Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (在线): 1-.
Pu Rui, Chen Ziyang, Yuan Lingyan
Received:
2020-10-13
Revised:
2020-10-14
Accepted:
2020-11-19
Online:
2021-01-28
Published:
2021-01-20
Contact:
Yuan Lingyan, MD, Professor, Doctoral supervisor, Institute of Physical Education, Shanghai Normal University, Shanghai 200234, China
About author:
Pu Rui, Master candidate, Institute of Physical Education, Shanghai Normal University, Shanghai 200234, China
Supported by:
CLC Number:
Pu Rui, Chen Ziyang, Yuan Lingyan. Characteristics and effects of exosomes from different cell sources in cardioprotection[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(在线): 1-.
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2.1 外泌体概述 外泌体最初被描述为是从肿瘤细胞系中释放出来的含有5'核苷酸酶活性的微泡[4]。1987年JOHNSTONE 等首次将这种从细胞内分泌出来的囊泡结构命名为外泌体。本质上,外泌体是在多囊泡内体的成熟过程中由内体膜以向内出芽的方式而形成的腔内囊泡[5],作为细胞、组织间信息交流的媒介,外泌体是多囊泡内体与细胞表面融合后向细胞外环境分泌而形成的[6]。此外,外泌体含有来自母细胞的大量丰富的活性物质,如蛋白质、脂质、核酸等各种分子,是一类呈现“杯状”或“茶托状”特征形态并具有细胞特异性脂质双分子层亚细胞结构的囊泡[7]。 外泌体普遍存在于不同类型的细胞中,包括网织红细 胞[8]、树突状细胞[9]、B细胞[10]、T细胞[11]、肥大细胞和肿瘤细胞等[12-13]。此外,在血液[14]、尿液[15]、羊水[16]、恶性腹水[17]、支气管肺泡灌洗液[18]、滑膜液和母乳等体液中也存在外泌体[19-20]。1996年RAPOSO等[21]发现外泌体具有抗原呈递并抑制肿瘤细胞的作用,之后外泌体更多的生物学功能被证明,包括介导细胞间通讯[22]、调节免疫反应[23]、癌症诊断等[24]。此后的研究逐渐发现外泌体在心脏保护中也具有重要作用。 2.2 外泌体作为心血管疾病诊断的生物标记物 2007年, VALADI等[25]首次在肥大细胞中发现外泌体含有miRNA,大量的细胞外miRNA被包裹在微小膜泡中(如外泌体),并证明外泌体被靶细胞摄取后,这些遗传内含物可发挥正常的生物学活性,由此掀起了对于它们在疾病治疗与预防及作为生物标志物的研究热潮。此后的研究发现,心脏特异性外泌体miRNA会在心肌受损后释放并进入血液循环,用于心血管疾病的监测。同理,心血管疾病患者血液外泌体miRNA水平变化也可作为研究心血管疾病潜在的生物标志物[26-27]。 由于外泌体miRNA的表达特异性,其作为心力衰竭、心肌梗死、围产期心肌病等多种心血管疾病的生物标志物在筛查和诊断中发挥着有益效应,而心肌细胞受损会释放富含心肌特异性的外泌体miRNA到体液中并以此作为心血管系统状态改变的信号[28]。研究发现,在急性心肌梗死时,与心肌肌钙蛋白(肌钙蛋白Ⅰ和肌钙蛋白T)相比,血液外泌体miR-1和miR-133a/b显示出更快且更早的适应性变化[29]。 MATSUMOTO等[30]提出了外泌体miRNA可作为缺血性心力衰竭的预测指标。研究发现,急性心肌梗死后发生心力衰竭患者体内的miR-192、miR-194和miR-34a浓度显著升高[31]。另一项重要实验表明,在接受心力衰竭治疗后,围产期心肌病患者的循环外泌体miR-146a水平降低,表明外泌体miR-146a 可能作为围产期心肌病相关急性心力衰竭的特异性生物标记物和治疗靶点,同一研究还发现了基于miRNA的细胞间通讯作用,即内皮细胞来源外泌体可携带miR-146a转移至心肌细胞,从而降低心肌细胞的代谢活性,导致发生围产期心肌病相关心力衰竭[32]。综上,外泌体miRNA水平变化与机体生理、病理条件密切相关,为外泌体在心血管疾病的诊断提供了理论基础。 2.3 不同细胞来源外泌体在心脏保护中的研究进展 外泌体自发现来,其初始研究主要集中于癌症的诊断,在近些年,外泌体已逐渐成为心血管疾病诊疗的研究热点。外泌体可被大多数细胞分泌(如心肌细胞、内皮细胞、心脏成纤维细胞、心脏祖细胞和间充质干细胞),这些细胞来源外泌体通过促进血管新生、抑制心肌纤维化、抑制心肌细胞凋亡、抑制炎症反应和改善心脏功能等方式在心脏保护中发挥重要作用。此外,外泌体中的miRNA和蛋白可调控生物信息,从而影响机体内各种生理病理进程,且不同来源外泌体具有不同的生物学功能。 2.3.1 心肌细胞来源的外泌体 在心肌细胞外泌体中不同的miRNA和蛋白发挥不同的心脏保护效应,如促进血管新生、抑制心肌细胞凋亡和抑制心肌纤维化等作用。此外,心肌细胞与其他细胞间(如内皮细胞)的通讯作用也在心脏保护中极为重要。 (1)促进血管新生:心肌细胞与内皮细胞之间的通讯与调节心脏功能关系密切并发挥重要的作用。RIBEIRO-RODRIGUES 等[33]通过研究首次表明在缺血条件下心肌细胞通过释放外泌体影响内皮细胞功能并促进血管生成,在缺血状态下心肌细胞来源外泌体促血管生成的主要特征包括内皮细胞的迁移、发芽和毛细血管样结构的形成,随后通过定量聚合酶链反应定量到外泌体中最丰富的miR-143和miR-222,发现心肌细胞在缺血状态分泌的外泌体在体外和体内均可促进血管生成,说明不同细胞间的通讯转导广泛参与血管生成的调节。 (2)抑制心肌细胞凋亡:心肌细胞会释放出大量特异性外泌体以应对缺血缺氧状态下的应激反应,抑制心肌细胞凋亡,而外泌体中的蛋白质也已成为心脏保护研究的新靶点。GUPTA等[34-35]首次分离出成年大鼠心肌细胞释放的含有热休克蛋白60的心肌细胞外泌体;在低氧条件下,热休克蛋白60紧密附着于心肌细胞外膜上,然后作为屏障将心肌细胞与细胞外空间中高水平的热休克蛋白60蛋白隔离,从而抑制心肌细胞凋亡并降低心肌细胞的毒性,这项研究阐述了热休克蛋白60作为心肌细胞来源外泌体靶点在心脏保护中的新机制。 (3)抑制心肌纤维化:血管紧张素Ⅱ水平上升会诱导心力衰竭并加重心血管相关疾病的进程,而心肌细胞来源外泌体可调节相关炎性因子的表达从而抑制心肌纤维化。 CAMBIER等[36]研究了心肌细胞来源外泌体在长期注射血管紧张素Ⅱ诱导的心肌肥大和肾脏损伤模型中的作用,发现心肌细胞来源外泌体通过调节抗炎细胞因子白细胞介素10的表达减轻心肌肥厚和改善肾脏功能,并减轻心脏和肾脏的炎症和纤维化。此外,来源于心肌细胞的外泌体miR-208a在心肌梗死模型和氧化还原酶诱导的心肌病大鼠中均表达上调,能抑制心肌纤维化,改善心脏功能,并确定了Dyrk2是miR-208a 的靶基因[37]。 综上所述,心肌细胞来源外泌体与心肌梗死及心力衰竭等心血管疾病关系密切,其具有抑制心肌纤维化、促进血管新生和改善心脏功能的特性。然而心肌细胞来源外泌体发挥其有益效益的分子机制尚未完全揭示,还需进一步深入探讨。 2.3.2 内皮细胞来源的外泌体 内皮细胞之间的信号传导依赖于细胞间通讯接触和分泌蛋白的交换,对于心脏保护与血管完整性的维持至关重要。同样,内皮细胞来源外泌体通过介导其miRNA与相关蛋白在促进血管生成、发挥抗炎作用以及抑制动脉粥样硬化中也发挥重要作用,是调节炎症和免疫反应的重要介质。 (1)促进血管新生:VAN BALKOM等[38]通过研究证明miR-214在内皮细胞来源外泌体介导的信号传导中起主导作用。内皮细胞通过释放含miR-214的外泌体抑制临近靶细胞中毛细血管的扩张来调节细胞迁移,从而刺激血管的生成。Zhan等[39]揭示了一种氧化低密度脂蛋白和高半胱氨酸诱导内皮细胞来源外泌体释放热休克蛋白70的机制,内皮细胞来源外泌体激活单核细胞与内皮细胞的黏附并诱导热休克蛋白70高表达,从而促进血管生成,这也为调节血管内皮功能完整性与血管新生提供一种新的旁分泌机制。 (2)抗炎作用:对人脐静脉内皮细胞和人冠状动脉内皮细胞来源外泌体的研究表明,这些内皮细胞来源外泌体可以调节炎症并诱导单核细胞的活化和迁移[40]。最近有研究报道了白细胞介素10敲除小鼠的内皮细胞分泌的外泌体,没有促血管生成和心脏修复特性,这些外泌体中整合素连接激酶表达上调,会诱导受体细胞中NF-κB介导的炎症基因激活,因此,抑制这些外泌体中的整合素连接激酶表达可以挽救炎症引起的修复活性丧失[41]。该研究为炎症如何改变外泌体介导的心脏修复提供了新的见解。 (3)心脏保护作用:动脉粥样硬化是冠心病、外周血管病等心血管疾病的主要患病原因,内皮细胞来源外泌体通过抑制炎症因子表达、促进血管新生和抗凝血等作用维持血管内环境稳定,从而抑制动脉粥样硬化形成和发展[42]。 内皮细胞与平滑肌细胞间的信息交流为内皮细胞来源外泌体发挥其有益效应提供了新的思路。HERGENREIDER等[43] 研究结果表明血管内皮细胞和平滑肌细胞能够通过血液转运、临近释放外泌体的方式实现miRNA介导在内皮细胞和平滑肌细胞之间的通讯,传导抗动脉粥样硬化的信号,从而保护心血管系统。此外,来自KLF2转导的内皮细胞来源外泌体以miR-143/145依赖的方式减少体内动脉粥样硬化病变的形成,当暴露于高动脉粥样硬化保护剪切应力时,内皮细胞分泌富含miR-143/145的外泌体,一旦转移到平滑肌细胞,外泌体抑制miR-143/145的表达,增加抗凝血的作用,抑制动脉粥样硬化的发展,从而发挥心脏保护作用[44]。此外,内皮细胞来源外泌体还参与免疫反应,SONG等[45]通过对小鼠心脏内皮细胞来源外泌体的分离纯化以及流式细胞术测定调节性B细胞的抑制功能,结果显示:内皮细胞来源外泌体携带整合素αvβ6,可促进B细胞释放转化生长因子β,抑制效应T细胞的增殖,具有免疫抑制功能,从而参与心脏保护。 综上所述,这些研究表明内皮细胞来源外泌体可发挥促进血管新生、抑制炎症反应与心脏保护等作用,其中 miR-214、miR-143、miR-145与热休克蛋白70、整合素连接激酶等miRNA和蛋白则是内皮细胞来源外泌体发挥其心脏保护效应的关键所在。 2.3.3 心脏成纤维细胞来源外泌体 心肌损伤会引发心肌纤维化,而过度的纤维化可能会逐渐发展成心脏重塑。纤维化的主要效应细胞被称为心脏成纤维细胞[46]。心脏成纤维细胞占所有正常心脏细胞的60%-70%,心脏成纤维细胞也能通过调节心脏细胞的增殖和迁移参与修复心肌损伤后的细胞外基质[47]。 (1)抑制心肌肥厚:心脏成纤维细胞来源外泌体与病理性心肌肥厚和心肌梗死等心血管疾病关系密切,且在心脏保护中具有两面性,其关键在于心脏成纤维细胞来源外泌体对相关miRNA及蛋白的调控作用。BANG等[48]首次对外泌体miRNA在心脏成纤维细胞和心肌细胞间的通讯进行了实质性研究,确定了心脏成纤维细胞来源外泌体中的miR-21-3p (miR-21*) 可通过内吞或受体介导的机制迁移到心肌细胞,从而影响相关靶基因进而产生细胞肥大,最终导致心肌肥厚。同一实验还表明,在血管紧张素Ⅱ诱导的病理性心肌肥厚小鼠中,通过注射miR-21*抑制剂减轻了心肌肥厚的发展,这表明了miR-21*抑制剂在心脏肥大中的潜在治疗用途,也为外泌体在心脏肥大的治疗中的应用提供了新的思路。类似实验还表明,特异性靶向血管紧张素Ⅱ诱导心脏成纤维细胞外泌体释放,可作为治疗心脏病理性肥大和心力衰竭的新方法[49]。 (2)抑制心肌细胞凋亡:近些年来,金属蛋白酶组织抑制因子1成为了心血管疾病研究的热点,也是心血管疾病中的重要调节因子。有学者探究了心脏成纤维细胞外泌体中金属蛋白酶组织抑制因子1在心肌梗死中的保护作用。ABRIA等[50]通过将心脏成纤维细胞外泌体注射到大鼠心肌梗死模型,发现外泌体注射减小了心肌梗死面积并抑制了心肌细胞凋亡,其机制可能是因为心脏成纤维细胞中大量存在金属蛋白酶组织抑制因子1,心脏成纤维细胞外泌体通过金属蛋白酶组织抑制因子1的旁分泌途径抑制心肌纤维化,从而减轻心肌损伤。随后LUO等[51]通过共培养体系发现在缺氧-复氧中心脏成纤维细胞显著增加并保护心肌细胞免受损失,证明了缺血再灌注损伤期间心脏成纤维细胞外泌体通过 miR-423-3p/RAP2C信号通路抑制心肌细胞凋亡,参与心脏保护。 综上,这些研究阐述了心脏成纤维细胞来源外泌体在心脏保护中的作用及相关机制,虽然心脏成纤维细胞外泌体miR-21-3p会加速心肌肥厚的进程,但外泌体抑制剂的应用也为干预和治疗病理性心肌肥厚提供了新的视角。此外,金属蛋白酶组织抑制因子1、miR-423-3p的研究为心肌梗死的治疗提供了新途径,也证明了外泌体在心血管疾病治疗与修复中的旁分泌效应。 2.3.4 心脏祖细胞来源外泌体 祖细胞,也被称为前体细胞,位于干细胞和成体细胞之间,是细胞在彻底分化之前转化的中间细胞,相较干细胞的分化具有更多明确性和目标性[47]。心脏祖细胞来源外泌体通过调节miRNA及蛋白或靶基因的表达,从而修复受损心肌与抑制心肌细胞凋亡。 (1)抑制心肌细胞凋亡:病毒性心肌炎是一种严重威胁人类健康的心血管疾病,且目前缺乏特定且有效的治疗方法。LI等[52]证明了心脏祖细胞分泌的外泌体在病毒性心肌炎模型中对心肌细胞的保护作用,其机制是心脏祖细胞通过分泌外泌体降低病毒增殖并通过调节mTOR信号以及Bcl-2、Caspase-3等基因的表达,在该病毒模型中发挥抗凋亡作用,这表明了心脏祖细胞来源外泌体是治疗病毒性心肌炎的新方向。急性心肌梗死在缺血区域产生的大量活性氧是心肌细胞凋亡和死亡的主要原因,且易造成心血管疾病进一步恶化。XIAO等[53]通过研究发现氧化应激增强心脏祖细胞来源外泌体中miR-21的产生,miR-21进一步抑制PDCD4的表达,从而保护心肌细胞免受氧化应激相关的凋亡。 (2)修复受损心肌:BARILE等[54]对于心脏祖细胞和骨髓祖细胞的细胞疗法进行了体内外实验比较,体外实验通过梯度离心分离培养细胞以及前体miRNA转染两种细胞,发现心脏祖细胞外泌体相比骨髓祖细胞外泌体能更有效地防止星形孢菌素诱导的心肌细胞凋亡,体内实验通过向大鼠心脏永久性冠状动脉结扎模型注射两种外泌体,4周后显示心脏祖细胞外泌体组瘢痕面积减小,心脏功能改善,蛋白质组学检测表明PAPP-A存在于心脏祖细胞外泌体表面,并介导胰岛素样生长因子1的释放,进而减少心肌细胞的凋亡,这一研究表明胰岛素样生长因子1作为一种关键的心脏保护因子可起到保护心脏的作用。同类型实验还发现,通过向急性心肌缺血再灌注损伤小鼠模型心肌内注射正常小鼠的心脏祖细胞外泌体,与对照组相比,心脏祖细胞外泌体组抑制了心肌细胞凋亡,且在高水平外泌体的调节下,miR-451能单独增强细胞存活的能力,这项研究证实了心脏祖细胞外泌体作为心脏保护介质的重要作用[55-56]。同样,心脏祖细胞外泌体在相对低的浓度下通过激活Akt/mTOR信号通路以时间依赖性的方式促进了H9C2细胞的生长,修复受损心肌,为心血管疾病提供新疗法[57]。 综上所述,心脏祖细胞来源外泌体对病毒性心肌炎、心肌梗死的治疗有促进作用,也在氧化应激中发挥其有益效应,保护心肌细胞。此外,心脏祖细胞和骨髓祖细胞来源外泌体对心脏保护间的不同效应,也证明了不同来源外泌体具有不同的生物学功能,因此未来的研究可对不同细胞来源外泌体的具体效应进行针对性研究,以此为心血管疾病治疗提供更多的途径。 2.3.5 间充质干细胞来源外泌体 干细胞疗法最初被作为用于恢复受损心肌功能的再生疗法,其中间充质干细胞研究最为广泛。间充质干细胞是自我更新的多能基质细胞,可从各种组织中分离,并具有分化成各种细胞类型的能力[58]。间充质干细胞来源外泌体已被证明在多种疾病治疗中发挥巨大潜力。基于外泌体的治疗最近被认为是一种新兴的心脏再生工具,在促进血管生成、心脏修复和抑制心肌凋亡中发挥重要作用[59]。 (1)促进血管新生:在间充质干细胞来源外泌体发挥其心脏保护效用中,miRNA扮演着重要角色。Luther等[60]研究发现了具有心脏保护效应miRNA中的miR-21a-5p,随后证实外泌体miR-21a-5p由骨髓间充质干细胞通过多种途径协同作用转移到心肌细胞,最终发挥促进血管生成作用。ZHAO等[61]通过向急性心肌梗死模型大鼠尾静脉注射人脐带间充质干细胞来源外泌体,给药4周后显著改善了心脏的收缩功能并抑制心肌纤维化,促进细胞增殖和血管生成。随后MA等[62]通过腺病毒转染系统转染人脐带间充质干细胞,分离外泌体并通过尾静脉注射至急性心肌梗死模型,结果发现其能促进血管内皮细胞的增殖,心脏功能得到了明显改善。此外,脂肪间充质干细胞来源外泌体通过调节miR-155表达,改善内皮细胞功能,促进血管生成,保护缺血心肌免受缺血再灌注损伤[63-64]。 (2)抑制心肌细胞凋亡:心肌缺血再灌注是一种临床病理特征,可导致心肌细胞凋亡和坏死甚至患者心脏骤停。骨髓间充质干细胞来源外泌体具有抗凋亡和抗炎的作用。在大鼠心肌缺血再灌注模型中外泌体miR-125b通过调节SIRT7增强缺血再灌注损伤心肌细胞的通透性,抑制其凋亡和损伤,并恢复心肌缺血再灌注大鼠的心脏功能[65]。同类型实验还表明,骨髓间充质干细胞来源外泌体通过介导miR-486-5p抑制PTEN表达,激活PI3K/AKT信号通路,从而诱导心肌细胞增殖,抑制受损心肌细胞的凋亡[66]。ZHU等[67]对比永久心肌梗死小鼠模型中常氧/缺氧条件下骨髓间充质干细胞来源外泌体的给药效果,发现在缺氧条件下骨髓间充质干细胞来源外泌体的miR-125b-5p通过抑制p53和BAK1的表达,从而在体内外证明了对缺血心肌细胞的抗凋亡以及促进缺血性心脏修复的新机制,提高了小鼠心肌的治疗效率,这表明骨髓间充质干细胞来源外泌体能减轻心肌缺血再灌注与心肌梗死面积,并抑制心肌细胞凋亡从而保护受损心肌。 (3)修复受损心肌:在心肌梗死小鼠模型中,心肌内注射骨髓间充质干细胞来源外泌体刺激血管形成并抑制炎症反应,减少梗死面积,改善缺血性损伤后的心脏功能,通过防止心脏重塑而明确发挥心脏保护作用[68]。此外,新近的研究发现人子宫内膜间充质干细胞来源外泌体具备更大的治疗潜力,具有重要的临床意义,是心脏衰竭临床治疗的新方 向[69-70]。Smad7作为转化生长因子β信号通路中一个重要的下游调节因子,其高表达在细胞增殖和促进心肌修复等方面具有重要意义。有研究发现人脐带间充质干细胞来源外泌体通过抑制miR-125b-5p促进Smad7的表达,从而修复受损心肌,增强心脏功能。该研究还表明miR-125b-5p在心肌梗死患者中的表达水平高于健康受试者,较高的表达水平可能对心肌梗死的早期诊断具有诊断价值[68],因此,它可能是心血管疾病发展的重要调节因子。WEI等[71]首次证明了骨髓间充质干细胞来源外泌体miR-181a可能通过抑制c-Fos蛋白来抑制炎症反应并提高Treg细胞比例,激活Treg细胞的免疫抑制作用和细胞靶向性,从而促进心肌修复。此外,有研究证实了子宫内膜间充质干细胞来源外泌体相对于人骨髓间充质干细胞和脂肪间充质干细胞来源外泌体具有更好的心脏保护作用,并证明了子宫内膜间充质干细胞来源外泌体miR-21通过PTEN/Akt信号途径提高了心肌梗死后的细胞存活率,促进了受损心肌的修复作用[72]。 综上所述,各种间充质干细胞来源外泌体通过介导miRNA与相关蛋白或靶基因的表达,在促进血管新生、抑制心肌纤维化、改善心脏功能和心脏修复中发挥重要作用,也为心血管疾病的治疗提供了一种新型治疗方法,见表1。"
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