现今仍然面临诸多
挑战例如EVs生物制品的规模化生产质量控制及安
全性评价等因此其临床转化仍需要走较长一段路[70]
4 总结及展望
EVs介导的细胞间通信在外源因素诱导的肝脏
病理生理过程中发挥着重要作用但如何精确地靶向
调控EVs的内容物组成和释放并阻断外源因素暴露
诱导的肝毒性损伤仍需进一步探索已知特定细胞来
源的EVs具有特异性修复作用如胎盘来源的EVs携带NK淋巴细胞和其他免疫系统组分的抑制性配
体可对胎儿起免疫保护作用[71]纤维化动物模型中
使用人脐带间充质干细胞源性外泌体可减少肝脏组
织中Ⅰ型和Ⅲ型胶原蛋白沉积并通过抑制TGF-βSmad信号通路最终实现细胞纤维化的逆转[72]鉴于
此更多特异性来源的EVs值得进一步的探究特别
是EVs的修饰及药物装载用于靶向递送治疗的深入
研究在EVs的功能化改造过程中供体细胞和EVs的变化可能影响其内容物组成因此还需要进一步探
索能够提高EVs稳定性的操作方式并开展更多的临
床转化实践动物模型及临床试验已证明EVs及其携
带的内容物可被用作鉴定肝脏疾病和监测宿主对各
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种治疗反应的潜在生物标志物因此广泛探索各种疾
病模型下EVs的特异性标志物有望推动EVs作为
肝脏疾病的非侵入性检测手段也可为外源因素诱导
的肝损伤提供有效的干预靶点
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845-854
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Researchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinducedbyexogenousfactors
JIANGShanLUumlPengLINZhongningLIUGang(StateKeyLaboratoryofMolecularVaccinologyandMolecularDiagnostics
SchoolofPublicHealthXiamenUniversityXiamen361102China)
AbstractLiveristhemainmetabolicorganwiththeuniquesinusoidstructureandabundantcelltypeswhichplaysanimportantroleinmetabolizingexogenousfactorsImportantlythefunctionalimpairmentofhepatocytesistheleadingcauseofhepatotoxicdamageExtracellularvesicles(EVs)withnanosizeandlipidbilayermembraneareproducedbyalmostalltypesofcellsEVsserveaspotentialcarriersbyloadingandtransportingspecificmoleculesmediatingcellularcross-talksbetweennearbyordistantcellsInthisreviewwemainlydiscusstheintercellularcommunicationandspecificapproachesoftargetedinterventionsintheprocessofEVs-mediatedhepatotoxicdamageunderexogenousfactorsexposurewhichprovidesfurtherguidanceandreferenceforpreventingandcontrolinghepatotoxicdamage
Keywordsextracellularvesiclesintercellularcommunicationhepatotoxicdamageexogenousfactorstargetedintervention105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
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南强青年学者简介刘刚(1979mdash )博士教授国家杰出青年基金(2019)和优秀青年基金(2014)获得者
入选南强青年拔尖A类人才(2018)中组部万人计划青年拔尖人才(2018)教育部新世纪
人才(2013)福建省科技创新领军人才(2016)现担任中国生物医学工程学会理事中国
生物材料学会理事中华医学会放射学分会分子影像学组副组长长期致力于分子影像探针及药物递送载体系统研发近5年作为通信作者在JCR一
区的PNASNatCommunSciAdvJACSAdvMater等主流期刊上发表论文60余篇并
入选科睿唯安(Clarivate)2019年度全球ldquo高被引科学家rdquo榜单参编全国高校规划教材4部英文专著11部获得国家专利授权7项其中2项已进行企业技术转移及临床转化并获国家或省级科技奖4项
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表1 EVs分类及标志物
Tab1 ClassificationandmarkersofEVs
分类 来源 直径nm 密度(gmiddotmL-1) 标志物
外泌体 内体 30~150 113~118 四跨膜蛋白Alix微囊泡 膜出芽 150~1000 116~119 整合素CD40凋亡小体 凋亡细胞膜出芽 gt1000 116~128 磷脂酰丝氨酸基因组DNA癌小体 癌细胞膜出芽 1000~10000 110~115 角蛋白CK18
载最后经多囊泡晚期内吞体即多泡体(multivesicularbodyMVB)与质膜融合释放外泌体[15-17](图1)
图1 EVs的形成及释放
Fig1 BiogenesisandsecretionofEVs
13 EVs的内容物组成及功能
细胞产生的EVs可携带大量的生物信息物质包括mRNA非编码RNADNA脂质和蛋白质等目前
Vesiclepedia数据库 (http∥wwwmicrovesiclesorg)中记录了来自于41个物种的共计1254份研究
数据(2018年8月前收录)统计分析出EVs中含有
349988 种蛋白质27646种 mRNAs10520种
miRNAs和639种脂质EVs主要存在于细胞生存的微环境以及生物体
液(血液淋巴液唾液尿液精液及乳汁等)中参与
多种病理进程[3]研究表明肝细胞通过释放EVs调
节肝脏与其他组织间的信息传递同时血液循环中大
量存在的其他细胞来源的EVs也能够将信息运载到
肝组织内[18]EVs将其携带的生物信息运输到周边靶
细胞或经血液循环及体液运输至远处以实现信息
传递[19]一旦附着至靶细胞EVs可触发受体与配体
的结合反应诱导下游信号通路的激活或通过胞吞
或膜融合作用等方式将内容物转移至靶细胞由此改
变靶细胞的生理状态及功能或对靶细胞遗传组进行
重新编排使靶细胞获得新功能或失去某种功能甚至
死亡进而影响疾病的发生及发展[20-21]
2 外源因素经由EVs诱导肝毒性损伤
肝脏血液供应丰富细胞组成亦丰富几乎所有
的肝脏细胞包括肝上皮细胞(即肝细胞和胆管细
胞)天然杀伤(naturalkillerNK)T细胞肝星状细
胞巨噬细胞成体肝干细胞和肝窦内皮细胞均可释
放EVs也可作为EVs的靶细胞[22-26]不同类型细胞
的共存需要建立细胞间通信网络以维持肝脏稳
态[27]大量研究表明EVs与肝脏疾病的发生及发展
相关在药物病毒酒精及脂毒性物质等外源因素刺
激下肝脏内各细胞响应刺激并分泌负载非编码
RNA脂质和蛋白质等内容物的EVs通过细胞间通
信调控靶细胞的信号通路共同导致肝脏毒性损伤因此EVs可作为肝脏疾病诊断及预后判断的潜在新
型生物标志物[28]
21 药 物
肝脏作为药物代谢的核心器官药物代谢产生异
生物质诱导的损伤即为药物性肝损伤(drug-inducedliverinjuryDILI)DILI是一种严重的全球性健康问
题占急性肝功能衰竭病因的50以上[29]例如含有对乙酰氨基酚(acetaminophenAPAP)的化合物是
最常用的处方药APAP蛋白质加合物的形成是
APAP肝毒性的关键特征[30]也是引起DILI最常见
的原因[31]在APAP所致的DILI中已有研究显示
肝脏血清EVs的数量增加且这些EVs中miR-122和白蛋白 mRNA的含量显著增加[32]当 APAP以
300mgkg暴露剂量经腹腔注射入小鼠24h后观察
发现BALBc小鼠肝脏小叶中心坏死并同步检测到
循环EVs数量的增加且其中肝脏特异性标志物
miR-122miR-192和miR-155的含量明显增加[33]双氯芬酸(diclofenacDCF)以400μmolL暴露于肝细
胞36h可改变EVs的释放量及内容物的组成经蛋
白质组学方法筛选发现存在25种特异性差异蛋白这
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些差异蛋白可作为DCF诱导肝损伤的关键因子[30]在D-氨基半乳糖胺(D-galactatosamineGalN)诱导的肝
损伤模型中18h后观察到EVs中AlbGnb2l和Rbp4等肝损伤指标的mRNA水平上调[3034]同时研究发
现源自小鼠肝细胞的EVs含有具活性的异生素代谢
酶如细胞色素P450尿苷-5-二磷酸葡糖醛酸基转移
酶和谷胱甘肽S-转移酶等药物代谢蛋白家族的几个
成员提示EVs可能参与靶细胞中药物和内源性有毒
物质的解毒过程[24]且与DILI密切相关[30]
22 酒 精
长期过量摄入酒精会导致酒精性肝损伤即酒精
性肝病(alcoholicliverdiseaseALD)并可能发展为
酒精性肝炎肝纤维化肝硬化肝癌等[35]ALD最显
著的特征是炎性单核细胞和巨噬细胞群的募集以及
库普夫细胞(KupffercellKC)的激活[36]多项研究
表明酒精性肝炎患者和慢性酒精喂养或急性酒精暴
露小鼠的循环血液中EVs的数量均显著增加[37-40]Verma等[41]的研究表明酒精通过肿瘤坏死因子
(TNF)相关诱导配体(TRAIL)受体-caspase3依赖性
途径诱导肝细胞释放携带CD40L的EVs进而诱导
巨噬细胞的浸润及激活而促炎细胞因子的释放进一
步促进ALD的发生酒精也可以通过诱导源细胞释
放携带miRNA的外泌体介导与其他肝脏细胞的通
信如诱导Huh75细胞释放携带miR-122的外泌体通过抑制HO-1途径并促进单核巨噬细胞对脂多糖
(LPS)刺激的响应上调促炎细胞因子TNF-αIL-1β和NOX2的水平[38]进而介导 ALD的发展提取
ALD小鼠血清EVs并经静脉滴注入未经酒精暴露的
小鼠体内结果显示肝细胞中单核细胞趋化蛋白1(MCP1)表达增强体内KCs(CD11b+F480+)数量增加其中M1型KCs(TNF-α+IL-1223+)百分
比增加M2型KCs(CD163+CD206+)百分比降低同时通过酒精暴露小鼠中循环EVs的蛋白质组学分
析发现EVs携带的热休克蛋白90(HSP90)也可作
为酒精暴露小鼠活化巨噬细胞群的介质[3642]
23 肝炎病毒
在病毒性肝炎的病理过程中EVs参与病毒的播
散宿主免疫抑制以及局部免疫微环境的维持导致
细胞持续感染分离慢性乙型肝炎患者血清中的
EVs发现其负载乙型肝炎病毒(HBV)的核酸和蛋
白同时分离患者的NK细胞也发现存在HBV的核
酸和蛋白表明EVs被NK细胞摄取而 HBV的核
酸可抑制NK细胞表面的模式识别受体表达特别是
视黄酸诱导基因Ⅰ (RIG-Ⅰ)的表达导致核因子κB(NF-κB)和有丝分裂原活化蛋白激酶p38途径的抑
制最终导致NK细胞的免疫功能障碍[43]HBV感染
状态下肝细胞释放 包 裹 具 有 免 疫 调 节 功 能 的
miRNA的EVs并传递至肝脏巨噬细胞抑制巨噬细
胞中IL-12和p35的mRNA表达介导病毒免疫逃逸
的发生[44]Devhare等[45]的研究表明丙型肝炎病毒
(HCV)感染肝细胞释放的外泌体携带miR-19a靶向
肝星状细胞(hepaticstellatecellHSC)经SOCS3-STAT3信号途径激活转化生长因子β(TGF-β)信号
传导诱导肝脏纤维化Cobb等[46]发现HCV感染肝
细胞释放含有TGF-β的外泌体通过扩增生发中心的
T滤泡调节(TfollicularregulatoryTfr)细胞抑制
T滤泡辅助(TfollicularhelperTfh)细胞最终导致
HCV患者中CD4+ T细胞功能失调同时抑制B细
胞产生高亲和力抗体引起抗病毒免疫失调此外Bukong等[47]发现慢性 HCV感染者血清中分离的
EVs包含HCV的RNA可以调节HCV通过非受体
依赖的方式转运到人原代正常肝细胞中
24 高 脂
研究表明脂毒性诱导肝实质细胞释放EVs其作
用于肝非实质细胞如KC和HSC等可促进非酒精性
脂肪性肝病(nonalcoholicfattyliverdiseaseNAFLD)进程[48-49]Hirsova等[50]研究证实在饱和脂肪酸刺激下
肝实质细胞死亡受体(DR5)被激活进而介导caspase8caspase3以及Rho关联含卷曲螺旋结合蛋白激酶1(ROCK1)的依次激活释放携带TRAIL的EVs随后被骨髓来源的巨噬细胞内吞进一步通过激活受体
相互作用蛋白1(RIP1)Fas相关死亡域蛋白(FADD)TNF相关死亡域蛋白(TRADD)和 NF-κB信号通
路上调促炎因子IL-6和IL-1β的表达介导巨噬细
胞炎症反应的发生棕榈酸酯或溶血磷脂酰胆碱可
通过混合谱系激酶3(MLK3)诱导肝细胞释放携带趋
化因子CXCL10的EVs从而诱导单核细胞巨噬细胞
对肝脏的趋化性引起KC的激活以及对外周血淋巴细
胞的招募反应促进非酒精性脂肪性肝炎(nonalcoholicsteatohepatitisNASH)的发生及发展[51-53]Kakazu等[54]发现棕榈酸酯激活内质网应激通过IRE1α-XBP1信号途经介导携带神经酰胺的EVs释放神经
酰胺形成的鞘氨醇-1-磷酸(S1P)再激活巨噬细胞的趋
化性该过程是脂毒性条件下肝脏募集巨噬细胞的潜
在机制脂质过载诱导肝细胞释放包含miR-128-3p的
EVsHSC内化后通过靶向调控过氧化物酶体增殖物
激活受体-γ(PPAR-γ)信号通路促使HSC中胶原蛋
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第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
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白α-SMA和TIMP-2等促纤维化因子的mRNA水
平显著上调并分泌细胞外基质及多种细胞因子在肝纤维化进程中起重要作用[3455-56]高脂饮食喂养的
小鼠血清中存在高水平的EVs可被KC吞噬而介导
细胞间通信其中内容物线粒体DNA(mtDNA)可经
干扰素(IFN)调节因子核转录因子激活蛋白1和
NF-κB等信号通路激活KC促进肝炎的发生[57]而富
含TRAIL的EVs有助于巨噬细胞活化导致在营养
过剩的NASH小鼠模型中观察到无菌性炎症反应共同参与肝细胞炎症反应的发生[50]
综上肝实质细胞在药物病毒酒精及脂毒性物
质等多种外源因素刺激下经细胞内相应信号通路诱
导负载miRNA蛋白质病毒核酸等内容物的EVs释
放通过受体-配体相互作用或直接与靶细胞膜融合的
方式释放内容物作用于巨噬细胞HSCNK细胞等
非实质细胞诱导促炎促纤维化相关信号通路的激
活并上调促炎因子IL-6IL-1βTNF-α和促纤维化
相关因子α-SMATGF-β的表达从而介导巨噬细胞
炎症反应及纤维化的发生引起NK细胞免疫功能障
碍最终导致肝脏毒性损伤(图2)
图2 外源因素经EVs诱导肝毒性损伤的相关机制
Fig2 EVs-relatedmechanismsofhepatotoxicdamageinducedbyexogenousfactors
3 EVs的靶向干预及功能化改造策略
细胞间通信是机体实现生理功能的方式也是诸
多病理过程的发生机制[58]近年来EVs作为参与细
胞间通信的新型介质引起了科研界的探索热潮随着肝脏毒理学机制越来越受到关注更深入地了解
EVs参与的细胞间通信对减轻或逆转肝损伤具有重
要意义同时基于EVs的高生物相容性低免疫原性
及高效递送等生物学特性建立起另一套功能化膜囊
泡体系用于小分子多肽及药物的靶向递送也为治疗
策略提供了新方向
31 干预EVs的内容物组成释放及摄取
APAP诱导细胞氧化损伤释放EVs对于其介导
的药物性肝损伤使用抗氧化剂 N-乙酰半胱氨酸
(NAC)或谷胱甘肽(GSH)联合APAP处理小鼠可
使EVs中蛋白质及miR-122等恢复至正常水平一定
程度上预防了肝毒性的发展[37]酒精通过TRAIL受
体-caspase3依赖性途径诱导肝细胞释放携带CD40L的EVs进而诱导巨噬细胞的浸润及激活而caspase3抑制剂IDN-7314可抑制EVs的释放减轻酒精诱导
的肝脏炎症反应[41]HBV感染的肝细胞释放负载病
毒核酸的EVs经过游走可被正常肝细胞摄取加剧
病毒的感染提示阻断EVs的释放可阻止病毒的播
散[4359]饱和脂肪酸刺激可诱导携带TRAIL的EVs释放募集巨噬细胞并激活其促炎性转化导致
NASH的发生及发展使用盐酸法舒地尔(fasudil)抑制ROCK1依赖性EVs释放可减轻饱和脂肪酸诱导
的肝脏炎症反应对NASH模型小鼠施用ROCK1依
赖性EVs释放抑制剂可有效降低循环EVs的数量这与谷丙转氨酶(ALT)谷草转氨酶(AST)等肝脏损
伤血清学指标以及IL-1β等炎性因子水平的降低呈现
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显著相关性减轻了纤维化的发展可据此开发治疗
NASH的策略[50]EVs的释放也依赖于胞内一系列蛋白的作用
Ras相关GTP结合蛋白(RAB)是EVs中常见的胞质
成分也是介导MVB与质膜融合的关键分子通过敲
除RAB基因的表达而抑制其GTPase活性能有效减
少EVs释放[60]此外棕榈酸酯通过MLK3诱导脂毒
性肝细胞释放携带趋化因子CXCL10的EVs诱导单
核细胞或巨噬细胞对肝脏的趋化性而促进炎症的发
展抑制MLK3活性则可以有效降低EVs中CXCL10的蛋白含量从而减少巨噬细胞的活化降低炎性因
子的表达[53]脂质过载诱导包含miR-128-3p的EVs靶向调控HSC中的PPAR-γ促进肝纤维化进程而靶向HSC的miR-128-3p功能化抑制可以逆转脂质诱
导的肝纤维化进程[56]CD40--小鼠经酒精暴露后炎症
反应明显减弱提示阻断EVs与靶细胞的受体-配体
结合可降低EVs介导的损伤[41]将组 装 有 表 皮 生 长 因 子 受 体 Ⅷ(EGFRⅧ)
mRNA的胶质瘤衍生EVs与肝素一起温育可以减
少受体细胞对EVs的摄取抑制促瘤信号向受体细胞
的转移因此肝素可能为研究EV功能提供独特的工
具并作为靶向EVs发挥作用的治疗药物[61]近期的
一项研究显示富含泛酰巯基乙胺酶1(Vanin-1)的EVs在NASH小鼠模型中介导内皮细胞迁移和体外
血管以及新血管形成用针对Vanin-1的中和抗体处
理会明显减少受体细胞对EVs的摄取[62]综上抑制EVs释放调控EVs内容物组成以及
阻断受体细胞对EVs的摄取为基于外源因素暴露下
靶向干预EVs介导的细胞间通信的治疗策略提供了
新契机
32 EVs衍生的功能化囊泡用于靶向递送治疗
EVs的磷脂双分子层稳定结构及纳米级的微小
尺寸能够保护其携带的活性物质免遭巨噬细胞或相
关补体的清除及破坏进而延长循环半衰期增强自
身生物活性因此成为具有高生物相容性低免疫原
性及高效递送的非常有前景的药物递送载体[63]采用纳米工程学方法将EVs作为靶向治疗的天
然载 体装 载 紫 杉 醇(paclitaxel)[64]和 多 柔 比 星
(doxorubicinDox)[65]等化疗药物可提高药物的靶
向性同时也能减少药物在靶点以外部位的聚集从而降低脏器毒性Zhang等[66]研发出一种新型病毒模
拟纳米囊泡(virus-mimeticnanovesicleVMV)由源
自哺乳动物细胞质膜的磷脂通过信号肽分选途径将
重组蛋白锚定至细胞膜并能够控制VMV大小和强
度的表面活性剂组成且VMV能够有效诱导针对活
包膜病毒的抗体产生经VMV接种的小鼠在H1N1病毒(H)致死剂量暴露后仍能存活该研究团队进而
设计了具有靶向配体的生物工程细胞膜纳米囊泡包
封溶瘤病毒(OABCMNs)结果显示OABCMNs可显著抑制针对溶瘤病毒的先天性和适应性免疫应
答且其表面的前S1蛋白(preS1)修饰增强了多种异
种移植肿瘤模型中的靶向递送能力可实现有效的抗
病毒免疫屏蔽并增强溶瘤病毒疗法的靶向性[67]此外将HBV特异性受体人类牛磺胆酸钠共转运多肽
(hNTCP)定向锚定表达至膜囊泡(hNTCP-MVs)可迅速阻断细胞模型的HBV感染从而有效预防HBV感染的人肝嵌合小鼠模型中的病毒感染传播和复
制[68]采用上述定向表达技术Liu等[69]设计了可以
展示全长单克隆抗体(mAb)的新型细胞膜衍生纳米
囊泡(nanovesicleNV)选择性将细胞毒性剂递送至
肿瘤细胞并发挥有效的抑制作用调节肿瘤免疫微环
境上述研究为推动囊泡的功能化设计研发做出了积
极探索对于解决目前棘手的公共卫生学问题具有理
论意义和潜在应用价值尽管目前已有大量研究表明EVs在药物装载及靶
向递送领域具有广阔的应用前景但现今仍然面临诸多
挑战例如EVs生物制品的规模化生产质量控制及安
全性评价等因此其临床转化仍需要走较长一段路[70]
4 总结及展望
EVs介导的细胞间通信在外源因素诱导的肝脏
病理生理过程中发挥着重要作用但如何精确地靶向
调控EVs的内容物组成和释放并阻断外源因素暴露
诱导的肝毒性损伤仍需进一步探索已知特定细胞来
源的EVs具有特异性修复作用如胎盘来源的EVs携带NK淋巴细胞和其他免疫系统组分的抑制性配
体可对胎儿起免疫保护作用[71]纤维化动物模型中
使用人脐带间充质干细胞源性外泌体可减少肝脏组
织中Ⅰ型和Ⅲ型胶原蛋白沉积并通过抑制TGF-βSmad信号通路最终实现细胞纤维化的逆转[72]鉴于
此更多特异性来源的EVs值得进一步的探究特别
是EVs的修饰及药物装载用于靶向递送治疗的深入
研究在EVs的功能化改造过程中供体细胞和EVs的变化可能影响其内容物组成因此还需要进一步探
索能够提高EVs稳定性的操作方式并开展更多的临
床转化实践动物模型及临床试验已证明EVs及其携
带的内容物可被用作鉴定肝脏疾病和监测宿主对各
middot41middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
种治疗反应的潜在生物标志物因此广泛探索各种疾
病模型下EVs的特异性标志物有望推动EVs作为
肝脏疾病的非侵入性检测手段也可为外源因素诱导
的肝损伤提供有效的干预靶点
参考文献[1] COLOMBO MRAPOSO GTHEacuteRY CBiogenesis
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[23] DENGZBZHUANGXJUSetalIntestinalmucus-derived nanoparticle-mediated activation of Wntβ-cateninsignalingplaysaroleininductionoflivernaturalkillerTcellanergyinmice[J]Hepatology201357(3)1250-1261
[24] CONDE-VANCELLS JRODRIGUEZ-SUAREZ E
EMBADENetalCharacterizationandcomprehensiveproteomeprofilingofexosomessecretedbyhepatocytes[J]JProteomeRes20087(12)5157-5166
middot51middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
[25] WITEKRPYANGLLIURSetalLivercell-derivedmicroparticlesactivatehedgehogsignalingandaltergeneexpressioninhepaticendothelialcells[J]Gastroenterology
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middot61middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
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[72] LITFYANYMWANGBYetalExosomesderivedfrom humanumbilicalcord mesenchymalstemcellsalleviateliverfibrosis[J]StemCellsDev201322(6)
845-854
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厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
Researchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinducedbyexogenousfactors
JIANGShanLUumlPengLINZhongningLIUGang(StateKeyLaboratoryofMolecularVaccinologyandMolecularDiagnostics
SchoolofPublicHealthXiamenUniversityXiamen361102China)
AbstractLiveristhemainmetabolicorganwiththeuniquesinusoidstructureandabundantcelltypeswhichplaysanimportantroleinmetabolizingexogenousfactorsImportantlythefunctionalimpairmentofhepatocytesistheleadingcauseofhepatotoxicdamageExtracellularvesicles(EVs)withnanosizeandlipidbilayermembraneareproducedbyalmostalltypesofcellsEVsserveaspotentialcarriersbyloadingandtransportingspecificmoleculesmediatingcellularcross-talksbetweennearbyordistantcellsInthisreviewwemainlydiscusstheintercellularcommunicationandspecificapproachesoftargetedinterventionsintheprocessofEVs-mediatedhepatotoxicdamageunderexogenousfactorsexposurewhichprovidesfurtherguidanceandreferenceforpreventingandcontrolinghepatotoxicdamage
Keywordsextracellularvesiclesintercellularcommunicationhepatotoxicdamageexogenousfactorstargetedintervention105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277 10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
南强青年学者简介刘刚(1979mdash )博士教授国家杰出青年基金(2019)和优秀青年基金(2014)获得者
入选南强青年拔尖A类人才(2018)中组部万人计划青年拔尖人才(2018)教育部新世纪
人才(2013)福建省科技创新领军人才(2016)现担任中国生物医学工程学会理事中国
生物材料学会理事中华医学会放射学分会分子影像学组副组长长期致力于分子影像探针及药物递送载体系统研发近5年作为通信作者在JCR一
区的PNASNatCommunSciAdvJACSAdvMater等主流期刊上发表论文60余篇并
入选科睿唯安(Clarivate)2019年度全球ldquo高被引科学家rdquo榜单参编全国高校规划教材4部英文专著11部获得国家专利授权7项其中2项已进行企业技术转移及临床转化并获国家或省级科技奖4项
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些差异蛋白可作为DCF诱导肝损伤的关键因子[30]在D-氨基半乳糖胺(D-galactatosamineGalN)诱导的肝
损伤模型中18h后观察到EVs中AlbGnb2l和Rbp4等肝损伤指标的mRNA水平上调[3034]同时研究发
现源自小鼠肝细胞的EVs含有具活性的异生素代谢
酶如细胞色素P450尿苷-5-二磷酸葡糖醛酸基转移
酶和谷胱甘肽S-转移酶等药物代谢蛋白家族的几个
成员提示EVs可能参与靶细胞中药物和内源性有毒
物质的解毒过程[24]且与DILI密切相关[30]
22 酒 精
长期过量摄入酒精会导致酒精性肝损伤即酒精
性肝病(alcoholicliverdiseaseALD)并可能发展为
酒精性肝炎肝纤维化肝硬化肝癌等[35]ALD最显
著的特征是炎性单核细胞和巨噬细胞群的募集以及
库普夫细胞(KupffercellKC)的激活[36]多项研究
表明酒精性肝炎患者和慢性酒精喂养或急性酒精暴
露小鼠的循环血液中EVs的数量均显著增加[37-40]Verma等[41]的研究表明酒精通过肿瘤坏死因子
(TNF)相关诱导配体(TRAIL)受体-caspase3依赖性
途径诱导肝细胞释放携带CD40L的EVs进而诱导
巨噬细胞的浸润及激活而促炎细胞因子的释放进一
步促进ALD的发生酒精也可以通过诱导源细胞释
放携带miRNA的外泌体介导与其他肝脏细胞的通
信如诱导Huh75细胞释放携带miR-122的外泌体通过抑制HO-1途径并促进单核巨噬细胞对脂多糖
(LPS)刺激的响应上调促炎细胞因子TNF-αIL-1β和NOX2的水平[38]进而介导 ALD的发展提取
ALD小鼠血清EVs并经静脉滴注入未经酒精暴露的
小鼠体内结果显示肝细胞中单核细胞趋化蛋白1(MCP1)表达增强体内KCs(CD11b+F480+)数量增加其中M1型KCs(TNF-α+IL-1223+)百分
比增加M2型KCs(CD163+CD206+)百分比降低同时通过酒精暴露小鼠中循环EVs的蛋白质组学分
析发现EVs携带的热休克蛋白90(HSP90)也可作
为酒精暴露小鼠活化巨噬细胞群的介质[3642]
23 肝炎病毒
在病毒性肝炎的病理过程中EVs参与病毒的播
散宿主免疫抑制以及局部免疫微环境的维持导致
细胞持续感染分离慢性乙型肝炎患者血清中的
EVs发现其负载乙型肝炎病毒(HBV)的核酸和蛋
白同时分离患者的NK细胞也发现存在HBV的核
酸和蛋白表明EVs被NK细胞摄取而 HBV的核
酸可抑制NK细胞表面的模式识别受体表达特别是
视黄酸诱导基因Ⅰ (RIG-Ⅰ)的表达导致核因子κB(NF-κB)和有丝分裂原活化蛋白激酶p38途径的抑
制最终导致NK细胞的免疫功能障碍[43]HBV感染
状态下肝细胞释放 包 裹 具 有 免 疫 调 节 功 能 的
miRNA的EVs并传递至肝脏巨噬细胞抑制巨噬细
胞中IL-12和p35的mRNA表达介导病毒免疫逃逸
的发生[44]Devhare等[45]的研究表明丙型肝炎病毒
(HCV)感染肝细胞释放的外泌体携带miR-19a靶向
肝星状细胞(hepaticstellatecellHSC)经SOCS3-STAT3信号途径激活转化生长因子β(TGF-β)信号
传导诱导肝脏纤维化Cobb等[46]发现HCV感染肝
细胞释放含有TGF-β的外泌体通过扩增生发中心的
T滤泡调节(TfollicularregulatoryTfr)细胞抑制
T滤泡辅助(TfollicularhelperTfh)细胞最终导致
HCV患者中CD4+ T细胞功能失调同时抑制B细
胞产生高亲和力抗体引起抗病毒免疫失调此外Bukong等[47]发现慢性 HCV感染者血清中分离的
EVs包含HCV的RNA可以调节HCV通过非受体
依赖的方式转运到人原代正常肝细胞中
24 高 脂
研究表明脂毒性诱导肝实质细胞释放EVs其作
用于肝非实质细胞如KC和HSC等可促进非酒精性
脂肪性肝病(nonalcoholicfattyliverdiseaseNAFLD)进程[48-49]Hirsova等[50]研究证实在饱和脂肪酸刺激下
肝实质细胞死亡受体(DR5)被激活进而介导caspase8caspase3以及Rho关联含卷曲螺旋结合蛋白激酶1(ROCK1)的依次激活释放携带TRAIL的EVs随后被骨髓来源的巨噬细胞内吞进一步通过激活受体
相互作用蛋白1(RIP1)Fas相关死亡域蛋白(FADD)TNF相关死亡域蛋白(TRADD)和 NF-κB信号通
路上调促炎因子IL-6和IL-1β的表达介导巨噬细
胞炎症反应的发生棕榈酸酯或溶血磷脂酰胆碱可
通过混合谱系激酶3(MLK3)诱导肝细胞释放携带趋
化因子CXCL10的EVs从而诱导单核细胞巨噬细胞
对肝脏的趋化性引起KC的激活以及对外周血淋巴细
胞的招募反应促进非酒精性脂肪性肝炎(nonalcoholicsteatohepatitisNASH)的发生及发展[51-53]Kakazu等[54]发现棕榈酸酯激活内质网应激通过IRE1α-XBP1信号途经介导携带神经酰胺的EVs释放神经
酰胺形成的鞘氨醇-1-磷酸(S1P)再激活巨噬细胞的趋
化性该过程是脂毒性条件下肝脏募集巨噬细胞的潜
在机制脂质过载诱导肝细胞释放包含miR-128-3p的
EVsHSC内化后通过靶向调控过氧化物酶体增殖物
激活受体-γ(PPAR-γ)信号通路促使HSC中胶原蛋
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白α-SMA和TIMP-2等促纤维化因子的mRNA水
平显著上调并分泌细胞外基质及多种细胞因子在肝纤维化进程中起重要作用[3455-56]高脂饮食喂养的
小鼠血清中存在高水平的EVs可被KC吞噬而介导
细胞间通信其中内容物线粒体DNA(mtDNA)可经
干扰素(IFN)调节因子核转录因子激活蛋白1和
NF-κB等信号通路激活KC促进肝炎的发生[57]而富
含TRAIL的EVs有助于巨噬细胞活化导致在营养
过剩的NASH小鼠模型中观察到无菌性炎症反应共同参与肝细胞炎症反应的发生[50]
综上肝实质细胞在药物病毒酒精及脂毒性物
质等多种外源因素刺激下经细胞内相应信号通路诱
导负载miRNA蛋白质病毒核酸等内容物的EVs释
放通过受体-配体相互作用或直接与靶细胞膜融合的
方式释放内容物作用于巨噬细胞HSCNK细胞等
非实质细胞诱导促炎促纤维化相关信号通路的激
活并上调促炎因子IL-6IL-1βTNF-α和促纤维化
相关因子α-SMATGF-β的表达从而介导巨噬细胞
炎症反应及纤维化的发生引起NK细胞免疫功能障
碍最终导致肝脏毒性损伤(图2)
图2 外源因素经EVs诱导肝毒性损伤的相关机制
Fig2 EVs-relatedmechanismsofhepatotoxicdamageinducedbyexogenousfactors
3 EVs的靶向干预及功能化改造策略
细胞间通信是机体实现生理功能的方式也是诸
多病理过程的发生机制[58]近年来EVs作为参与细
胞间通信的新型介质引起了科研界的探索热潮随着肝脏毒理学机制越来越受到关注更深入地了解
EVs参与的细胞间通信对减轻或逆转肝损伤具有重
要意义同时基于EVs的高生物相容性低免疫原性
及高效递送等生物学特性建立起另一套功能化膜囊
泡体系用于小分子多肽及药物的靶向递送也为治疗
策略提供了新方向
31 干预EVs的内容物组成释放及摄取
APAP诱导细胞氧化损伤释放EVs对于其介导
的药物性肝损伤使用抗氧化剂 N-乙酰半胱氨酸
(NAC)或谷胱甘肽(GSH)联合APAP处理小鼠可
使EVs中蛋白质及miR-122等恢复至正常水平一定
程度上预防了肝毒性的发展[37]酒精通过TRAIL受
体-caspase3依赖性途径诱导肝细胞释放携带CD40L的EVs进而诱导巨噬细胞的浸润及激活而caspase3抑制剂IDN-7314可抑制EVs的释放减轻酒精诱导
的肝脏炎症反应[41]HBV感染的肝细胞释放负载病
毒核酸的EVs经过游走可被正常肝细胞摄取加剧
病毒的感染提示阻断EVs的释放可阻止病毒的播
散[4359]饱和脂肪酸刺激可诱导携带TRAIL的EVs释放募集巨噬细胞并激活其促炎性转化导致
NASH的发生及发展使用盐酸法舒地尔(fasudil)抑制ROCK1依赖性EVs释放可减轻饱和脂肪酸诱导
的肝脏炎症反应对NASH模型小鼠施用ROCK1依
赖性EVs释放抑制剂可有效降低循环EVs的数量这与谷丙转氨酶(ALT)谷草转氨酶(AST)等肝脏损
伤血清学指标以及IL-1β等炎性因子水平的降低呈现
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显著相关性减轻了纤维化的发展可据此开发治疗
NASH的策略[50]EVs的释放也依赖于胞内一系列蛋白的作用
Ras相关GTP结合蛋白(RAB)是EVs中常见的胞质
成分也是介导MVB与质膜融合的关键分子通过敲
除RAB基因的表达而抑制其GTPase活性能有效减
少EVs释放[60]此外棕榈酸酯通过MLK3诱导脂毒
性肝细胞释放携带趋化因子CXCL10的EVs诱导单
核细胞或巨噬细胞对肝脏的趋化性而促进炎症的发
展抑制MLK3活性则可以有效降低EVs中CXCL10的蛋白含量从而减少巨噬细胞的活化降低炎性因
子的表达[53]脂质过载诱导包含miR-128-3p的EVs靶向调控HSC中的PPAR-γ促进肝纤维化进程而靶向HSC的miR-128-3p功能化抑制可以逆转脂质诱
导的肝纤维化进程[56]CD40--小鼠经酒精暴露后炎症
反应明显减弱提示阻断EVs与靶细胞的受体-配体
结合可降低EVs介导的损伤[41]将组 装 有 表 皮 生 长 因 子 受 体 Ⅷ(EGFRⅧ)
mRNA的胶质瘤衍生EVs与肝素一起温育可以减
少受体细胞对EVs的摄取抑制促瘤信号向受体细胞
的转移因此肝素可能为研究EV功能提供独特的工
具并作为靶向EVs发挥作用的治疗药物[61]近期的
一项研究显示富含泛酰巯基乙胺酶1(Vanin-1)的EVs在NASH小鼠模型中介导内皮细胞迁移和体外
血管以及新血管形成用针对Vanin-1的中和抗体处
理会明显减少受体细胞对EVs的摄取[62]综上抑制EVs释放调控EVs内容物组成以及
阻断受体细胞对EVs的摄取为基于外源因素暴露下
靶向干预EVs介导的细胞间通信的治疗策略提供了
新契机
32 EVs衍生的功能化囊泡用于靶向递送治疗
EVs的磷脂双分子层稳定结构及纳米级的微小
尺寸能够保护其携带的活性物质免遭巨噬细胞或相
关补体的清除及破坏进而延长循环半衰期增强自
身生物活性因此成为具有高生物相容性低免疫原
性及高效递送的非常有前景的药物递送载体[63]采用纳米工程学方法将EVs作为靶向治疗的天
然载 体装 载 紫 杉 醇(paclitaxel)[64]和 多 柔 比 星
(doxorubicinDox)[65]等化疗药物可提高药物的靶
向性同时也能减少药物在靶点以外部位的聚集从而降低脏器毒性Zhang等[66]研发出一种新型病毒模
拟纳米囊泡(virus-mimeticnanovesicleVMV)由源
自哺乳动物细胞质膜的磷脂通过信号肽分选途径将
重组蛋白锚定至细胞膜并能够控制VMV大小和强
度的表面活性剂组成且VMV能够有效诱导针对活
包膜病毒的抗体产生经VMV接种的小鼠在H1N1病毒(H)致死剂量暴露后仍能存活该研究团队进而
设计了具有靶向配体的生物工程细胞膜纳米囊泡包
封溶瘤病毒(OABCMNs)结果显示OABCMNs可显著抑制针对溶瘤病毒的先天性和适应性免疫应
答且其表面的前S1蛋白(preS1)修饰增强了多种异
种移植肿瘤模型中的靶向递送能力可实现有效的抗
病毒免疫屏蔽并增强溶瘤病毒疗法的靶向性[67]此外将HBV特异性受体人类牛磺胆酸钠共转运多肽
(hNTCP)定向锚定表达至膜囊泡(hNTCP-MVs)可迅速阻断细胞模型的HBV感染从而有效预防HBV感染的人肝嵌合小鼠模型中的病毒感染传播和复
制[68]采用上述定向表达技术Liu等[69]设计了可以
展示全长单克隆抗体(mAb)的新型细胞膜衍生纳米
囊泡(nanovesicleNV)选择性将细胞毒性剂递送至
肿瘤细胞并发挥有效的抑制作用调节肿瘤免疫微环
境上述研究为推动囊泡的功能化设计研发做出了积
极探索对于解决目前棘手的公共卫生学问题具有理
论意义和潜在应用价值尽管目前已有大量研究表明EVs在药物装载及靶
向递送领域具有广阔的应用前景但现今仍然面临诸多
挑战例如EVs生物制品的规模化生产质量控制及安
全性评价等因此其临床转化仍需要走较长一段路[70]
4 总结及展望
EVs介导的细胞间通信在外源因素诱导的肝脏
病理生理过程中发挥着重要作用但如何精确地靶向
调控EVs的内容物组成和释放并阻断外源因素暴露
诱导的肝毒性损伤仍需进一步探索已知特定细胞来
源的EVs具有特异性修复作用如胎盘来源的EVs携带NK淋巴细胞和其他免疫系统组分的抑制性配
体可对胎儿起免疫保护作用[71]纤维化动物模型中
使用人脐带间充质干细胞源性外泌体可减少肝脏组
织中Ⅰ型和Ⅲ型胶原蛋白沉积并通过抑制TGF-βSmad信号通路最终实现细胞纤维化的逆转[72]鉴于
此更多特异性来源的EVs值得进一步的探究特别
是EVs的修饰及药物装载用于靶向递送治疗的深入
研究在EVs的功能化改造过程中供体细胞和EVs的变化可能影响其内容物组成因此还需要进一步探
索能够提高EVs稳定性的操作方式并开展更多的临
床转化实践动物模型及临床试验已证明EVs及其携
带的内容物可被用作鉴定肝脏疾病和监测宿主对各
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种治疗反应的潜在生物标志物因此广泛探索各种疾
病模型下EVs的特异性标志物有望推动EVs作为
肝脏疾病的非侵入性检测手段也可为外源因素诱导
的肝损伤提供有效的干预靶点
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[23] DENGZBZHUANGXJUSetalIntestinalmucus-derived nanoparticle-mediated activation of Wntβ-cateninsignalingplaysaroleininductionoflivernaturalkillerTcellanergyinmice[J]Hepatology201357(3)1250-1261
[24] CONDE-VANCELLS JRODRIGUEZ-SUAREZ E
EMBADENetalCharacterizationandcomprehensiveproteomeprofilingofexosomessecretedbyhepatocytes[J]JProteomeRes20087(12)5157-5166
middot51middot
厦门大学学报(自然科学版) 2020年
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[25] WITEKRPYANGLLIURSetalLivercell-derivedmicroparticlesactivatehedgehogsignalingandaltergeneexpressioninhepaticendothelialcells[J]Gastroenterology
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Hepaticcell-to-celltransmissionofsmallsilencingRNAcanextendthetherapeuticreachofRNAinterference(RNAi)[J]Gut201261(9)1330-1339
[27] CAISPCHENGXYPANXYetalEmergingroleofexosomesinliverphysiologyandpathology[J]HepatolRes201747(2)194-203
[28] SZABOGMOMEN-HERAVIFExtracellularvesiclesinliverdiseaseandpotentialasbiomarkersandtherapeutictargets[J]NatRevGastroenterolHepatol201714(8)455-466
[29] PALOMOLMLECZKOJEAZKARGORTA MetalAbundanceofcytochromesinhepaticextracellularvesiclesisalteredbydrugsrelatedwithdrug-inducedliverinjury[J]HepatolCommun20182(9)1064-1079
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[31] PATELSJMILWIDJMKINGKRetalGapjunctioninhibition prevents drug-induced livertoxicity andfulminanthepaticfailure[J]NatBiotechnol201230(2)179-183
[32] HOLMANNSMOSEDALE MWOLFKKetalSubtoxicalterationsinhepatocyte-derivedexosomesanearlystepindrug-inducedliverinjury [J]ToxicolSci
2016151(2)365-375[33] CHOYEKIMSHLEEBHetalCirculatingplasma
andexosomalmicroRNAsasindicatorsofdrug-inducedorganinjuryinrodentmodels[J]BiomolTher201725(4)367-373
[34] ROYO FSCHLANGEN KPALOMO LetalTranscriptome ofextracellularvesiclesreleased byhepatocytes[J]PLoSOne20138(7)e68693
[35] STICKELFDATZCHAMPEJetalPathophysiologyandmanagementofalcoholicliverdiseaseupdate2016[J]GutLiver201711(2)173-188
[36] SAHABMOMEN-HERAVIFFURIIetalExtracellularvesiclesfrommicewithalcoholicliverdiseasecarryadistinctproteincargoandinducemacrophageactivationthroughheatshockprotein90[J]Hepatology201867(5)1986-2000
[37] CHOYEIMEJMOONPGetalIncreasedliver-specificproteinsincirculatingextracellularvesiclesas
potentialbiomarkersfordrug-andalcohol-inducedliverinjury[J]PLoSOne201712(2)e0172463
[38] MOMEN-HERAVIFBALASSKODYSKetalExosomes derived from alcohol-treated hepatocyteshorizontallytransferliverspecific miRNA-122 andsensitizemonocytestoLPS[J]SciRep201559991
[39] SAHAMALLONMDiagnosistreatmentandpreventionofhemodialysisemergencies[J]ClinJAmSocNephrol
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MicroRNAcargoofextracellularvesiclesfromalcohol-exposed monocytes signals naive monocytes todifferentiateintoM2macrophages[J]JBiolChem
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[42] EGUCHIALAZARORGWANGJetalExtracellularvesiclesreleasedbyhepatocytesfromgastricinfusionmodelofalcoholicliverdiseasecontainamicroRNAbarcodethatcanbedetectedinblood[J]Hepatology
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hepatitisBvirus (HBV)transmissionand NK-celldysfunction[J]Cell MolImmunol201714(5)
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ExtracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisBvirusinfection[J]FrontImmunol20167335
[45] DEVHAREPBSASAKIRSHRIVASTAVASetalExosome-mediatedintercellularcommunicationbetweenhepatitis C virus-infected hepatocytes and hepaticstellatecells[J]JVirol201791(10)jvi02555-16
[46] COBBD AKIM O KGOLDEN-MASONLetalHepatocyte-derived exosomes promote T follicularregulatorycellexpansion during hepatitis C virusinfection[J]Hepatology201867(1)71-85
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[48] MAJISMATSUDAAYANIKetalExtracellularvesiclesinliverdiseases[J]AmJPhysiolGastrointestLiverPhysiol2017312(3)194-200
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第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
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[49] SCHATTENBERGJMLEEMSExtracellularvesiclesasmessengersbetweenhepatocytesand macrophagesinnonalcoholicsteatohepatitis[J]Gastroenterology2016
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Lipid-inducedsignalingcausesreleaseofinflammatoryextracellularvesiclesfromhepatocytes[J]Gastroente-rology2016150(4)956-967
[51] IBRAHIM H SHIRSOVA PTOMITA KetalCorrectionmixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology
201664(2)70-72[52] TOMITAKKABASHIMAAFREEMANBLetal
Mixedlineagekinase3mediatestheinductionofCXCL10byaSTAT1-dependentmechanismduringhepatocytelipotoxicity[J]2017118(10)3249-3259
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[54] KAKAZUEMAUERASYINMetalHepatocytesreleaseceramide-enrichedpro-inflammatoryextracellularvesiclesinanIRE1α-dependentmanner[J]JLipidRes
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vesiclesanewfrontierinbiomarkerdiscoveryfornon-alcoholicfattyliverdisease[J]IntJMolSci201617(3)376
[56] POVERODPANERA NEGUCHIAetalLipid-inducedhepatocyte-derivedextracellularvesiclesregulatehepaticstellatecellviamicroRNAstargetingPPAR-γ[J]CellMolGastroenterolHepatol20151(6)
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extracellularvesiclesinliverdiseases[J]LiverRes
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[59] LIJHLIUKCLIUYetalExosomesmediatethecell-to-celltransmission of IFN-α-induced antiviralactivity[J]NatImmunol201314(8)793-803
[60] TURTURICIGTINNIRELLORSCONZOGetalExtracellularmembranevesiclesasamechanismofcell-to-cellcommunicationadvantagesand disadvantages[J]AmJPhysiolCellPhysiol2014306(7)C621-C633
[61] ATAINABALAJLVANVEENHetalHeparinblockstransferofextracellularvesiclesbetweendonorandrecipientcells[J]JNeurooncol2013115(3)
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induced toxicity stimulates hepatocytes to releaseangiogenic microparticles thatrequire Vanin-1 foruptakebyendothelialcells[J]SciSignal20136(296)
ra88[63] ZHANGPFLIUGCHENXYNanobiotechnology
cellmembrane-baseddeliverysystems[J]NanoToday
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isincorporated by mesenchymalstromalcellsandreleasedinexosomesthatinhibitinvitrotumorgrowth
anewapproachfordrugdelivery[J]JControlRelease
2014192262-270[65] HADLAMPALAZZOLOSCORONAGetalExosomes
increasethetherapeuticindexofdoxorubicininbreastandovariancancermousemodels[J]Nanomedicine
201611(18)2431-2441[66] ZHANGPFCHENYXZENGYetalVirus-mimetic
nanovesiclesasaversatileantigen-deliverysystem[J]ProcNatlAcadSciUSA2015112(45)E6129-E6138
[67] LUumlPLIUXCHENXMetalGeneticallyengineeredcellmembranenanovesiclesforoncolyticadenovirusdeliveryaversatileplatformforcancervirotherapy[J]NanoLetters201919(5)2993-3001
[68] LIUXYUANLZZHANGLetalBioinspiredartificialnanodecoysforhepatitisBvirus[J]AngewChemIntEdEngl201857(38)12499-12503
[69] LIUXLIUCZHENGZetalVesicularantibodiesabioactive multifunctional combination platform fortargetedtherapeuticdeliveryandcancerimmunotherapy[J]AdvMater201931(17)e1808294
[70] GUDBERGSSONJMJNSSONKSIMONSENJB
etalSystematicreviewoftargetedextracellularvesiclesfordrugdeliveryconsiderationson methodologicalandbiologicalheterogeneity[J]JControlRelease2019
306108-120[71] TOMINAGA NKOSAKA NONO MetalBrain
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[72] LITFYANYMWANGBYetalExosomesderivedfrom humanumbilicalcord mesenchymalstemcellsalleviateliverfibrosis[J]StemCellsDev201322(6)
845-854
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Researchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinducedbyexogenousfactors
JIANGShanLUumlPengLINZhongningLIUGang(StateKeyLaboratoryofMolecularVaccinologyandMolecularDiagnostics
SchoolofPublicHealthXiamenUniversityXiamen361102China)
AbstractLiveristhemainmetabolicorganwiththeuniquesinusoidstructureandabundantcelltypeswhichplaysanimportantroleinmetabolizingexogenousfactorsImportantlythefunctionalimpairmentofhepatocytesistheleadingcauseofhepatotoxicdamageExtracellularvesicles(EVs)withnanosizeandlipidbilayermembraneareproducedbyalmostalltypesofcellsEVsserveaspotentialcarriersbyloadingandtransportingspecificmoleculesmediatingcellularcross-talksbetweennearbyordistantcellsInthisreviewwemainlydiscusstheintercellularcommunicationandspecificapproachesoftargetedinterventionsintheprocessofEVs-mediatedhepatotoxicdamageunderexogenousfactorsexposurewhichprovidesfurtherguidanceandreferenceforpreventingandcontrolinghepatotoxicdamage
Keywordsextracellularvesiclesintercellularcommunicationhepatotoxicdamageexogenousfactorstargetedintervention105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277 10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
南强青年学者简介刘刚(1979mdash )博士教授国家杰出青年基金(2019)和优秀青年基金(2014)获得者
入选南强青年拔尖A类人才(2018)中组部万人计划青年拔尖人才(2018)教育部新世纪
人才(2013)福建省科技创新领军人才(2016)现担任中国生物医学工程学会理事中国
生物材料学会理事中华医学会放射学分会分子影像学组副组长长期致力于分子影像探针及药物递送载体系统研发近5年作为通信作者在JCR一
区的PNASNatCommunSciAdvJACSAdvMater等主流期刊上发表论文60余篇并
入选科睿唯安(Clarivate)2019年度全球ldquo高被引科学家rdquo榜单参编全国高校规划教材4部英文专著11部获得国家专利授权7项其中2项已进行企业技术转移及临床转化并获国家或省级科技奖4项
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第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
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白α-SMA和TIMP-2等促纤维化因子的mRNA水
平显著上调并分泌细胞外基质及多种细胞因子在肝纤维化进程中起重要作用[3455-56]高脂饮食喂养的
小鼠血清中存在高水平的EVs可被KC吞噬而介导
细胞间通信其中内容物线粒体DNA(mtDNA)可经
干扰素(IFN)调节因子核转录因子激活蛋白1和
NF-κB等信号通路激活KC促进肝炎的发生[57]而富
含TRAIL的EVs有助于巨噬细胞活化导致在营养
过剩的NASH小鼠模型中观察到无菌性炎症反应共同参与肝细胞炎症反应的发生[50]
综上肝实质细胞在药物病毒酒精及脂毒性物
质等多种外源因素刺激下经细胞内相应信号通路诱
导负载miRNA蛋白质病毒核酸等内容物的EVs释
放通过受体-配体相互作用或直接与靶细胞膜融合的
方式释放内容物作用于巨噬细胞HSCNK细胞等
非实质细胞诱导促炎促纤维化相关信号通路的激
活并上调促炎因子IL-6IL-1βTNF-α和促纤维化
相关因子α-SMATGF-β的表达从而介导巨噬细胞
炎症反应及纤维化的发生引起NK细胞免疫功能障
碍最终导致肝脏毒性损伤(图2)
图2 外源因素经EVs诱导肝毒性损伤的相关机制
Fig2 EVs-relatedmechanismsofhepatotoxicdamageinducedbyexogenousfactors
3 EVs的靶向干预及功能化改造策略
细胞间通信是机体实现生理功能的方式也是诸
多病理过程的发生机制[58]近年来EVs作为参与细
胞间通信的新型介质引起了科研界的探索热潮随着肝脏毒理学机制越来越受到关注更深入地了解
EVs参与的细胞间通信对减轻或逆转肝损伤具有重
要意义同时基于EVs的高生物相容性低免疫原性
及高效递送等生物学特性建立起另一套功能化膜囊
泡体系用于小分子多肽及药物的靶向递送也为治疗
策略提供了新方向
31 干预EVs的内容物组成释放及摄取
APAP诱导细胞氧化损伤释放EVs对于其介导
的药物性肝损伤使用抗氧化剂 N-乙酰半胱氨酸
(NAC)或谷胱甘肽(GSH)联合APAP处理小鼠可
使EVs中蛋白质及miR-122等恢复至正常水平一定
程度上预防了肝毒性的发展[37]酒精通过TRAIL受
体-caspase3依赖性途径诱导肝细胞释放携带CD40L的EVs进而诱导巨噬细胞的浸润及激活而caspase3抑制剂IDN-7314可抑制EVs的释放减轻酒精诱导
的肝脏炎症反应[41]HBV感染的肝细胞释放负载病
毒核酸的EVs经过游走可被正常肝细胞摄取加剧
病毒的感染提示阻断EVs的释放可阻止病毒的播
散[4359]饱和脂肪酸刺激可诱导携带TRAIL的EVs释放募集巨噬细胞并激活其促炎性转化导致
NASH的发生及发展使用盐酸法舒地尔(fasudil)抑制ROCK1依赖性EVs释放可减轻饱和脂肪酸诱导
的肝脏炎症反应对NASH模型小鼠施用ROCK1依
赖性EVs释放抑制剂可有效降低循环EVs的数量这与谷丙转氨酶(ALT)谷草转氨酶(AST)等肝脏损
伤血清学指标以及IL-1β等炎性因子水平的降低呈现
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厦门大学学报(自然科学版) 2020年
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显著相关性减轻了纤维化的发展可据此开发治疗
NASH的策略[50]EVs的释放也依赖于胞内一系列蛋白的作用
Ras相关GTP结合蛋白(RAB)是EVs中常见的胞质
成分也是介导MVB与质膜融合的关键分子通过敲
除RAB基因的表达而抑制其GTPase活性能有效减
少EVs释放[60]此外棕榈酸酯通过MLK3诱导脂毒
性肝细胞释放携带趋化因子CXCL10的EVs诱导单
核细胞或巨噬细胞对肝脏的趋化性而促进炎症的发
展抑制MLK3活性则可以有效降低EVs中CXCL10的蛋白含量从而减少巨噬细胞的活化降低炎性因
子的表达[53]脂质过载诱导包含miR-128-3p的EVs靶向调控HSC中的PPAR-γ促进肝纤维化进程而靶向HSC的miR-128-3p功能化抑制可以逆转脂质诱
导的肝纤维化进程[56]CD40--小鼠经酒精暴露后炎症
反应明显减弱提示阻断EVs与靶细胞的受体-配体
结合可降低EVs介导的损伤[41]将组 装 有 表 皮 生 长 因 子 受 体 Ⅷ(EGFRⅧ)
mRNA的胶质瘤衍生EVs与肝素一起温育可以减
少受体细胞对EVs的摄取抑制促瘤信号向受体细胞
的转移因此肝素可能为研究EV功能提供独特的工
具并作为靶向EVs发挥作用的治疗药物[61]近期的
一项研究显示富含泛酰巯基乙胺酶1(Vanin-1)的EVs在NASH小鼠模型中介导内皮细胞迁移和体外
血管以及新血管形成用针对Vanin-1的中和抗体处
理会明显减少受体细胞对EVs的摄取[62]综上抑制EVs释放调控EVs内容物组成以及
阻断受体细胞对EVs的摄取为基于外源因素暴露下
靶向干预EVs介导的细胞间通信的治疗策略提供了
新契机
32 EVs衍生的功能化囊泡用于靶向递送治疗
EVs的磷脂双分子层稳定结构及纳米级的微小
尺寸能够保护其携带的活性物质免遭巨噬细胞或相
关补体的清除及破坏进而延长循环半衰期增强自
身生物活性因此成为具有高生物相容性低免疫原
性及高效递送的非常有前景的药物递送载体[63]采用纳米工程学方法将EVs作为靶向治疗的天
然载 体装 载 紫 杉 醇(paclitaxel)[64]和 多 柔 比 星
(doxorubicinDox)[65]等化疗药物可提高药物的靶
向性同时也能减少药物在靶点以外部位的聚集从而降低脏器毒性Zhang等[66]研发出一种新型病毒模
拟纳米囊泡(virus-mimeticnanovesicleVMV)由源
自哺乳动物细胞质膜的磷脂通过信号肽分选途径将
重组蛋白锚定至细胞膜并能够控制VMV大小和强
度的表面活性剂组成且VMV能够有效诱导针对活
包膜病毒的抗体产生经VMV接种的小鼠在H1N1病毒(H)致死剂量暴露后仍能存活该研究团队进而
设计了具有靶向配体的生物工程细胞膜纳米囊泡包
封溶瘤病毒(OABCMNs)结果显示OABCMNs可显著抑制针对溶瘤病毒的先天性和适应性免疫应
答且其表面的前S1蛋白(preS1)修饰增强了多种异
种移植肿瘤模型中的靶向递送能力可实现有效的抗
病毒免疫屏蔽并增强溶瘤病毒疗法的靶向性[67]此外将HBV特异性受体人类牛磺胆酸钠共转运多肽
(hNTCP)定向锚定表达至膜囊泡(hNTCP-MVs)可迅速阻断细胞模型的HBV感染从而有效预防HBV感染的人肝嵌合小鼠模型中的病毒感染传播和复
制[68]采用上述定向表达技术Liu等[69]设计了可以
展示全长单克隆抗体(mAb)的新型细胞膜衍生纳米
囊泡(nanovesicleNV)选择性将细胞毒性剂递送至
肿瘤细胞并发挥有效的抑制作用调节肿瘤免疫微环
境上述研究为推动囊泡的功能化设计研发做出了积
极探索对于解决目前棘手的公共卫生学问题具有理
论意义和潜在应用价值尽管目前已有大量研究表明EVs在药物装载及靶
向递送领域具有广阔的应用前景但现今仍然面临诸多
挑战例如EVs生物制品的规模化生产质量控制及安
全性评价等因此其临床转化仍需要走较长一段路[70]
4 总结及展望
EVs介导的细胞间通信在外源因素诱导的肝脏
病理生理过程中发挥着重要作用但如何精确地靶向
调控EVs的内容物组成和释放并阻断外源因素暴露
诱导的肝毒性损伤仍需进一步探索已知特定细胞来
源的EVs具有特异性修复作用如胎盘来源的EVs携带NK淋巴细胞和其他免疫系统组分的抑制性配
体可对胎儿起免疫保护作用[71]纤维化动物模型中
使用人脐带间充质干细胞源性外泌体可减少肝脏组
织中Ⅰ型和Ⅲ型胶原蛋白沉积并通过抑制TGF-βSmad信号通路最终实现细胞纤维化的逆转[72]鉴于
此更多特异性来源的EVs值得进一步的探究特别
是EVs的修饰及药物装载用于靶向递送治疗的深入
研究在EVs的功能化改造过程中供体细胞和EVs的变化可能影响其内容物组成因此还需要进一步探
索能够提高EVs稳定性的操作方式并开展更多的临
床转化实践动物模型及临床试验已证明EVs及其携
带的内容物可被用作鉴定肝脏疾病和监测宿主对各
middot41middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
种治疗反应的潜在生物标志物因此广泛探索各种疾
病模型下EVs的特异性标志物有望推动EVs作为
肝脏疾病的非侵入性检测手段也可为外源因素诱导
的肝损伤提供有效的干预靶点
参考文献[1] COLOMBO MRAPOSO GTHEacuteRY CBiogenesis
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[23] DENGZBZHUANGXJUSetalIntestinalmucus-derived nanoparticle-mediated activation of Wntβ-cateninsignalingplaysaroleininductionoflivernaturalkillerTcellanergyinmice[J]Hepatology201357(3)1250-1261
[24] CONDE-VANCELLS JRODRIGUEZ-SUAREZ E
EMBADENetalCharacterizationandcomprehensiveproteomeprofilingofexosomessecretedbyhepatocytes[J]JProteomeRes20087(12)5157-5166
middot51middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
[25] WITEKRPYANGLLIURSetalLivercell-derivedmicroparticlesactivatehedgehogsignalingandaltergeneexpressioninhepaticendothelialcells[J]Gastroenterology
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middot61middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
[49] SCHATTENBERGJMLEEMSExtracellularvesiclesasmessengersbetweenhepatocytesand macrophagesinnonalcoholicsteatohepatitis[J]Gastroenterology2016
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[51] IBRAHIM H SHIRSOVA PTOMITA KetalCorrectionmixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology
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[54] KAKAZUEMAUERASYINMetalHepatocytesreleaseceramide-enrichedpro-inflammatoryextracellularvesiclesinanIRE1α-dependentmanner[J]JLipidRes
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ra88[63] ZHANGPFLIUGCHENXYNanobiotechnology
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isincorporated by mesenchymalstromalcellsandreleasedinexosomesthatinhibitinvitrotumorgrowth
anewapproachfordrugdelivery[J]JControlRelease
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nanovesiclesasaversatileantigen-deliverysystem[J]ProcNatlAcadSciUSA2015112(45)E6129-E6138
[67] LUumlPLIUXCHENXMetalGeneticallyengineeredcellmembranenanovesiclesforoncolyticadenovirusdeliveryaversatileplatformforcancervirotherapy[J]NanoLetters201919(5)2993-3001
[68] LIUXYUANLZZHANGLetalBioinspiredartificialnanodecoysforhepatitisBvirus[J]AngewChemIntEdEngl201857(38)12499-12503
[69] LIUXLIUCZHENGZetalVesicularantibodiesabioactive multifunctional combination platform fortargetedtherapeuticdeliveryandcancerimmunotherapy[J]AdvMater201931(17)e1808294
[70] GUDBERGSSONJMJNSSONKSIMONSENJB
etalSystematicreviewoftargetedextracellularvesiclesfordrugdeliveryconsiderationson methodologicalandbiologicalheterogeneity[J]JControlRelease2019
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[72] LITFYANYMWANGBYetalExosomesderivedfrom humanumbilicalcord mesenchymalstemcellsalleviateliverfibrosis[J]StemCellsDev201322(6)
845-854
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厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
Researchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinducedbyexogenousfactors
JIANGShanLUumlPengLINZhongningLIUGang(StateKeyLaboratoryofMolecularVaccinologyandMolecularDiagnostics
SchoolofPublicHealthXiamenUniversityXiamen361102China)
AbstractLiveristhemainmetabolicorganwiththeuniquesinusoidstructureandabundantcelltypeswhichplaysanimportantroleinmetabolizingexogenousfactorsImportantlythefunctionalimpairmentofhepatocytesistheleadingcauseofhepatotoxicdamageExtracellularvesicles(EVs)withnanosizeandlipidbilayermembraneareproducedbyalmostalltypesofcellsEVsserveaspotentialcarriersbyloadingandtransportingspecificmoleculesmediatingcellularcross-talksbetweennearbyordistantcellsInthisreviewwemainlydiscusstheintercellularcommunicationandspecificapproachesoftargetedinterventionsintheprocessofEVs-mediatedhepatotoxicdamageunderexogenousfactorsexposurewhichprovidesfurtherguidanceandreferenceforpreventingandcontrolinghepatotoxicdamage
Keywordsextracellularvesiclesintercellularcommunicationhepatotoxicdamageexogenousfactorstargetedintervention105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277 10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
南强青年学者简介刘刚(1979mdash )博士教授国家杰出青年基金(2019)和优秀青年基金(2014)获得者
入选南强青年拔尖A类人才(2018)中组部万人计划青年拔尖人才(2018)教育部新世纪
人才(2013)福建省科技创新领军人才(2016)现担任中国生物医学工程学会理事中国
生物材料学会理事中华医学会放射学分会分子影像学组副组长长期致力于分子影像探针及药物递送载体系统研发近5年作为通信作者在JCR一
区的PNASNatCommunSciAdvJACSAdvMater等主流期刊上发表论文60余篇并
入选科睿唯安(Clarivate)2019年度全球ldquo高被引科学家rdquo榜单参编全国高校规划教材4部英文专著11部获得国家专利授权7项其中2项已进行企业技术转移及临床转化并获国家或省级科技奖4项
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厦门大学学报(自然科学版) 2020年
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显著相关性减轻了纤维化的发展可据此开发治疗
NASH的策略[50]EVs的释放也依赖于胞内一系列蛋白的作用
Ras相关GTP结合蛋白(RAB)是EVs中常见的胞质
成分也是介导MVB与质膜融合的关键分子通过敲
除RAB基因的表达而抑制其GTPase活性能有效减
少EVs释放[60]此外棕榈酸酯通过MLK3诱导脂毒
性肝细胞释放携带趋化因子CXCL10的EVs诱导单
核细胞或巨噬细胞对肝脏的趋化性而促进炎症的发
展抑制MLK3活性则可以有效降低EVs中CXCL10的蛋白含量从而减少巨噬细胞的活化降低炎性因
子的表达[53]脂质过载诱导包含miR-128-3p的EVs靶向调控HSC中的PPAR-γ促进肝纤维化进程而靶向HSC的miR-128-3p功能化抑制可以逆转脂质诱
导的肝纤维化进程[56]CD40--小鼠经酒精暴露后炎症
反应明显减弱提示阻断EVs与靶细胞的受体-配体
结合可降低EVs介导的损伤[41]将组 装 有 表 皮 生 长 因 子 受 体 Ⅷ(EGFRⅧ)
mRNA的胶质瘤衍生EVs与肝素一起温育可以减
少受体细胞对EVs的摄取抑制促瘤信号向受体细胞
的转移因此肝素可能为研究EV功能提供独特的工
具并作为靶向EVs发挥作用的治疗药物[61]近期的
一项研究显示富含泛酰巯基乙胺酶1(Vanin-1)的EVs在NASH小鼠模型中介导内皮细胞迁移和体外
血管以及新血管形成用针对Vanin-1的中和抗体处
理会明显减少受体细胞对EVs的摄取[62]综上抑制EVs释放调控EVs内容物组成以及
阻断受体细胞对EVs的摄取为基于外源因素暴露下
靶向干预EVs介导的细胞间通信的治疗策略提供了
新契机
32 EVs衍生的功能化囊泡用于靶向递送治疗
EVs的磷脂双分子层稳定结构及纳米级的微小
尺寸能够保护其携带的活性物质免遭巨噬细胞或相
关补体的清除及破坏进而延长循环半衰期增强自
身生物活性因此成为具有高生物相容性低免疫原
性及高效递送的非常有前景的药物递送载体[63]采用纳米工程学方法将EVs作为靶向治疗的天
然载 体装 载 紫 杉 醇(paclitaxel)[64]和 多 柔 比 星
(doxorubicinDox)[65]等化疗药物可提高药物的靶
向性同时也能减少药物在靶点以外部位的聚集从而降低脏器毒性Zhang等[66]研发出一种新型病毒模
拟纳米囊泡(virus-mimeticnanovesicleVMV)由源
自哺乳动物细胞质膜的磷脂通过信号肽分选途径将
重组蛋白锚定至细胞膜并能够控制VMV大小和强
度的表面活性剂组成且VMV能够有效诱导针对活
包膜病毒的抗体产生经VMV接种的小鼠在H1N1病毒(H)致死剂量暴露后仍能存活该研究团队进而
设计了具有靶向配体的生物工程细胞膜纳米囊泡包
封溶瘤病毒(OABCMNs)结果显示OABCMNs可显著抑制针对溶瘤病毒的先天性和适应性免疫应
答且其表面的前S1蛋白(preS1)修饰增强了多种异
种移植肿瘤模型中的靶向递送能力可实现有效的抗
病毒免疫屏蔽并增强溶瘤病毒疗法的靶向性[67]此外将HBV特异性受体人类牛磺胆酸钠共转运多肽
(hNTCP)定向锚定表达至膜囊泡(hNTCP-MVs)可迅速阻断细胞模型的HBV感染从而有效预防HBV感染的人肝嵌合小鼠模型中的病毒感染传播和复
制[68]采用上述定向表达技术Liu等[69]设计了可以
展示全长单克隆抗体(mAb)的新型细胞膜衍生纳米
囊泡(nanovesicleNV)选择性将细胞毒性剂递送至
肿瘤细胞并发挥有效的抑制作用调节肿瘤免疫微环
境上述研究为推动囊泡的功能化设计研发做出了积
极探索对于解决目前棘手的公共卫生学问题具有理
论意义和潜在应用价值尽管目前已有大量研究表明EVs在药物装载及靶
向递送领域具有广阔的应用前景但现今仍然面临诸多
挑战例如EVs生物制品的规模化生产质量控制及安
全性评价等因此其临床转化仍需要走较长一段路[70]
4 总结及展望
EVs介导的细胞间通信在外源因素诱导的肝脏
病理生理过程中发挥着重要作用但如何精确地靶向
调控EVs的内容物组成和释放并阻断外源因素暴露
诱导的肝毒性损伤仍需进一步探索已知特定细胞来
源的EVs具有特异性修复作用如胎盘来源的EVs携带NK淋巴细胞和其他免疫系统组分的抑制性配
体可对胎儿起免疫保护作用[71]纤维化动物模型中
使用人脐带间充质干细胞源性外泌体可减少肝脏组
织中Ⅰ型和Ⅲ型胶原蛋白沉积并通过抑制TGF-βSmad信号通路最终实现细胞纤维化的逆转[72]鉴于
此更多特异性来源的EVs值得进一步的探究特别
是EVs的修饰及药物装载用于靶向递送治疗的深入
研究在EVs的功能化改造过程中供体细胞和EVs的变化可能影响其内容物组成因此还需要进一步探
索能够提高EVs稳定性的操作方式并开展更多的临
床转化实践动物模型及临床试验已证明EVs及其携
带的内容物可被用作鉴定肝脏疾病和监测宿主对各
middot41middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
种治疗反应的潜在生物标志物因此广泛探索各种疾
病模型下EVs的特异性标志物有望推动EVs作为
肝脏疾病的非侵入性检测手段也可为外源因素诱导
的肝损伤提供有效的干预靶点
参考文献[1] COLOMBO MRAPOSO GTHEacuteRY CBiogenesis
secretionandintercellularinteractionsofexosomesandotherextracellularvesicles[J]AnnuRevCellDevBiol
201430(1)255-89[2] YANEZ-MOMSILJANDERPRANDREUZetal
Biologicalpropertiesofextracellularvesiclesandtheirphysiologicalfunctions[J]JExtracellVesicles2015
427066[3] VANNIELGDANGELOGRAPOSOGShedding
lightonthecellbiologyofextracellularvesicles[J]NatRevMolCellBiol201819(4)213-228
[4] MATHIEU MMARTIN-JAULARLAVIEUGetalSpecificitiesofsecretionanduptakeofexosomesandotherextracellularvesiclesforcell-to-cellcommunication[J]NatCellBiol201921(1)9-17
[5] BORRELLID AYANKSON KSHUKLA NetalExtracellularvesicletherapeuticsforliverdisease[J]JControlRelease201827386-98
[6] SHAOHIMHNewtechnologiesforanalysisofextracellularvesicles[J]ChemicalReviews2018118(4)1917-1950
[7] AKERSJCGONDADKIM RetalBiogenesisofextracellularvesicles (EV)exosomesmicrovesicles
retrovirus-likevesiclesand apoptotic bodies[J]JNeurooncol2013113(1)1-11
[8] MEEHANBRAKJDIVIZIODOncosomeslargeandsmallwhataretheywheretheycamefrom [J]JExtracellVesicles20165(1)33109
[9] MINCIACCHIVRYOUSSPINELLICetalLargeoncosomescontaindistinctproteincargoandrepresentaseparatefunctionalclassoftumor-derivedextracellularvesicles[J]Oncotarget20156(13)11327-11341
[10] DIVIZIODMORELLOMDUDLEYACetalLargeoncosomesinhumanprostatecancertissuesandinthecirculationofmicewithmetastaticdisease[J]AmJPathol2012181(5)1573-1584
[11] MORELLOMMINCIACCHIVRDECANDIAPetalLargeoncosomesmediateintercellulartransferoffunctionalmicroRNA[J]CellCycle201312(22)
3526-3536[12] SCHOREYJSCHENGYSINGHPPetalExosomes
andotherextracellularvesiclesinhost-pathogeninteractions
[J]EMBORep201516(1)24-43[13] DEATHERAGEBLCOOKSONBTMembranevesicle
releaseinbacteriaeukaryotesandarchaeaaconservedyetunderappreciatedaspectofmicrobiallife[J]InfectImmun201280(6)1948-1957
[14] ROBINSONDGDINGYJIANGLUnconventionalproteinsecretioninplantsacriticalassessment[J]Protoplasma2016253(1)31-43
[15] CHOUDHURIKLLODRAacuteJROTHEWetalPolarizedreleaseofT-cell-receptor-enrichedmicrovesiclesattheimmunologicalsynapse[J]Nature2014507(7490)
118-123[16] NABHANJFHUROHRSetalFormationand
releaseofarrestindomain-containingprotein1-mediatedmicrovesicles (ARMMs)atplasma membrane byrecruitmentofTSG101protein[J]ProcNatlAcadSciUSA2012109(11)4146-4151
[17] COLOMBOMMOITACVANNIELGetalAnalysisofESCRTfunctionsinexosomebiogenesiscompositionandsecretionhighlightstheheterogeneityofextracellularvesicles[J]JCellSci2013126(Pt24)5553-5565
[18] MOHANKUMARSPATELTExtracellularvesiclelongnoncodingRNAaspotentialbiomarkersoflivercancer[J]BriefFunctGenomics201615(3)249-256
[19] LILPIONTEKKISHIDAMetalExtracellularvesiclescarrymicroRNA-195tointrahepaticcholangiocarcinomaandimprovesurvivalinaratmodel[J]Hepatology
201765(2)501-514[20] ARRAUDNLINARESRTANSetalExtracellular
vesiclesfrom blood plasmadetermination oftheirmorphologysizephenotypeandconcentration[J]JThrombHaemost201412(5)614-627
[21] SATOKMENGFYGLASERSetalExosomesinliverpathology[J]JHepatol201665(1)213-221
[22] MASYUKAIHUANGBQWARDCJetalBiliaryexosomesinfluencecholangiocyteregulatorymechanismsandproliferationthroughinteractionwithprimarycilia[J]AmJPhysiolGastrointestLiverPhysiol2010299(4)G990-9
[23] DENGZBZHUANGXJUSetalIntestinalmucus-derived nanoparticle-mediated activation of Wntβ-cateninsignalingplaysaroleininductionoflivernaturalkillerTcellanergyinmice[J]Hepatology201357(3)1250-1261
[24] CONDE-VANCELLS JRODRIGUEZ-SUAREZ E
EMBADENetalCharacterizationandcomprehensiveproteomeprofilingofexosomessecretedbyhepatocytes[J]JProteomeRes20087(12)5157-5166
middot51middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
[25] WITEKRPYANGLLIURSetalLivercell-derivedmicroparticlesactivatehedgehogsignalingandaltergeneexpressioninhepaticendothelialcells[J]Gastroenterology
2009136(1)320-330[26] PANQRAMAKRISHNAIAH VHENRYSetal
Hepaticcell-to-celltransmissionofsmallsilencingRNAcanextendthetherapeuticreachofRNAinterference(RNAi)[J]Gut201261(9)1330-1339
[27] CAISPCHENGXYPANXYetalEmergingroleofexosomesinliverphysiologyandpathology[J]HepatolRes201747(2)194-203
[28] SZABOGMOMEN-HERAVIFExtracellularvesiclesinliverdiseaseandpotentialasbiomarkersandtherapeutictargets[J]NatRevGastroenterolHepatol201714(8)455-466
[29] PALOMOLMLECZKOJEAZKARGORTA MetalAbundanceofcytochromesinhepaticextracellularvesiclesisalteredbydrugsrelatedwithdrug-inducedliverinjury[J]HepatolCommun20182(9)1064-1079
[30] DUANLQRAMACHANDRANAAKAKPOJYetalRoleofextracellularvesiclesinreleaseofproteinadductsafteracetaminophen-inducedliverinjuryinmiceandhumans[J]ToxicolLett2019301125-132
[31] PATELSJMILWIDJMKINGKRetalGapjunctioninhibition prevents drug-induced livertoxicity andfulminanthepaticfailure[J]NatBiotechnol201230(2)179-183
[32] HOLMANNSMOSEDALE MWOLFKKetalSubtoxicalterationsinhepatocyte-derivedexosomesanearlystepindrug-inducedliverinjury [J]ToxicolSci
2016151(2)365-375[33] CHOYEKIMSHLEEBHetalCirculatingplasma
andexosomalmicroRNAsasindicatorsofdrug-inducedorganinjuryinrodentmodels[J]BiomolTher201725(4)367-373
[34] ROYO FSCHLANGEN KPALOMO LetalTranscriptome ofextracellularvesiclesreleased byhepatocytes[J]PLoSOne20138(7)e68693
[35] STICKELFDATZCHAMPEJetalPathophysiologyandmanagementofalcoholicliverdiseaseupdate2016[J]GutLiver201711(2)173-188
[36] SAHABMOMEN-HERAVIFFURIIetalExtracellularvesiclesfrommicewithalcoholicliverdiseasecarryadistinctproteincargoandinducemacrophageactivationthroughheatshockprotein90[J]Hepatology201867(5)1986-2000
[37] CHOYEIMEJMOONPGetalIncreasedliver-specificproteinsincirculatingextracellularvesiclesas
potentialbiomarkersfordrug-andalcohol-inducedliverinjury[J]PLoSOne201712(2)e0172463
[38] MOMEN-HERAVIFBALASSKODYSKetalExosomes derived from alcohol-treated hepatocyteshorizontallytransferliverspecific miRNA-122 andsensitizemonocytestoLPS[J]SciRep201559991
[39] SAHAMALLONMDiagnosistreatmentandpreventionofhemodialysisemergencies[J]ClinJAmSocNephrol
201712(2)357-369[40] SAHABMOMEN-HERAVIFKODYS Ketal
MicroRNAcargoofextracellularvesiclesfromalcohol-exposed monocytes signals naive monocytes todifferentiateintoM2macrophages[J]JBiolChem
2016291(1)149-159[41] VERMAVKLIHYWANGRSetalAlcoholstimulates
macrophage activation through caspase-dependenthepatocyte derived release of CD40L containingextracellularvesicles[J]JHepatol201664(3)651-660
[42] EGUCHIALAZARORGWANGJetalExtracellularvesiclesreleasedbyhepatocytesfromgastricinfusionmodelofalcoholicliverdiseasecontainamicroRNAbarcodethatcanbedetectedinblood[J]Hepatology
201765(2)475-490[43] YANGYLHANQJHOUZHetalExosomesmediate
hepatitisBvirus (HBV)transmissionand NK-celldysfunction[J]Cell MolImmunol201714(5)
465-475[44] KOUWAKITFUKUSHIMA YDAITO Tetal
ExtracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisBvirusinfection[J]FrontImmunol20167335
[45] DEVHAREPBSASAKIRSHRIVASTAVASetalExosome-mediatedintercellularcommunicationbetweenhepatitis C virus-infected hepatocytes and hepaticstellatecells[J]JVirol201791(10)jvi02555-16
[46] COBBD AKIM O KGOLDEN-MASONLetalHepatocyte-derived exosomes promote T follicularregulatorycellexpansion during hepatitis C virusinfection[J]Hepatology201867(1)71-85
[47] BUKONGTNMOMEN-HERAVIFKODYSKetalExosomesfromhepatitisCinfectedpatientstransmitHCVinfectionandcontainreplicationcompetentviralRNAincomplexwithAgo2-miR122-HSP90[J]PLoSPathog201410(10)1004424
[48] MAJISMATSUDAAYANIKetalExtracellularvesiclesinliverdiseases[J]AmJPhysiolGastrointestLiverPhysiol2017312(3)194-200
middot61middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
[49] SCHATTENBERGJMLEEMSExtracellularvesiclesasmessengersbetweenhepatocytesand macrophagesinnonalcoholicsteatohepatitis[J]Gastroenterology2016
150(4)815-818[50] HIRSOVAPIBRAHIMSHKRISHNANAetal
Lipid-inducedsignalingcausesreleaseofinflammatoryextracellularvesiclesfromhepatocytes[J]Gastroente-rology2016150(4)956-967
[51] IBRAHIM H SHIRSOVA PTOMITA KetalCorrectionmixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology
201664(2)70-72[52] TOMITAKKABASHIMAAFREEMANBLetal
Mixedlineagekinase3mediatestheinductionofCXCL10byaSTAT1-dependentmechanismduringhepatocytelipotoxicity[J]2017118(10)3249-3259
[53] IBRAHIMSHHIRSOVAPTOMITAKetalMixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology201663(3)731-744
[54] KAKAZUEMAUERASYINMetalHepatocytesreleaseceramide-enrichedpro-inflammatoryextracellularvesiclesinanIRE1α-dependentmanner[J]JLipidRes
201657(2)233-245[55] BANLDSHACKELNAMCLENNANSVExtracellular
vesiclesanewfrontierinbiomarkerdiscoveryfornon-alcoholicfattyliverdisease[J]IntJMolSci201617(3)376
[56] POVERODPANERA NEGUCHIAetalLipid-inducedhepatocyte-derivedextracellularvesiclesregulatehepaticstellatecellviamicroRNAstargetingPPAR-γ[J]CellMolGastroenterolHepatol20151(6)
646-663[57] DENGFMAGEENZHANGYDecodingtheroleof
extracellularvesiclesinliverdiseases[J]LiverRes
20171(3)147-155[58] PERUMPAILBJKHAN M AYOO E Retal
Clinicalepidemiologyanddiseaseburdenofnonalcoholicfattyliverdisease[J]WorldJGastroenterol201723(47)8263-8276
[59] LIJHLIUKCLIUYetalExosomesmediatethecell-to-celltransmission of IFN-α-induced antiviralactivity[J]NatImmunol201314(8)793-803
[60] TURTURICIGTINNIRELLORSCONZOGetalExtracellularmembranevesiclesasamechanismofcell-to-cellcommunicationadvantagesand disadvantages[J]AmJPhysiolCellPhysiol2014306(7)C621-C633
[61] ATAINABALAJLVANVEENHetalHeparinblockstransferofextracellularvesiclesbetweendonorandrecipientcells[J]JNeurooncol2013115(3)
343-351[62] POVERODEGUCHIANIESMANIRetalLipid-
induced toxicity stimulates hepatocytes to releaseangiogenic microparticles thatrequire Vanin-1 foruptakebyendothelialcells[J]SciSignal20136(296)
ra88[63] ZHANGPFLIUGCHENXYNanobiotechnology
cellmembrane-baseddeliverysystems[J]NanoToday
2017137-9[64] PASCUCCILCOCCEgraveVBONOMIAetalPaclitaxel
isincorporated by mesenchymalstromalcellsandreleasedinexosomesthatinhibitinvitrotumorgrowth
anewapproachfordrugdelivery[J]JControlRelease
2014192262-270[65] HADLAMPALAZZOLOSCORONAGetalExosomes
increasethetherapeuticindexofdoxorubicininbreastandovariancancermousemodels[J]Nanomedicine
201611(18)2431-2441[66] ZHANGPFCHENYXZENGYetalVirus-mimetic
nanovesiclesasaversatileantigen-deliverysystem[J]ProcNatlAcadSciUSA2015112(45)E6129-E6138
[67] LUumlPLIUXCHENXMetalGeneticallyengineeredcellmembranenanovesiclesforoncolyticadenovirusdeliveryaversatileplatformforcancervirotherapy[J]NanoLetters201919(5)2993-3001
[68] LIUXYUANLZZHANGLetalBioinspiredartificialnanodecoysforhepatitisBvirus[J]AngewChemIntEdEngl201857(38)12499-12503
[69] LIUXLIUCZHENGZetalVesicularantibodiesabioactive multifunctional combination platform fortargetedtherapeuticdeliveryandcancerimmunotherapy[J]AdvMater201931(17)e1808294
[70] GUDBERGSSONJMJNSSONKSIMONSENJB
etalSystematicreviewoftargetedextracellularvesiclesfordrugdeliveryconsiderationson methodologicalandbiologicalheterogeneity[J]JControlRelease2019
306108-120[71] TOMINAGA NKOSAKA NONO MetalBrain
metastaticcancercellsreleasemicroRNA-181c-containingextracellularvesiclescapableofdestructingblood-brainbarrier[J]NatCommun201566716
[72] LITFYANYMWANGBYetalExosomesderivedfrom humanumbilicalcord mesenchymalstemcellsalleviateliverfibrosis[J]StemCellsDev201322(6)
845-854
middot71middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
Researchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinducedbyexogenousfactors
JIANGShanLUumlPengLINZhongningLIUGang(StateKeyLaboratoryofMolecularVaccinologyandMolecularDiagnostics
SchoolofPublicHealthXiamenUniversityXiamen361102China)
AbstractLiveristhemainmetabolicorganwiththeuniquesinusoidstructureandabundantcelltypeswhichplaysanimportantroleinmetabolizingexogenousfactorsImportantlythefunctionalimpairmentofhepatocytesistheleadingcauseofhepatotoxicdamageExtracellularvesicles(EVs)withnanosizeandlipidbilayermembraneareproducedbyalmostalltypesofcellsEVsserveaspotentialcarriersbyloadingandtransportingspecificmoleculesmediatingcellularcross-talksbetweennearbyordistantcellsInthisreviewwemainlydiscusstheintercellularcommunicationandspecificapproachesoftargetedinterventionsintheprocessofEVs-mediatedhepatotoxicdamageunderexogenousfactorsexposurewhichprovidesfurtherguidanceandreferenceforpreventingandcontrolinghepatotoxicdamage
Keywordsextracellularvesiclesintercellularcommunicationhepatotoxicdamageexogenousfactorstargetedintervention105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277 10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
南强青年学者简介刘刚(1979mdash )博士教授国家杰出青年基金(2019)和优秀青年基金(2014)获得者
入选南强青年拔尖A类人才(2018)中组部万人计划青年拔尖人才(2018)教育部新世纪
人才(2013)福建省科技创新领军人才(2016)现担任中国生物医学工程学会理事中国
生物材料学会理事中华医学会放射学分会分子影像学组副组长长期致力于分子影像探针及药物递送载体系统研发近5年作为通信作者在JCR一
区的PNASNatCommunSciAdvJACSAdvMater等主流期刊上发表论文60余篇并
入选科睿唯安(Clarivate)2019年度全球ldquo高被引科学家rdquo榜单参编全国高校规划教材4部英文专著11部获得国家专利授权7项其中2项已进行企业技术转移及临床转化并获国家或省级科技奖4项
middot81middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
种治疗反应的潜在生物标志物因此广泛探索各种疾
病模型下EVs的特异性标志物有望推动EVs作为
肝脏疾病的非侵入性检测手段也可为外源因素诱导
的肝损伤提供有效的干预靶点
参考文献[1] COLOMBO MRAPOSO GTHEacuteRY CBiogenesis
secretionandintercellularinteractionsofexosomesandotherextracellularvesicles[J]AnnuRevCellDevBiol
201430(1)255-89[2] YANEZ-MOMSILJANDERPRANDREUZetal
Biologicalpropertiesofextracellularvesiclesandtheirphysiologicalfunctions[J]JExtracellVesicles2015
427066[3] VANNIELGDANGELOGRAPOSOGShedding
lightonthecellbiologyofextracellularvesicles[J]NatRevMolCellBiol201819(4)213-228
[4] MATHIEU MMARTIN-JAULARLAVIEUGetalSpecificitiesofsecretionanduptakeofexosomesandotherextracellularvesiclesforcell-to-cellcommunication[J]NatCellBiol201921(1)9-17
[5] BORRELLID AYANKSON KSHUKLA NetalExtracellularvesicletherapeuticsforliverdisease[J]JControlRelease201827386-98
[6] SHAOHIMHNewtechnologiesforanalysisofextracellularvesicles[J]ChemicalReviews2018118(4)1917-1950
[7] AKERSJCGONDADKIM RetalBiogenesisofextracellularvesicles (EV)exosomesmicrovesicles
retrovirus-likevesiclesand apoptotic bodies[J]JNeurooncol2013113(1)1-11
[8] MEEHANBRAKJDIVIZIODOncosomeslargeandsmallwhataretheywheretheycamefrom [J]JExtracellVesicles20165(1)33109
[9] MINCIACCHIVRYOUSSPINELLICetalLargeoncosomescontaindistinctproteincargoandrepresentaseparatefunctionalclassoftumor-derivedextracellularvesicles[J]Oncotarget20156(13)11327-11341
[10] DIVIZIODMORELLOMDUDLEYACetalLargeoncosomesinhumanprostatecancertissuesandinthecirculationofmicewithmetastaticdisease[J]AmJPathol2012181(5)1573-1584
[11] MORELLOMMINCIACCHIVRDECANDIAPetalLargeoncosomesmediateintercellulartransferoffunctionalmicroRNA[J]CellCycle201312(22)
3526-3536[12] SCHOREYJSCHENGYSINGHPPetalExosomes
andotherextracellularvesiclesinhost-pathogeninteractions
[J]EMBORep201516(1)24-43[13] DEATHERAGEBLCOOKSONBTMembranevesicle
releaseinbacteriaeukaryotesandarchaeaaconservedyetunderappreciatedaspectofmicrobiallife[J]InfectImmun201280(6)1948-1957
[14] ROBINSONDGDINGYJIANGLUnconventionalproteinsecretioninplantsacriticalassessment[J]Protoplasma2016253(1)31-43
[15] CHOUDHURIKLLODRAacuteJROTHEWetalPolarizedreleaseofT-cell-receptor-enrichedmicrovesiclesattheimmunologicalsynapse[J]Nature2014507(7490)
118-123[16] NABHANJFHUROHRSetalFormationand
releaseofarrestindomain-containingprotein1-mediatedmicrovesicles (ARMMs)atplasma membrane byrecruitmentofTSG101protein[J]ProcNatlAcadSciUSA2012109(11)4146-4151
[17] COLOMBOMMOITACVANNIELGetalAnalysisofESCRTfunctionsinexosomebiogenesiscompositionandsecretionhighlightstheheterogeneityofextracellularvesicles[J]JCellSci2013126(Pt24)5553-5565
[18] MOHANKUMARSPATELTExtracellularvesiclelongnoncodingRNAaspotentialbiomarkersoflivercancer[J]BriefFunctGenomics201615(3)249-256
[19] LILPIONTEKKISHIDAMetalExtracellularvesiclescarrymicroRNA-195tointrahepaticcholangiocarcinomaandimprovesurvivalinaratmodel[J]Hepatology
201765(2)501-514[20] ARRAUDNLINARESRTANSetalExtracellular
vesiclesfrom blood plasmadetermination oftheirmorphologysizephenotypeandconcentration[J]JThrombHaemost201412(5)614-627
[21] SATOKMENGFYGLASERSetalExosomesinliverpathology[J]JHepatol201665(1)213-221
[22] MASYUKAIHUANGBQWARDCJetalBiliaryexosomesinfluencecholangiocyteregulatorymechanismsandproliferationthroughinteractionwithprimarycilia[J]AmJPhysiolGastrointestLiverPhysiol2010299(4)G990-9
[23] DENGZBZHUANGXJUSetalIntestinalmucus-derived nanoparticle-mediated activation of Wntβ-cateninsignalingplaysaroleininductionoflivernaturalkillerTcellanergyinmice[J]Hepatology201357(3)1250-1261
[24] CONDE-VANCELLS JRODRIGUEZ-SUAREZ E
EMBADENetalCharacterizationandcomprehensiveproteomeprofilingofexosomessecretedbyhepatocytes[J]JProteomeRes20087(12)5157-5166
middot51middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
[25] WITEKRPYANGLLIURSetalLivercell-derivedmicroparticlesactivatehedgehogsignalingandaltergeneexpressioninhepaticendothelialcells[J]Gastroenterology
2009136(1)320-330[26] PANQRAMAKRISHNAIAH VHENRYSetal
Hepaticcell-to-celltransmissionofsmallsilencingRNAcanextendthetherapeuticreachofRNAinterference(RNAi)[J]Gut201261(9)1330-1339
[27] CAISPCHENGXYPANXYetalEmergingroleofexosomesinliverphysiologyandpathology[J]HepatolRes201747(2)194-203
[28] SZABOGMOMEN-HERAVIFExtracellularvesiclesinliverdiseaseandpotentialasbiomarkersandtherapeutictargets[J]NatRevGastroenterolHepatol201714(8)455-466
[29] PALOMOLMLECZKOJEAZKARGORTA MetalAbundanceofcytochromesinhepaticextracellularvesiclesisalteredbydrugsrelatedwithdrug-inducedliverinjury[J]HepatolCommun20182(9)1064-1079
[30] DUANLQRAMACHANDRANAAKAKPOJYetalRoleofextracellularvesiclesinreleaseofproteinadductsafteracetaminophen-inducedliverinjuryinmiceandhumans[J]ToxicolLett2019301125-132
[31] PATELSJMILWIDJMKINGKRetalGapjunctioninhibition prevents drug-induced livertoxicity andfulminanthepaticfailure[J]NatBiotechnol201230(2)179-183
[32] HOLMANNSMOSEDALE MWOLFKKetalSubtoxicalterationsinhepatocyte-derivedexosomesanearlystepindrug-inducedliverinjury [J]ToxicolSci
2016151(2)365-375[33] CHOYEKIMSHLEEBHetalCirculatingplasma
andexosomalmicroRNAsasindicatorsofdrug-inducedorganinjuryinrodentmodels[J]BiomolTher201725(4)367-373
[34] ROYO FSCHLANGEN KPALOMO LetalTranscriptome ofextracellularvesiclesreleased byhepatocytes[J]PLoSOne20138(7)e68693
[35] STICKELFDATZCHAMPEJetalPathophysiologyandmanagementofalcoholicliverdiseaseupdate2016[J]GutLiver201711(2)173-188
[36] SAHABMOMEN-HERAVIFFURIIetalExtracellularvesiclesfrommicewithalcoholicliverdiseasecarryadistinctproteincargoandinducemacrophageactivationthroughheatshockprotein90[J]Hepatology201867(5)1986-2000
[37] CHOYEIMEJMOONPGetalIncreasedliver-specificproteinsincirculatingextracellularvesiclesas
potentialbiomarkersfordrug-andalcohol-inducedliverinjury[J]PLoSOne201712(2)e0172463
[38] MOMEN-HERAVIFBALASSKODYSKetalExosomes derived from alcohol-treated hepatocyteshorizontallytransferliverspecific miRNA-122 andsensitizemonocytestoLPS[J]SciRep201559991
[39] SAHAMALLONMDiagnosistreatmentandpreventionofhemodialysisemergencies[J]ClinJAmSocNephrol
201712(2)357-369[40] SAHABMOMEN-HERAVIFKODYS Ketal
MicroRNAcargoofextracellularvesiclesfromalcohol-exposed monocytes signals naive monocytes todifferentiateintoM2macrophages[J]JBiolChem
2016291(1)149-159[41] VERMAVKLIHYWANGRSetalAlcoholstimulates
macrophage activation through caspase-dependenthepatocyte derived release of CD40L containingextracellularvesicles[J]JHepatol201664(3)651-660
[42] EGUCHIALAZARORGWANGJetalExtracellularvesiclesreleasedbyhepatocytesfromgastricinfusionmodelofalcoholicliverdiseasecontainamicroRNAbarcodethatcanbedetectedinblood[J]Hepatology
201765(2)475-490[43] YANGYLHANQJHOUZHetalExosomesmediate
hepatitisBvirus (HBV)transmissionand NK-celldysfunction[J]Cell MolImmunol201714(5)
465-475[44] KOUWAKITFUKUSHIMA YDAITO Tetal
ExtracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisBvirusinfection[J]FrontImmunol20167335
[45] DEVHAREPBSASAKIRSHRIVASTAVASetalExosome-mediatedintercellularcommunicationbetweenhepatitis C virus-infected hepatocytes and hepaticstellatecells[J]JVirol201791(10)jvi02555-16
[46] COBBD AKIM O KGOLDEN-MASONLetalHepatocyte-derived exosomes promote T follicularregulatorycellexpansion during hepatitis C virusinfection[J]Hepatology201867(1)71-85
[47] BUKONGTNMOMEN-HERAVIFKODYSKetalExosomesfromhepatitisCinfectedpatientstransmitHCVinfectionandcontainreplicationcompetentviralRNAincomplexwithAgo2-miR122-HSP90[J]PLoSPathog201410(10)1004424
[48] MAJISMATSUDAAYANIKetalExtracellularvesiclesinliverdiseases[J]AmJPhysiolGastrointestLiverPhysiol2017312(3)194-200
middot61middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
[49] SCHATTENBERGJMLEEMSExtracellularvesiclesasmessengersbetweenhepatocytesand macrophagesinnonalcoholicsteatohepatitis[J]Gastroenterology2016
150(4)815-818[50] HIRSOVAPIBRAHIMSHKRISHNANAetal
Lipid-inducedsignalingcausesreleaseofinflammatoryextracellularvesiclesfromhepatocytes[J]Gastroente-rology2016150(4)956-967
[51] IBRAHIM H SHIRSOVA PTOMITA KetalCorrectionmixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology
201664(2)70-72[52] TOMITAKKABASHIMAAFREEMANBLetal
Mixedlineagekinase3mediatestheinductionofCXCL10byaSTAT1-dependentmechanismduringhepatocytelipotoxicity[J]2017118(10)3249-3259
[53] IBRAHIMSHHIRSOVAPTOMITAKetalMixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology201663(3)731-744
[54] KAKAZUEMAUERASYINMetalHepatocytesreleaseceramide-enrichedpro-inflammatoryextracellularvesiclesinanIRE1α-dependentmanner[J]JLipidRes
201657(2)233-245[55] BANLDSHACKELNAMCLENNANSVExtracellular
vesiclesanewfrontierinbiomarkerdiscoveryfornon-alcoholicfattyliverdisease[J]IntJMolSci201617(3)376
[56] POVERODPANERA NEGUCHIAetalLipid-inducedhepatocyte-derivedextracellularvesiclesregulatehepaticstellatecellviamicroRNAstargetingPPAR-γ[J]CellMolGastroenterolHepatol20151(6)
646-663[57] DENGFMAGEENZHANGYDecodingtheroleof
extracellularvesiclesinliverdiseases[J]LiverRes
20171(3)147-155[58] PERUMPAILBJKHAN M AYOO E Retal
Clinicalepidemiologyanddiseaseburdenofnonalcoholicfattyliverdisease[J]WorldJGastroenterol201723(47)8263-8276
[59] LIJHLIUKCLIUYetalExosomesmediatethecell-to-celltransmission of IFN-α-induced antiviralactivity[J]NatImmunol201314(8)793-803
[60] TURTURICIGTINNIRELLORSCONZOGetalExtracellularmembranevesiclesasamechanismofcell-to-cellcommunicationadvantagesand disadvantages[J]AmJPhysiolCellPhysiol2014306(7)C621-C633
[61] ATAINABALAJLVANVEENHetalHeparinblockstransferofextracellularvesiclesbetweendonorandrecipientcells[J]JNeurooncol2013115(3)
343-351[62] POVERODEGUCHIANIESMANIRetalLipid-
induced toxicity stimulates hepatocytes to releaseangiogenic microparticles thatrequire Vanin-1 foruptakebyendothelialcells[J]SciSignal20136(296)
ra88[63] ZHANGPFLIUGCHENXYNanobiotechnology
cellmembrane-baseddeliverysystems[J]NanoToday
2017137-9[64] PASCUCCILCOCCEgraveVBONOMIAetalPaclitaxel
isincorporated by mesenchymalstromalcellsandreleasedinexosomesthatinhibitinvitrotumorgrowth
anewapproachfordrugdelivery[J]JControlRelease
2014192262-270[65] HADLAMPALAZZOLOSCORONAGetalExosomes
increasethetherapeuticindexofdoxorubicininbreastandovariancancermousemodels[J]Nanomedicine
201611(18)2431-2441[66] ZHANGPFCHENYXZENGYetalVirus-mimetic
nanovesiclesasaversatileantigen-deliverysystem[J]ProcNatlAcadSciUSA2015112(45)E6129-E6138
[67] LUumlPLIUXCHENXMetalGeneticallyengineeredcellmembranenanovesiclesforoncolyticadenovirusdeliveryaversatileplatformforcancervirotherapy[J]NanoLetters201919(5)2993-3001
[68] LIUXYUANLZZHANGLetalBioinspiredartificialnanodecoysforhepatitisBvirus[J]AngewChemIntEdEngl201857(38)12499-12503
[69] LIUXLIUCZHENGZetalVesicularantibodiesabioactive multifunctional combination platform fortargetedtherapeuticdeliveryandcancerimmunotherapy[J]AdvMater201931(17)e1808294
[70] GUDBERGSSONJMJNSSONKSIMONSENJB
etalSystematicreviewoftargetedextracellularvesiclesfordrugdeliveryconsiderationson methodologicalandbiologicalheterogeneity[J]JControlRelease2019
306108-120[71] TOMINAGA NKOSAKA NONO MetalBrain
metastaticcancercellsreleasemicroRNA-181c-containingextracellularvesiclescapableofdestructingblood-brainbarrier[J]NatCommun201566716
[72] LITFYANYMWANGBYetalExosomesderivedfrom humanumbilicalcord mesenchymalstemcellsalleviateliverfibrosis[J]StemCellsDev201322(6)
845-854
middot71middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
Researchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinducedbyexogenousfactors
JIANGShanLUumlPengLINZhongningLIUGang(StateKeyLaboratoryofMolecularVaccinologyandMolecularDiagnostics
SchoolofPublicHealthXiamenUniversityXiamen361102China)
AbstractLiveristhemainmetabolicorganwiththeuniquesinusoidstructureandabundantcelltypeswhichplaysanimportantroleinmetabolizingexogenousfactorsImportantlythefunctionalimpairmentofhepatocytesistheleadingcauseofhepatotoxicdamageExtracellularvesicles(EVs)withnanosizeandlipidbilayermembraneareproducedbyalmostalltypesofcellsEVsserveaspotentialcarriersbyloadingandtransportingspecificmoleculesmediatingcellularcross-talksbetweennearbyordistantcellsInthisreviewwemainlydiscusstheintercellularcommunicationandspecificapproachesoftargetedinterventionsintheprocessofEVs-mediatedhepatotoxicdamageunderexogenousfactorsexposurewhichprovidesfurtherguidanceandreferenceforpreventingandcontrolinghepatotoxicdamage
Keywordsextracellularvesiclesintercellularcommunicationhepatotoxicdamageexogenousfactorstargetedintervention105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277 10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
南强青年学者简介刘刚(1979mdash )博士教授国家杰出青年基金(2019)和优秀青年基金(2014)获得者
入选南强青年拔尖A类人才(2018)中组部万人计划青年拔尖人才(2018)教育部新世纪
人才(2013)福建省科技创新领军人才(2016)现担任中国生物医学工程学会理事中国
生物材料学会理事中华医学会放射学分会分子影像学组副组长长期致力于分子影像探针及药物递送载体系统研发近5年作为通信作者在JCR一
区的PNASNatCommunSciAdvJACSAdvMater等主流期刊上发表论文60余篇并
入选科睿唯安(Clarivate)2019年度全球ldquo高被引科学家rdquo榜单参编全国高校规划教材4部英文专著11部获得国家专利授权7项其中2项已进行企业技术转移及临床转化并获国家或省级科技奖4项
middot81middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
[25] WITEKRPYANGLLIURSetalLivercell-derivedmicroparticlesactivatehedgehogsignalingandaltergeneexpressioninhepaticendothelialcells[J]Gastroenterology
2009136(1)320-330[26] PANQRAMAKRISHNAIAH VHENRYSetal
Hepaticcell-to-celltransmissionofsmallsilencingRNAcanextendthetherapeuticreachofRNAinterference(RNAi)[J]Gut201261(9)1330-1339
[27] CAISPCHENGXYPANXYetalEmergingroleofexosomesinliverphysiologyandpathology[J]HepatolRes201747(2)194-203
[28] SZABOGMOMEN-HERAVIFExtracellularvesiclesinliverdiseaseandpotentialasbiomarkersandtherapeutictargets[J]NatRevGastroenterolHepatol201714(8)455-466
[29] PALOMOLMLECZKOJEAZKARGORTA MetalAbundanceofcytochromesinhepaticextracellularvesiclesisalteredbydrugsrelatedwithdrug-inducedliverinjury[J]HepatolCommun20182(9)1064-1079
[30] DUANLQRAMACHANDRANAAKAKPOJYetalRoleofextracellularvesiclesinreleaseofproteinadductsafteracetaminophen-inducedliverinjuryinmiceandhumans[J]ToxicolLett2019301125-132
[31] PATELSJMILWIDJMKINGKRetalGapjunctioninhibition prevents drug-induced livertoxicity andfulminanthepaticfailure[J]NatBiotechnol201230(2)179-183
[32] HOLMANNSMOSEDALE MWOLFKKetalSubtoxicalterationsinhepatocyte-derivedexosomesanearlystepindrug-inducedliverinjury [J]ToxicolSci
2016151(2)365-375[33] CHOYEKIMSHLEEBHetalCirculatingplasma
andexosomalmicroRNAsasindicatorsofdrug-inducedorganinjuryinrodentmodels[J]BiomolTher201725(4)367-373
[34] ROYO FSCHLANGEN KPALOMO LetalTranscriptome ofextracellularvesiclesreleased byhepatocytes[J]PLoSOne20138(7)e68693
[35] STICKELFDATZCHAMPEJetalPathophysiologyandmanagementofalcoholicliverdiseaseupdate2016[J]GutLiver201711(2)173-188
[36] SAHABMOMEN-HERAVIFFURIIetalExtracellularvesiclesfrommicewithalcoholicliverdiseasecarryadistinctproteincargoandinducemacrophageactivationthroughheatshockprotein90[J]Hepatology201867(5)1986-2000
[37] CHOYEIMEJMOONPGetalIncreasedliver-specificproteinsincirculatingextracellularvesiclesas
potentialbiomarkersfordrug-andalcohol-inducedliverinjury[J]PLoSOne201712(2)e0172463
[38] MOMEN-HERAVIFBALASSKODYSKetalExosomes derived from alcohol-treated hepatocyteshorizontallytransferliverspecific miRNA-122 andsensitizemonocytestoLPS[J]SciRep201559991
[39] SAHAMALLONMDiagnosistreatmentandpreventionofhemodialysisemergencies[J]ClinJAmSocNephrol
201712(2)357-369[40] SAHABMOMEN-HERAVIFKODYS Ketal
MicroRNAcargoofextracellularvesiclesfromalcohol-exposed monocytes signals naive monocytes todifferentiateintoM2macrophages[J]JBiolChem
2016291(1)149-159[41] VERMAVKLIHYWANGRSetalAlcoholstimulates
macrophage activation through caspase-dependenthepatocyte derived release of CD40L containingextracellularvesicles[J]JHepatol201664(3)651-660
[42] EGUCHIALAZARORGWANGJetalExtracellularvesiclesreleasedbyhepatocytesfromgastricinfusionmodelofalcoholicliverdiseasecontainamicroRNAbarcodethatcanbedetectedinblood[J]Hepatology
201765(2)475-490[43] YANGYLHANQJHOUZHetalExosomesmediate
hepatitisBvirus (HBV)transmissionand NK-celldysfunction[J]Cell MolImmunol201714(5)
465-475[44] KOUWAKITFUKUSHIMA YDAITO Tetal
ExtracellularvesiclesincludingexosomesregulateinnateimmuneresponsestohepatitisBvirusinfection[J]FrontImmunol20167335
[45] DEVHAREPBSASAKIRSHRIVASTAVASetalExosome-mediatedintercellularcommunicationbetweenhepatitis C virus-infected hepatocytes and hepaticstellatecells[J]JVirol201791(10)jvi02555-16
[46] COBBD AKIM O KGOLDEN-MASONLetalHepatocyte-derived exosomes promote T follicularregulatorycellexpansion during hepatitis C virusinfection[J]Hepatology201867(1)71-85
[47] BUKONGTNMOMEN-HERAVIFKODYSKetalExosomesfromhepatitisCinfectedpatientstransmitHCVinfectionandcontainreplicationcompetentviralRNAincomplexwithAgo2-miR122-HSP90[J]PLoSPathog201410(10)1004424
[48] MAJISMATSUDAAYANIKetalExtracellularvesiclesinliverdiseases[J]AmJPhysiolGastrointestLiverPhysiol2017312(3)194-200
middot61middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
[49] SCHATTENBERGJMLEEMSExtracellularvesiclesasmessengersbetweenhepatocytesand macrophagesinnonalcoholicsteatohepatitis[J]Gastroenterology2016
150(4)815-818[50] HIRSOVAPIBRAHIMSHKRISHNANAetal
Lipid-inducedsignalingcausesreleaseofinflammatoryextracellularvesiclesfromhepatocytes[J]Gastroente-rology2016150(4)956-967
[51] IBRAHIM H SHIRSOVA PTOMITA KetalCorrectionmixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology
201664(2)70-72[52] TOMITAKKABASHIMAAFREEMANBLetal
Mixedlineagekinase3mediatestheinductionofCXCL10byaSTAT1-dependentmechanismduringhepatocytelipotoxicity[J]2017118(10)3249-3259
[53] IBRAHIMSHHIRSOVAPTOMITAKetalMixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology201663(3)731-744
[54] KAKAZUEMAUERASYINMetalHepatocytesreleaseceramide-enrichedpro-inflammatoryextracellularvesiclesinanIRE1α-dependentmanner[J]JLipidRes
201657(2)233-245[55] BANLDSHACKELNAMCLENNANSVExtracellular
vesiclesanewfrontierinbiomarkerdiscoveryfornon-alcoholicfattyliverdisease[J]IntJMolSci201617(3)376
[56] POVERODPANERA NEGUCHIAetalLipid-inducedhepatocyte-derivedextracellularvesiclesregulatehepaticstellatecellviamicroRNAstargetingPPAR-γ[J]CellMolGastroenterolHepatol20151(6)
646-663[57] DENGFMAGEENZHANGYDecodingtheroleof
extracellularvesiclesinliverdiseases[J]LiverRes
20171(3)147-155[58] PERUMPAILBJKHAN M AYOO E Retal
Clinicalepidemiologyanddiseaseburdenofnonalcoholicfattyliverdisease[J]WorldJGastroenterol201723(47)8263-8276
[59] LIJHLIUKCLIUYetalExosomesmediatethecell-to-celltransmission of IFN-α-induced antiviralactivity[J]NatImmunol201314(8)793-803
[60] TURTURICIGTINNIRELLORSCONZOGetalExtracellularmembranevesiclesasamechanismofcell-to-cellcommunicationadvantagesand disadvantages[J]AmJPhysiolCellPhysiol2014306(7)C621-C633
[61] ATAINABALAJLVANVEENHetalHeparinblockstransferofextracellularvesiclesbetweendonorandrecipientcells[J]JNeurooncol2013115(3)
343-351[62] POVERODEGUCHIANIESMANIRetalLipid-
induced toxicity stimulates hepatocytes to releaseangiogenic microparticles thatrequire Vanin-1 foruptakebyendothelialcells[J]SciSignal20136(296)
ra88[63] ZHANGPFLIUGCHENXYNanobiotechnology
cellmembrane-baseddeliverysystems[J]NanoToday
2017137-9[64] PASCUCCILCOCCEgraveVBONOMIAetalPaclitaxel
isincorporated by mesenchymalstromalcellsandreleasedinexosomesthatinhibitinvitrotumorgrowth
anewapproachfordrugdelivery[J]JControlRelease
2014192262-270[65] HADLAMPALAZZOLOSCORONAGetalExosomes
increasethetherapeuticindexofdoxorubicininbreastandovariancancermousemodels[J]Nanomedicine
201611(18)2431-2441[66] ZHANGPFCHENYXZENGYetalVirus-mimetic
nanovesiclesasaversatileantigen-deliverysystem[J]ProcNatlAcadSciUSA2015112(45)E6129-E6138
[67] LUumlPLIUXCHENXMetalGeneticallyengineeredcellmembranenanovesiclesforoncolyticadenovirusdeliveryaversatileplatformforcancervirotherapy[J]NanoLetters201919(5)2993-3001
[68] LIUXYUANLZZHANGLetalBioinspiredartificialnanodecoysforhepatitisBvirus[J]AngewChemIntEdEngl201857(38)12499-12503
[69] LIUXLIUCZHENGZetalVesicularantibodiesabioactive multifunctional combination platform fortargetedtherapeuticdeliveryandcancerimmunotherapy[J]AdvMater201931(17)e1808294
[70] GUDBERGSSONJMJNSSONKSIMONSENJB
etalSystematicreviewoftargetedextracellularvesiclesfordrugdeliveryconsiderationson methodologicalandbiologicalheterogeneity[J]JControlRelease2019
306108-120[71] TOMINAGA NKOSAKA NONO MetalBrain
metastaticcancercellsreleasemicroRNA-181c-containingextracellularvesiclescapableofdestructingblood-brainbarrier[J]NatCommun201566716
[72] LITFYANYMWANGBYetalExosomesderivedfrom humanumbilicalcord mesenchymalstemcellsalleviateliverfibrosis[J]StemCellsDev201322(6)
845-854
middot71middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
Researchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinducedbyexogenousfactors
JIANGShanLUumlPengLINZhongningLIUGang(StateKeyLaboratoryofMolecularVaccinologyandMolecularDiagnostics
SchoolofPublicHealthXiamenUniversityXiamen361102China)
AbstractLiveristhemainmetabolicorganwiththeuniquesinusoidstructureandabundantcelltypeswhichplaysanimportantroleinmetabolizingexogenousfactorsImportantlythefunctionalimpairmentofhepatocytesistheleadingcauseofhepatotoxicdamageExtracellularvesicles(EVs)withnanosizeandlipidbilayermembraneareproducedbyalmostalltypesofcellsEVsserveaspotentialcarriersbyloadingandtransportingspecificmoleculesmediatingcellularcross-talksbetweennearbyordistantcellsInthisreviewwemainlydiscusstheintercellularcommunicationandspecificapproachesoftargetedinterventionsintheprocessofEVs-mediatedhepatotoxicdamageunderexogenousfactorsexposurewhichprovidesfurtherguidanceandreferenceforpreventingandcontrolinghepatotoxicdamage
Keywordsextracellularvesiclesintercellularcommunicationhepatotoxicdamageexogenousfactorstargetedintervention105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277 10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
南强青年学者简介刘刚(1979mdash )博士教授国家杰出青年基金(2019)和优秀青年基金(2014)获得者
入选南强青年拔尖A类人才(2018)中组部万人计划青年拔尖人才(2018)教育部新世纪
人才(2013)福建省科技创新领军人才(2016)现担任中国生物医学工程学会理事中国
生物材料学会理事中华医学会放射学分会分子影像学组副组长长期致力于分子影像探针及药物递送载体系统研发近5年作为通信作者在JCR一
区的PNASNatCommunSciAdvJACSAdvMater等主流期刊上发表论文60余篇并
入选科睿唯安(Clarivate)2019年度全球ldquo高被引科学家rdquo榜单参编全国高校规划教材4部英文专著11部获得国家专利授权7项其中2项已进行企业技术转移及临床转化并获国家或省级科技奖4项
middot81middot
第1期 江 珊等细胞外囊泡参与调控外源因素诱导的肝毒性损伤的研究进展
http∥jxmuxmueducn
[49] SCHATTENBERGJMLEEMSExtracellularvesiclesasmessengersbetweenhepatocytesand macrophagesinnonalcoholicsteatohepatitis[J]Gastroenterology2016
150(4)815-818[50] HIRSOVAPIBRAHIMSHKRISHNANAetal
Lipid-inducedsignalingcausesreleaseofinflammatoryextracellularvesiclesfromhepatocytes[J]Gastroente-rology2016150(4)956-967
[51] IBRAHIM H SHIRSOVA PTOMITA KetalCorrectionmixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology
201664(2)70-72[52] TOMITAKKABASHIMAAFREEMANBLetal
Mixedlineagekinase3mediatestheinductionofCXCL10byaSTAT1-dependentmechanismduringhepatocytelipotoxicity[J]2017118(10)3249-3259
[53] IBRAHIMSHHIRSOVAPTOMITAKetalMixedlineagekinase3mediatesreleaseofC-X-Cmotifligand10-bearingchemotacticextracellularvesiclesfromlipotoxichepatocytes[J]Hepatology201663(3)731-744
[54] KAKAZUEMAUERASYINMetalHepatocytesreleaseceramide-enrichedpro-inflammatoryextracellularvesiclesinanIRE1α-dependentmanner[J]JLipidRes
201657(2)233-245[55] BANLDSHACKELNAMCLENNANSVExtracellular
vesiclesanewfrontierinbiomarkerdiscoveryfornon-alcoholicfattyliverdisease[J]IntJMolSci201617(3)376
[56] POVERODPANERA NEGUCHIAetalLipid-inducedhepatocyte-derivedextracellularvesiclesregulatehepaticstellatecellviamicroRNAstargetingPPAR-γ[J]CellMolGastroenterolHepatol20151(6)
646-663[57] DENGFMAGEENZHANGYDecodingtheroleof
extracellularvesiclesinliverdiseases[J]LiverRes
20171(3)147-155[58] PERUMPAILBJKHAN M AYOO E Retal
Clinicalepidemiologyanddiseaseburdenofnonalcoholicfattyliverdisease[J]WorldJGastroenterol201723(47)8263-8276
[59] LIJHLIUKCLIUYetalExosomesmediatethecell-to-celltransmission of IFN-α-induced antiviralactivity[J]NatImmunol201314(8)793-803
[60] TURTURICIGTINNIRELLORSCONZOGetalExtracellularmembranevesiclesasamechanismofcell-to-cellcommunicationadvantagesand disadvantages[J]AmJPhysiolCellPhysiol2014306(7)C621-C633
[61] ATAINABALAJLVANVEENHetalHeparinblockstransferofextracellularvesiclesbetweendonorandrecipientcells[J]JNeurooncol2013115(3)
343-351[62] POVERODEGUCHIANIESMANIRetalLipid-
induced toxicity stimulates hepatocytes to releaseangiogenic microparticles thatrequire Vanin-1 foruptakebyendothelialcells[J]SciSignal20136(296)
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isincorporated by mesenchymalstromalcellsandreleasedinexosomesthatinhibitinvitrotumorgrowth
anewapproachfordrugdelivery[J]JControlRelease
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845-854
middot71middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
Researchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinducedbyexogenousfactors
JIANGShanLUumlPengLINZhongningLIUGang(StateKeyLaboratoryofMolecularVaccinologyandMolecularDiagnostics
SchoolofPublicHealthXiamenUniversityXiamen361102China)
AbstractLiveristhemainmetabolicorganwiththeuniquesinusoidstructureandabundantcelltypeswhichplaysanimportantroleinmetabolizingexogenousfactorsImportantlythefunctionalimpairmentofhepatocytesistheleadingcauseofhepatotoxicdamageExtracellularvesicles(EVs)withnanosizeandlipidbilayermembraneareproducedbyalmostalltypesofcellsEVsserveaspotentialcarriersbyloadingandtransportingspecificmoleculesmediatingcellularcross-talksbetweennearbyordistantcellsInthisreviewwemainlydiscusstheintercellularcommunicationandspecificapproachesoftargetedinterventionsintheprocessofEVs-mediatedhepatotoxicdamageunderexogenousfactorsexposurewhichprovidesfurtherguidanceandreferenceforpreventingandcontrolinghepatotoxicdamage
Keywordsextracellularvesiclesintercellularcommunicationhepatotoxicdamageexogenousfactorstargetedintervention105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277 10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
南强青年学者简介刘刚(1979mdash )博士教授国家杰出青年基金(2019)和优秀青年基金(2014)获得者
入选南强青年拔尖A类人才(2018)中组部万人计划青年拔尖人才(2018)教育部新世纪
人才(2013)福建省科技创新领军人才(2016)现担任中国生物医学工程学会理事中国
生物材料学会理事中华医学会放射学分会分子影像学组副组长长期致力于分子影像探针及药物递送载体系统研发近5年作为通信作者在JCR一
区的PNASNatCommunSciAdvJACSAdvMater等主流期刊上发表论文60余篇并
入选科睿唯安(Clarivate)2019年度全球ldquo高被引科学家rdquo榜单参编全国高校规划教材4部英文专著11部获得国家专利授权7项其中2项已进行企业技术转移及临床转化并获国家或省级科技奖4项
middot81middot
厦门大学学报(自然科学版) 2020年
http∥jxmuxmueducn
Researchprogressesofextracellularvesiclesinregulatinghepatotoxicdamageinducedbyexogenousfactors
JIANGShanLUumlPengLINZhongningLIUGang(StateKeyLaboratoryofMolecularVaccinologyandMolecularDiagnostics
SchoolofPublicHealthXiamenUniversityXiamen361102China)
AbstractLiveristhemainmetabolicorganwiththeuniquesinusoidstructureandabundantcelltypeswhichplaysanimportantroleinmetabolizingexogenousfactorsImportantlythefunctionalimpairmentofhepatocytesistheleadingcauseofhepatotoxicdamageExtracellularvesicles(EVs)withnanosizeandlipidbilayermembraneareproducedbyalmostalltypesofcellsEVsserveaspotentialcarriersbyloadingandtransportingspecificmoleculesmediatingcellularcross-talksbetweennearbyordistantcellsInthisreviewwemainlydiscusstheintercellularcommunicationandspecificapproachesoftargetedinterventionsintheprocessofEVs-mediatedhepatotoxicdamageunderexogenousfactorsexposurewhichprovidesfurtherguidanceandreferenceforpreventingandcontrolinghepatotoxicdamage
Keywordsextracellularvesiclesintercellularcommunicationhepatotoxicdamageexogenousfactorstargetedintervention105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277 10512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
105127710512771051277105127710512771051277105127710512771051277105127710512771051277105127710512771051277
南强青年学者简介刘刚(1979mdash )博士教授国家杰出青年基金(2019)和优秀青年基金(2014)获得者
入选南强青年拔尖A类人才(2018)中组部万人计划青年拔尖人才(2018)教育部新世纪
人才(2013)福建省科技创新领军人才(2016)现担任中国生物医学工程学会理事中国
生物材料学会理事中华医学会放射学分会分子影像学组副组长长期致力于分子影像探针及药物递送载体系统研发近5年作为通信作者在JCR一
区的PNASNatCommunSciAdvJACSAdvMater等主流期刊上发表论文60余篇并
入选科睿唯安(Clarivate)2019年度全球ldquo高被引科学家rdquo榜单参编全国高校规划教材4部英文专著11部获得国家专利授权7项其中2项已进行企业技术转移及临床转化并获国家或省级科技奖4项
middot81middot
