Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (25): 4053-4057.doi: 10.12307/2021.019
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Yu Dan1, Xu Guanglan2, Zhao Mei2, Li Jiao2, Li Guosheng2, Wang Guangyao1, Lin Hao1, Zheng Manli1, Li Yuanling1#br#
Received:
2020-06-01
Revised:
2020-06-04
Accepted:
2020-07-23
Online:
2021-09-08
Published:
2021-03-30
Contact:
Yu Dan, Master candidate, Graduate School of Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region, China
About author:
Xu Guanglan, Professor, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
Supported by:
CLC Number:
Yu Dan, Xu Guanglan, Zhao Mei, Li Jiao, Li Guosheng, Wang Guangyao, Lin Hao, Zheng Manli, Li Yuanling. Significance and possibility of stem cells and multiple cell derived exosomes in the treatment of chronic respiratory diseases[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(25): 4053-4057.
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2.1 不同细胞来源外泌体干预慢性呼吸系统疾病的途径 2.1.1 嗜酸性粒细胞来源外泌体 嗜酸性粒细胞是导致慢性呼吸系统疾病的重要炎性效应细胞,亦是慢性炎症的重要致病因素[6]。研究表明,嗜酸性粒细胞来源外泌体可促进一氧化氮和活性氧的产生,增加外周血及肺组织中嗜酸性粒细胞的募集与活化,最终导致嗜酸性粒细胞在气道中大量迁移、黏附,致使细胞间黏附分子及整联蛋白α2等黏附分子的特异性升高,促进炎症反应的进展,加重哮喘、慢性阻塞性肺疾病的临床症状。研究发现嗜酸性粒细胞来源外泌体可干预PI3K/AKT和JAK-STAT信号通路,加速气道上皮细胞凋亡,进而影响气道修复,最终影响慢性阻塞性肺疾病、哮喘等疾病的预后[7]。 2.1.2 间充质干细胞来源外泌体 间充质干细胞是一类具有免疫调节、抗炎、多项分化等作用的细胞群体,其作用与旁分泌体系所携带的生物活性物质关系密切[8]。研究证实,外泌体为调节旁分泌的主要影响因素,通过在小鼠移植模型实验中证实,间充质干细胞来源外泌体提高Foxp3+Treg细胞比例、降低Th17细胞比例,进而调节机体因慢性炎症而导致的Foxp3+Treg/Th17的失衡,延缓疾病进程,促进预后[9]。 2.1.3 巨噬细胞来源外泌体 巨噬细胞作为人体主要免疫细胞,其防御机制主要通过激活淋巴细胞及其他免疫细胞的方式参与机体内的特异性及非特异性防卫过程[10]。研究证实,巨噬细胞来源外泌体可激活TLR/MyD88信号通路,然后活化NF-κВ信号通路,促进炎性因子的释放,进而干预炎症反应的发生发展[11]。此外,有研究通过Transwell等实验方法证实巨噬细胞来源外泌体可促进白细胞介素1β、白细胞介素6、肿瘤坏死因子α等炎症因子的表达[12],促使上皮-间质转化,进而加剧气道受损程度,延长病程,因而通过干预巨噬细胞来源外泌体有望为慢性呼吸系统的治疗提供新方向。 2.1.4 其他 树突状细胞、淋巴细胞、NK细胞等免疫细胞均可分泌外泌体,其外泌体表面所携带的蛋白类物质,例如跨膜蛋白(CD9、CD63、CD81与CD82)、ESCRT-1复合物的成分TSG101跨膜蛋白、核酸类物质(microRNA,DNA)等,参与细胞间物质交换、信息交流、免疫逃逸、细胞凋亡等过程,是发挥免疫调节、抑制变态反应等作用的主要活性物质[13-17],具有较强的靶向性。研究证实树突状细胞来源外泌体表面所携带的miR-142-3p、miR-142-5p等活性物质可影响机体中 1 000余种特异性免疫相关基因的表达,在哮喘治疗中可发挥独特的作用[18]。 2.2 外泌体与慢性呼吸系统疾病 2.2.1 外泌体与哮喘 流行病学证实,哮喘在全球范围内有较高发病率,每年新增确诊人数超过3.15亿人,为世界上流行的慢性疾病之一[19]。不同细胞来源外泌体可通过多种途径参与哮喘的发生及进展[20]。间充质干细胞所分泌的外泌体可上调哮喘患者外周血中白细胞介素10和转化生长因子β1水平,同时能够限制肿瘤坏死因子α与白细胞介素1β等促炎性细胞基因的表达,提高调节性T细胞的增殖和免疫抑制能力,进而抑制气道细胞凋亡、坏死及氧化应激反应,减轻气道炎症[21]。未成熟树突状细胞来源外泌体(imDECs)的表面抗原miR-682可抑制DEC17+CD4+T细胞的表达,促进 Foxp3+CD4+T的高表达,从而促进Treg细胞分裂,均可减轻气道炎症反应,延缓疾病进程[22]。嗜酸性粒细胞作为引发气道炎症最主要的效应细胞之一,其激活是疾病发生发展的重要因素之一[23]。研究表明,嗜酸性粒细胞来源外泌体表面的特异性蛋白(嗜酸性粒细胞过氧化物酶,嗜酸性粒细胞阳离子基因)和靶向组织受体联合后,可刺激LCN2、白细胞介素8、LTC、S100等炎性因子的释放,使其表达量显著升高,从而加重炎性反应[24]。综上所述,嗜酸性粒细胞来源外泌体可广泛参与哮喘的发病机制,增加气道高反应,加重气道重塑。 2.2.2 外泌体与慢性阻塞性肺疾病 慢性阻塞性肺疾病是以慢性气管炎性病变和气管重塑为特点的慢性呼吸系统疾病,目前,其发病机制主要为肺内蛋白与抗蛋白酶系统失衡、氧化与抗氧化机制失调以及慢性气道炎症学说[25]。随着研究的不断进展,关于多种因素通过干预外泌体调控慢性阻塞性肺疾病发展进程的研究不断涌现。刘超[26]通过构建大鼠实验模型发现,诱导外泌体膜表面的热休克蛋白70表达可以影响TLR4/NF-κB信号通路的传导,引起支气管肺泡灌洗液中白细胞介素6和神经生长因子的表达上调,进而发挥促炎作用,证明其是导致慢性气道炎症的重要原因。此外,巨噬细胞来源外泌体细胞膜表层所包含的miR-223可活化靶向器官,诱导巨噬细胞分化,发挥调节炎症反应的作用[27]。经香烟烟雾提取物处理的支气管上皮细胞(HBE)与支气管成纤维细胞(MRC-5细胞),其分泌的外泌体中所含有的miR-21可调控pVHL/HIF-1α通路,靶向调节vonHippel-Lindau蛋白(pVHL)与Smad7,同时诱发缺氧诱导因子1α(HIF-1α)信号基因的形成,调节α-SMA基因,干预成肌纤维细胞分化,进而影响气道重塑[28]。当前,外泌体有望被应用于慢性阻塞性肺疾病的诊断,已有多项研究证实其可行性[29-30]。例如,BUDDING 等[31]通过设计对照试验论证慢性阻塞性肺疾病患者血液循环中的miRNA(miR-21,miR-29a,miR-103,miR-191) 激活程度显著高于对照组。研究发现患有慢性阻塞性肺疾病的吸烟者和没有慢性阻塞性肺疾病的吸烟者中,有70个miRNA和2 667个mRNA出现差异表达,其中miR-223 和miR-1274a的差异较为明显[32]。MicroRNA(miRNA或者miR) 是一类非编码RNA分子,可通过干预转化生长因子β、Wnt信号通道及黏附渠道等,影响病症的产生和演变。另外,外泌体评估慢性阻塞性肺疾病的分级也得到越来越多研究的证实[33],例如,let-7c和miR-125b与FEV1/FVC呈负相关,miR-181a,miR-203,miR-338,miR-1,miR-199a与FEV1/FVC呈正相关,其表达上调会延缓炎症的发展,减轻肺损害[34]。众多研究证实,不同细胞来源外泌体在慢性阻塞性肺疾病的诊治过程中可发挥不同的作用,例如支气管上皮细胞来源外泌体可影响成纤维细胞的募集与活化,参与气道重塑,加重慢性阻塞性肺疾病进程。外泌体表面的生物活性物质的表达量亦可作为评估疾病严重程度的指标。因此,通过检测外泌体膜表面特异性蛋白或核酸的募集与活化,评估气道上皮细胞损伤程度的特点,使外泌体成为真正意义上的一种无创性生物标志物,未来可利用其靶向性强的优势为慢性阻塞性肺疾病的诊疗提供新思路。 2.2.3 外泌体与间质性肺疾病 间质性肺疾病是一种以发生慢性肺泡炎症、肺部损伤与间质纤维化等病理变化为特征的弥漫性肺部疾病,其包括以特发性肺纤维化、特发性间质性肺炎为代表的200余种急性和慢性呼吸系统疾病。成纤维细胞的广泛增殖与迁移是目前间质性肺疾病中公认的重要致病因素之一,研究发现E-cadherin、Ncadherin、LATS2的选择性聚集对成纤维细胞的增殖与迁移起着至关重要的作用[34],其采用划痕实验等方法检测人羊膜间充质干细胞外泌体(hAMSC-Exo)对成纤维细胞迁移的作用,miR-135a为成纤维细胞源外泌体表面所携带的生物活性物质,其表达量与E-cadherin、Ncadherin、LATS2呈正相关,与纤维化标志蛋白α-SMA的激活量呈反比例关系,上调miR-135a的激活量,会增强Ncadherin、LATS2的表达水平,降低α-SMA的表达水平,进而促进成纤维细胞转移和增殖,加速其分化,促进纤维瘢痕、蜂窝囊的形成。国内外大量研究证实,外泌体不仅可靶向调控与间质性肺疾病相关的基因及特异性蛋白,对影响间质性肺疾病进程的相关信号通路也可发挥重要作用。有研究通过构建miR-28-5p模拟物,发现其可促进VEGF、HGF、LL-37和Ang-1的旁分泌,同时激活PI3K/Akt信号通道,进而促进间充质干细胞的增殖与转移,增强间充质干细胞的免疫调节特性[35]。亦有研究发现Wnt/β-catenin信号通路在上皮-间质转化的发生发展和肺纤维化的形成过程中发挥重要的调节作用[36]。杨旭等[37]通过构建矽肺大鼠模型对此进行证实,移植外泌体和骨髓间充质干细胞可下调CyclinD1及促纤维化因子转化生长因子β1的表达水平,进而降低Wnt/β-catenin信号传导通路异常启动的发生率,最终延缓肺纤维化进程。与此同时,随着对miRNA-141的深入研究,越来越多的证据证明miRNA-141对氧化应激反应中重要的调控因子Keap1起负调控作用[38],其通过靶向调控该因子,激活Nrf2/ARE信号通路,诱发抗氧化酶的活化,降低细胞氧化应激水平,维持细胞的有效再生,进而促进上皮细胞的修复,实现减慢肺纤维化进展的目的。因此,靶向干预外泌体中的活性蛋白、核酸等活性物质,可为诊断、治疗间质性肺疾病提供新方向。 2.2.4 外泌体与肺癌 肺癌是源自于支气管黏膜或者腺体的高度致死性病症,2017年国家癌症中心发布中国肺癌新发病例数为380万例,其患病率处在第2位[39]。随着研究深入,如肺癌细胞、树突状细胞等细胞来源泌体外所运载的生物活性物质可调控FOSL2等基因的表达,同时干预NF-κB、 TGF-β/Smad等信号通道的转导。研究证实,转化生长因子β1、NF-κB信号通路具有促进肿瘤细胞迁移,抑制免疫细胞等作用,而FOSL2蛋白可调节肺癌中转化生长因子β1、NF-κB信号通路,其高表达量可增加癌细胞侵犯肺组织的潜能,因此在肺癌的早期诊断、治疗及预后等方面扮演着重要角色[40]。研究发现miR-19-3p、miR-21-5p、miR-184、miR-221-3p、miR-20b-5p等在非小细胞肺癌患者血清外泌体中表达异常[41-42]。魏萍等[43]通过qRT-PCR技术,检测144例非小细胞肺癌患者和138例健康对照者的血清外泌体,发现在非小细胞肺癌患者血清外泌体中miR-20b-5p水平显著高于对照组,进一步证实检测外泌体的差异性表达可为肺癌的早期诊断提供重要的支持。亦有国外研究证实在抑制免疫反应或免疫逃逸过程中外泌体亦可发挥其独特的作用[44],LCC-exosome所携带的表皮生长因子受体可诱导产生免疫耐受性树突状细胞,树突状细胞作为一种抗原呈递细胞,参与特异性免疫和耐受过程,其大量生成可一定程度上增强调节性T细胞的特异性,进而抑制CD4+T、CD8+T细胞抗肿瘤功能,从而调控肺癌的发生发展。miR-23a位于人类基因组的19号染色体上,孟庆威[45]研究证实miR-23a 直接靶向抑制TRS-1的表达,而TRS-1可抑制miR-23a诱导的转移能力。TRS-1在非小细胞肺癌中的表达水平与预后相关。Cao等[46]发现miR-23a可靶向作用于A549细胞,并调节Smad依赖性的转化生长因子β水平,其过表达可以明显抑制E-cadherin、N-cadherin的表达并刺激成纤维细胞的增殖,进而影响肺癌的预后。由此可进一步证明通过干预外泌体作用的靶基因,可为肺癌治疗提供新靶点。"
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