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通讯作者:

周青,E-mail:qingzhou.wh.edu@hot⁃mail.com

中图分类号:R542.2

文献标识码:A

文章编号:1007-4368(2022)04-588-07

DOI:10.7655/NYDXBNS20220421

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目录contents

    摘要

    大量研究表明间充质干细胞(mesenchymal stem cell,MSC)主要通过旁分泌作用抑制细胞凋亡、抑制心肌纤维化、促进血管生成、抑制免疫反应来修复心肌损伤,外泌体在其中起主要作用。外泌体是细胞分泌的天然的纳米载体,内含细胞特异性蛋白、核酸和脂质。与脂质体载体相比,还具有低免疫原性、无细胞毒性及能够穿透生物屏障等优点。目前已有多种靶向心脏的工程外泌体在动物心肌梗死模型中取得很好的疗效。本文就MSC及MSC来源外泌体促进心肌梗死后受损心肌修复的机制及研究进展作一综述。

    Abstract

    There is mounting evidence that mesenchymal stem cell(MSC)help repair damage myocardial tissues primarily by means of secreting paracrine factors to inhibit cell apoptosis,inhibit myocardial fibrosis,promote angiogenesis and inhibit immune response. Recent studies have confirmed that these effects may be mainly mediated by exosomes. Exosomes are natural nano carriers secreted by cells,and contain cell⁃specific nucleic acids,proteins and lipids. Compared to liposome carriers,exosomes are low toxicity, less immunogenic,and can penetrate biological barriers. At present,many kinds of engineered exosomes targeting the heart have achieved good curative effects in animal models of myocardial infarction. This article reviews the mechanism research progress of MSC and exosomes derived from MSC in promoting the repair of damaged myocardium after myocardial infarction.

  • 心肌梗死(myocardial infarction,MI)是一种严重的心血管疾病,虽然通过介入治疗、药物溶栓或冠脉搭桥等治疗手段重建血运可以挽救濒死心肌,但《柳叶刀》发布的《1990—2017年中国及其各省的死亡率、发病率和危险因素》报告显示缺血性心脏病为中国人目前的第二大死亡原因,90%由冠状动脉狭窄和梗塞诱发[1]。AMI发病2h内是黄金救治时间;发病后6h内进行血管开通最佳;发病后12h为再灌注治疗时间窗。而对于超过治疗时间窗的患者,目前临床治疗效果欠佳。

  • 1 间充质干细胞(mesenchymal stem cell,MSC)治疗MI

  • 1.1 MSC治疗MI的主要机制

  • MSC治疗MI的机制复杂,研究认为干细胞可通过分化为心肌细胞发挥修复作用[2],然而梗死区域微环境恶劣,移植干细胞难以存活,与明显改善的心功能不相匹配,目前研究认为修复梗死心肌主要是通过旁分泌实现的。MSC以细胞外囊泡的方式分泌生长因子、细胞因子、趋化因子及外泌体等并作用于邻近的细胞,通过促血管生成、抗凋亡、抑制炎症反应、改善微环境,促进损伤修复[3]

  • 1.2 MSC治疗MI的疗效

  • Mazo等[4] 通过心内膜注射移植脂肪间充质干细胞(adipose⁃derived stem cell,ADSC)来治疗MI猪心肌缺血再灌注损伤(ischemia⁃reperfusion injury,I/R),发现3个月后其心肌内血管密度增加,心室重构减轻。Gautam等[5] 研究发现,通过向梗死心肌组织内注射ADSC治疗大鼠MI,可有效改善其心肌收缩功能,并减少继发性室性心律失常的发生率。目前已有大量临床研究证实干细胞移植能促进受损心肌修复。干细胞移植治疗MI的第1个重要的临床随机试验BOOST研究共入组60例ST段抬高型MI患者,这些患者在经皮冠状动脉介入后,随机分为治疗后最优药物治疗组(对照组)和最优药物治疗加术后平均4.8d冠状动脉内移植自体骨髓间充质干细胞 (bone marrow stromal cell,BMSC)(BMSC组)[6]。6个月后随访BMSC组左心室射血分数(left ventricular ejection fraction,LVEF)提高6.7%,而对照组仅提高0.7%。BMSC移植也未增加支架内再狭窄发生率和心律失常发生率。REPAIR试验是1项随机、对照、双盲、多中心研究,发现移植BMSC后LVEF平均升高5.5%,LVEF可达54%,且心脏扩大程度更小,提示心脏重构减轻[7]。该研究还发现BMSC移植明显提高MI区动脉的血流储备,提示可能通过生成新生血管来修复损伤区心肌。亚组分析发现大面积MI患者在MI后4个月就可以发现明显获益。1项Meta分析研究表明,经过移植BMSC治疗,基础LVEF低于42%的MI患者,其LVEF在2年后增加了5.09%,说明MSC治疗能改善MI患者的远期左室收缩功能[8]

  • 1.3 干细胞治疗MI在临床应用中受限

  • 近年来,干细胞移植给MI的治疗带来了新的希望。然而Assis等[9]发现经静脉注射的干细胞约70%分布在肺部,其余主要分布在肾脏、脾脏和膀胱,只有很少量干细胞能到达梗死区域,过量注射干细胞可能发生静脉栓塞。经冠脉注射干细胞若操作不当也可能引起微循环堵塞而加重MI症状。此外干细胞疗法还存在法律和伦理问题,诸多因素使其在临床中的应用受到很大限制[10]

  • 2 外泌体治疗MI

  • 2.1 外泌体的特征

  • 外泌体是由真核细胞分泌至细胞外的直径30~150nm具有脂质双层膜结构的微小囊泡,表面具有特异性标志,可携带母体细胞的小分子蛋白质、 DNA、mRNA、microRNA和非编码RNA(long non ⁃ coding RNA,lncRNA)等,发挥细胞间信号传导的生物学作用[11-13]。外泌体的双层膜结构不但能阻止其内含物被酶消化或化学分解,与其他常见的基因载体如质粒、病毒和脂质体等相比,还具有高携载率、低免疫原性、无细胞毒性及能够穿透生物屏障等优点[14]。大量研究表明外泌体在心血管疾病的旁分泌信号传导中发挥重要作用,其可参与介导血管平滑肌细胞之间[15]、血管平滑肌和内皮细胞之间[16]、心肌细胞和心肌成纤维细胞之间[17] 的信号交流,正是由于该特性,越来越多的研究将其作为天然的纳米载体来治疗疾病。

  • 2.2 外泌体治疗MI的机制

  • 近年来已有大量研究报道了用干细胞来源的外泌体治疗MI和I/R。2010年Lai等[18] 首次报道了人类胚胎干细胞分化成的MSC来源的外泌体(MSC⁃ derived exosome,MSC⁃exo)可以有效减轻MI小鼠的心肌I/R;后续报道进一步证实,MSC ⁃exo能减少45%心梗面积,且在治疗后28d仍可有效抑制心室负性重构,推测该作用与外泌体减少组织氧化应激有关[19]。该团队的研究表明外泌体不仅在急性期有治疗作用,还能改善MI后的长期预后。研究显示[20],将人类诱导的多能干细胞分化而来的心肌细胞、平滑肌细胞和内皮细胞接种于纤维蛋白基质形成心肌补片,再将心肌补片移植至MI猪的心脏,4周后评价疗效,发现由“补片”释放的外泌体能减小梗死面积,降低心脏壁压力,减轻心肌肥大,提高左室收缩功能,促进心肌细胞存活。研究表明,间充质干细胞来源外泌体可以通过多种途径促进受损心肌修复。

  • 2.2.1 抑制心肌细胞凋亡

  • 研究表明MSC释放富含miR⁃22和miR⁃221的外泌体,被缺血心肌细胞内吞后,可分别抑制心肌细胞内的甲基化CpG结合蛋白2及p53,上调凋亡调控因子,减轻缺血心肌损伤及凋亡[21-22]。过表达GATA4的MSC⁃exo通过上调miRNA⁃199a激活Akt及Erk信号通路起到心肌细胞保护作用[19]。ADSC来源外泌体(ADSC⁃derived exosome,ADSC⁃exo)携带的miR⁃320d可以通过靶向STAT3来减少细胞凋亡并提高细胞活力来保护心肌细胞[23]。人脐带间充质干细胞来源外泌体(human umbilical cord mesenchymal stem cell⁃derived exosome,hucMSC⁃exo)能通过miR⁃19a下调PTEN和BIM表达,激活AKT和ERK信号通路,同时通过靶向SRY⁃box转录因子⁃6(SRY⁃box transcription factor 6,SOX⁃6)抑制JNK/caspase⁃3激活,抑制MI大鼠受损心肌细胞凋亡[24]。BMSC来源外泌体(BMSC⁃ derived exosome,BMSC ⁃ exo)携带的miR ⁃ 486 ⁃ 5p、 miR⁃21、miR⁃144通过抑制PTEN表达,激活PI3K/AKT信号通路,进而抑制受损心肌细胞的凋亡[25-27]。 MSC⁃exo可以通过AMPK/mTOR和Akt/mTOR通路诱导心肌细胞自噬来减少缺氧心肌细胞凋亡,I/R模型大鼠体内注射MSC⁃exo可上调心肌LC3B表达,明显减少细胞凋亡和心肌梗死面积,改善心脏功能[28]。人间充质干细胞(human mesenchymal stem cell,hMSC) 分泌的外泌体中,lncRNA KLF3⁃AS1可通过抑制Sirt1来抑制MI大鼠受损心肌凋亡并减缓MI进展[29]。MSC⁃exo携带的miR⁃25⁃3p可通过下调FASL、 PTEN、EZH2和H3K27me3,上调心脏保护基因eNOS和抗炎基因SOCS3,减少小鼠MI受损心肌凋亡[30]。MI大鼠心肌内注射过表达miR⁃210的MSC⁃exo可以通过下调凋亡诱导因子3(apoptosis inducing factor 3,AIFM3),减少受损心肌细胞凋亡[31]。心肌细胞H9C2与过表达miR⁃338的外泌体共培养,能明显下调Bax、caspase3和凋亡率,上调Bcl⁃2,心肌内注射过表达miR ⁃ 338的外泌体可以通过靶向MAP3K2调节JNK,减少MI大鼠受损细胞凋亡[32]

  • 2.2.2 调节免疫细胞和炎症水平

  • MSC⁃exo通过miR⁃182,抑制其下游靶点Toll样受体4(Toll like receptor 4,TLR4),可促进I/R受损组织中的M1型巨噬细胞向M2型巨噬细胞转化,促进巨噬细胞由促炎型向抑炎型转化,降低I/R心脏炎症水平,减少心肌细胞损伤[33]。ADSC⁃exo通过miR⁃126,抑制NF⁃κB和转化生长因子(transforming growth factor,TGF)⁃β1表达,促进梗死心肌组织的M1型巨噬细胞向M2型巨噬细胞转化,降低炎症细胞因子的表达和心脏纤维化[34-35]。BMSC⁃exo可通过miR⁃25⁃3p抑制炎症细胞因子白细胞介素(interleu⁃ kin,IL)⁃1β、IL ⁃6和肿瘤坏死因子(tumor necrosis factor,TNF)⁃α及促凋亡蛋白如FASL和PTEN,减轻MI心肌损伤[30]。脂多糖预处理的BMSC分泌的外泌体能抑制脂多糖依赖性NF⁃κB信号通路并部分激活AKT1/AKT2信号通路,增加M2型巨噬细胞极化并降低M1型巨噬细胞极化,减轻小鼠MI后梗死区域炎症和心肌细胞凋亡[36]。ADSC⁃exo通过激活S1P/SK1/S1PR1信号转导,促进巨噬细胞向M2型极化,抑制NF⁃κB和TGF⁃β1表达,抑制炎症反应并减轻心肌纤维化来改善MI后的心脏损伤[35]。低温预处理的ADSC⁃exo可进一步下调MI大鼠炎症因子IL⁃1β/TNF⁃α/NF⁃κB/MMP⁃9,上调抑炎因子IL⁃10,减轻梗死后炎症反应;激活PI3K/Akt/GSK3β 和pm⁃TOR,抑制氧化应激相关蛋白(NOX⁃1/NOX⁃2/NOX⁃4/氧化蛋白)、凋亡/线粒体损伤相关蛋白(线粒体⁃Bax/caspase3/PARP/p53/cytosolic⁃cytochrome⁃C),减轻氧化应激损伤[37]

  • 2.2.3 促进内皮细胞增殖、迁移及血管新生

  • MI后心肌细胞发生凋亡,心脏组织处于修复状态,梗死区的新生血管形成尤为重要。血小板分泌的生长因子能够诱导ADSC分泌富含促血管生成的外泌体,促进血管再生[38]。Bian等[39] 发现在急性MI小鼠模型心肌中注射MSC ⁃exo可显著促进血管新生。阿托伐他汀预处理的MSC⁃exo可以通过lncRNA H19上调促血管内皮生长因子和细胞间黏附分子⁃1,促进血管新生[40]。ADSC⁃exo通过miRNA⁃31上调缺氧诱导因子⁃1α,促进人脐静脉内皮细胞迁移及管腔形成[41]。心脏祖/干细胞源外泌体可促进内皮细胞迁移,并且通过上调miRNA⁃132及miRNA⁃146a促进人脐静脉内皮细胞管腔形成[42]。miRNA ⁃132与TGF⁃β协同作用抑制p120Ras GAP表达,活化Ras通路,导致内皮细胞发生表型转换[43];另外miRNA⁃ 146a还能通过抑制CARD10进而激活NF⁃κB信号通路[44]。除了miRNA⁃132及miRNA⁃146a参与内皮细胞迁移及血管形成进程外,miRNA⁃320、miRNA⁃143等亦参与其中[45]

  • 2.2.4 减轻心脏重构

  • 研究发现小鼠缺血再灌注模型中,MSCs⁃exo能激活PI3K/Akt通路,减少心肌细胞凋亡,减弱氧化应激,增加ATP以及NADH修复心肌能量,继而促进心肌细胞存活,抑制心肌重构[19]。心肌内注射hucMSC⁃exo能明显减少MI大鼠心肌纤维化,改善心脏收缩功能[46]。ADSC⁃exo携带的miR⁃146通过下调早期生长反应因子⁃1抑制MI后的心肌纤维化[47]。外泌体携带的miR⁃29b和miR⁃455可下调MMP⁃9的表达,从而降低心肌纤维化程度[48]。BMSC⁃exo携带的miR⁃19a/19b能明显抑制心肌细胞的凋亡,且Exo/miR⁃19a/19b和MSC移植的组合增强了MI模型中心脏功能的恢复并减少了心脏纤维化[49]。BMSC⁃exo携带的miR⁃185可通过抑制SOCS2减少MI小鼠的心室重塑,改善心脏功能[50]。MSC⁃Exo能促进心肌细胞H9C2增殖,抑制H2O2诱导的细胞凋亡,并抑制TGF⁃β 诱导的成纤维细胞向肌成纤维细胞转化,减轻心脏纤维化[51]

  • 3 新型外泌体及外泌体载体

  • 外泌体静脉注射进入体内后会迅速聚积在肝脏、脾脏、肾脏等器官中并迅速被胆管系统、泌尿系统排除体外或被网状内皮细胞吞噬,在心脏组织中含量极低[52],因此延长外泌体在心肌组织的滞留时间、增加其靶向特异性是提高其疗效的必然要求[53]。目前的研究主要集中在构建工程化外泌体和研发新型外泌体载体。

  • 3.1 靶向心脏的工程外泌体

  • 3.1.1 用肽/蛋白质对外泌体膜进行化学修饰

  • 科学家们通过噬菌体展示技术以及体内淘选技术研发出可以特异性结合到心血管系统的归巢肽。 Kanki等[54] 通过该技术发现多肽序列CSTSMLKAC可以靶向缺血心肌组织。 Vandergriff等[55]通过DOPE⁃NHS与CHP反应,使DOPE⁃CHP的亲脂性尾部插入外泌体膜中,从而使外泌体膜携带CSTSMLKAC肽。体外研究表明,使用CHP肽外泌体可以增加外泌体摄取,提高细胞活力,减少细胞凋亡。通过I/R大鼠模型,证实该技术可以有效改善心脏功能,减少梗死面积,促进细胞增殖和血管生成。研究表明,给MI小鼠静脉注射携带缺血心肌靶向肽的缺氧条件下衍生的BMSC⁃exo,能靶向心脏缺血病变部位,通过抑制心肌细胞凋亡促进受损心肌修复[56]

  • 3.1.2 通过基因或化学修饰使外泌体分泌细胞表达肽/蛋白质

  • Wang等[57] 采用分子克隆技术,将CSTSMLKAC肽插入到外泌体表面普遍富集的跨膜蛋白Lamp2b基因序列上,通过慢病毒包装技术,使BMSC高表达CSTSMLKAC肽和Lamp2b。体外实验结果表明,该技术可以使缺氧损伤的H9C2细胞外泌体摄取明显增加。在小鼠MI模型中,与空白外泌体相比,缺血区CSTSMLKAC肽外泌体明显增多。同时,该外泌体治疗可减轻缺血心肌的炎症和细胞凋亡,减少纤维化,促进血管生成,改善心功能。

  • Wang等[58] 将靶向心肌肌钙蛋白I的STSMLKA肽融合到Lamp2b的N端并通过基因转染技术使其在BMSC中高表达,收集高表达STSMLKA肽的外泌体,再通过电穿孔技术将下调细胞增殖抑制基因表达的hsa⁃miR⁃590⁃3p加载到修饰后的外泌体,通过静脉注射的方式,该工程化外泌体能聚集在MI大鼠梗死区域,增强了梗死周围区域的心肌细胞增殖并改善心脏功能。

  • 3.2 外泌体载体

  • 外泌体的理想载体材料应具有以下特点:①在目标部位有效保留外泌体并保持其结构完整性;② 将外泌体释放到基质中,发挥其生物学功能;③与目标部位紧密贴合,促进外泌体被周围细胞吞噬。构建外泌体载体的常用方法如下。

  • 3.2.1 磁性纳米颗粒

  • 有研究团队共同构建纳米颗粒,该颗粒由Fe3O4核和二氧化硅外壳组成,外壳上修饰聚乙二醇,通过腙键与抗CD63和抗肌球蛋白轻链(myosin light chain,MLC)结合,双抗体通过与外泌体表面的CD63抗原结合捕获外泌体,再与受损心肌细胞上的MLC表面标志物结合,在受损心肌组织酸性pH环境中,腙键发生断裂导致捕获的外泌体局部释放[59]。在兔和大鼠MI模型中,磁引导下捕捉到的表达CD63的外泌体积聚在梗死组织中,使梗死面积减小, LVEF和血管生成得到改善。该研究首次提出通过操纵内源性外泌体生物学分布,建立了外泌体治疗MI的新方法。

  • 3.2.2 功能性多肽水凝胶

  • 有研究利用肽两亲物PA和NapFF自组装肽水凝胶,将心脏保护肽(GHRPS)和基质金属蛋白酶 (matrix metalloproteinase,MMP)⁃2可降解序列Gly⁃ Thr⁃Ala⁃Gly⁃Leu⁃Ile⁃Gly⁃Gln(GTAGLIGQ)加入水凝胶中制备出PGN水凝胶,再用PGN水凝胶包封外泌体[60]。其中GHRPS属于生长激素释放肽的成员,可以激活促存活途径并抑制炎症和纤维化,而MMP⁃2可降解序列能够使水凝胶降解,确保包封的外泌体和GHRPS肽释放到周围组织中。研究结果证实外泌体⁃PGN水凝胶能够有效包封外泌体并确保外泌体的稳定性和持续释放,将外泌体⁃PGN水凝胶注入大鼠心脏的梗死边界区,治疗后21d仍能在缺血心脏组织中检测到PKH⁃26标记的外泌体。

  • 有研究团队采用微创的方式,通过经皮心包膜内导管在MI小鼠心包腔内喷涂含MSC⁃exo的血小板纤维蛋白凝胶,明显改善了心脏功能并减少了纤维化,并促进了内源性血管生成[61⁃62]。该团队还在猪MI模型中比较了外泌体凝胶开胸递送方法与胸腔镜引导的微创外泌体凝胶注射方法,血常规报告显示开胸手术组的中性粒细胞和白细胞计数高于微创组,炎症反应较重。该微创凝胶注射技术减少了创伤性手术的不利影响,更有利于临床转化[62]

  • 4 小结与展望

  • 综上所述,MSC主要通过旁分泌作用抑制细胞凋亡、抑制心肌纤维化、促进血管生成、抑制免疫反应来修复心肌损伤。外泌体是低免疫原性、无毒、高度稳定的天然纳米载体,目前已有多种靶向心脏的工程外泌体及新型外泌体载体在动物MI模型中取得很好疗效。然而外泌体进入MI临床研究仍存在诸多困难,如目前通过超速离心法提取外泌体耗时长效率低,诸多研究中外泌体仍通过有创方式进入体内且在心脏停留时间较短。MSC⁃exo用于治疗MI,机遇与挑战并存,困难与希望同在,亟待进一步研究改进。

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    • [26] SHI B,WANG Y,ZHAO R,et al.Bone marrow mesenchy⁃ mal stem cell ⁃ derived exosomal miR ⁃21 protects C ⁃ kit+ cardiac stem cells from oxidative injury through the PTEN/PI3K/Akt axis[J].PLoS One,2018,13(2):e0191616

    • [27] WEN Z,MAI Z,ZHU X,et al.Mesenchymal stem cell⁃de⁃ rived exosomes ameliorate cardiomyocyte apoptosis in hy⁃ poxic conditions through microRNA144 by targeting the PTEN/AKT pathway[J].Stem Cell Res Ther,2020,11(1):36

    • [28] LIU L,JIN X,HU C F,et al.Exosomes derived from mes⁃ enchymal stem cells rescue myocardial ischaemia/reperfu⁃ sion injury by inducing cardiomyocyte autophagy via AMPK and Akt pathways[J].Cell Physiol Biochem,2017,43(1):52-68

    • [29] MAO Q,LIANG X L,ZHANG C L,et al.LncRNA KLF3⁃ AS1 in human mesenchymal stem cell ⁃ derived exosomes ameliorates pyroptosis of cardiomyocytes and myocardial infarction through miR ⁃ 138 ⁃ 5p/Sirt1 axis[J].Stem Cell Res Ther,2019,10(1):393

    • [30] PENG Y,ZHAO J L,PENG Z Y,et al.Exosomal miR⁃25⁃ 3p from mesenchymal stem cells alleviates myocardial in⁃ farction by targeting pro⁃apoptotic proteins and EZH2[J].Cell Death Dis,2020,11(5):317

    • [31] CHENG H,CHANG S,XU R,et al.Hypoxia ⁃challenged MSC⁃derived exosomes deliver miR⁃210 to attenuate post⁃ infarction cardiac apoptosis[J].Stem Cell Res Ther,2020,11(1):224

    • [32] FU D L,JIANG H,LI C Y,et al.MicroRNA⁃338 in MSCs⁃ derived exosomes inhibits cardiomyocyte apoptosis in myocardial infarction[J].Eur Rev Med Pharmacol Sci,2020,24(19):10107-10117

    • [33] ZHAO J,LI X,HU J,et al.Mesenchymal stromal cell⁃de⁃ rived exosomes attenuate myocardial ischaemia ⁃ reperfu⁃ sion injury through miR⁃182⁃regulated macrophage polar⁃ ization[J].Cardiovasc Res,2019,115(7):1205-1216

    • [34] LUO Q,GUO D,LIU G,et al.Exosomes from MiR ⁃126⁃ overexpressing adscs are therapeutic in relieving acute myocardial ischaemic injury[J].Cell Physiol Biochem,2017,44(6):2105-2116

    • [35] DENG S,ZHOU X,GE Z,et al.Exosomes from adipose⁃ derived mesenchymal stem cells ameliorate cardiac dam⁃ age after myocardial infarction by activating S1P/SK1/S1PR1 signaling and promoting macrophage M2 polariza⁃ tion[J].Int J Biochem Cell Biol,2019,114:105564

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    • [37] CHAI H T,SHEU J J,CHIANG J Y,et al.Early adminis⁃ tration of cold water and adipose derived mesenchymal stem cell derived exosome effectively protects the heart from ischemia ⁃ reperfusion injury[J].Am J Transl Res,2019,11(9):5375-5389

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    • [40] HUANG P,WANG L,LI Q,et al.Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells ⁃ de⁃ rived exosomes in acute myocardial infarction via up⁃regu⁃ lating long non ⁃ coding RNA H19[J].Cardiovasc Res,2020,116(2):353-367

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    • [44] RAU C S,YANG J C,CHEN Y C,et al.Lipopolysaccha⁃ ride⁃induced microRNA⁃146a targets CARD10 and regu⁃lates angiogenesis in human umbilical vein endothelial cells[J].Toxicol Sci,2014,140(2):315-326

    • [45] PARIKH M,PIERCE G N.A brief review on the biology and effects of cellular and circulating microRNAs on car⁃ diac remodeling after infarction[J].Int J Mol Sci,2021,22(9):4995

    • [46] ZHAO Y,SUN X,CAO W,et al.Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury[J].Stem Cells Int,2015,2015:761643

    • [47] PAN J,ALIMUJIANG M,CHEN Q,et al.Exosomes de⁃ rived from miR⁃146a⁃modified adipose⁃derived stem cells attenuate acute myocardial infarction⁃induced myocardial damage via downregulation of early growth response fac⁃ tor 1[J].J Cell Biochem,2019,120(3):4433-4443

    • [48] QI Z,WU D,LI M,et al.The pluripotent role of exosomes in mediating non ⁃ coding RNA in ventricular remodeling after myocardial infarction[J].Life Sci,2020,254:117761

    • [49] WANG S,LI L,LIU T,et al.miR ⁃ 19a/19b ⁃loaded exo⁃ somes in combination with mesenchymal stem cell trans⁃ plantation in a preclinical model of myocardial infarction [J].Regen Med,2020,15(6):1749-1759

    • [50] LI Y,ZHOU J,ZHANG O,et al.Bone marrow mesenchy⁃ mal stem cells⁃derived exosomal microRNA⁃185 repress⁃ es ventricular remolding of mice with myocardial infarc⁃ tion by inhibiting SOCS2[J].Int Immunopharmacol,2020,80:106156

    • [51] SHAO L,ZHANG Y,LAN B,et al.MiRNA⁃sequence in⁃ dicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair[J].Biomed Res Int,2017,2017:4150705

    • [52] PULIAFICO S B,PENN M S,SILVER K H.Stem cell therapy for heart disease[J].J Gen Intern Med,2013,28(10):1353-1363

    • [53] TANG J,SHEN D,CARANASOS T G,et al.Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome[J].Nat Commun,2017,8:13724

    • [54] KANKI S,JAALOUK D E,LEE S,et al.Identification of targeting peptides for ischemic myocardium by in vivo phage display[J].J Mol Cell Cardiol,2011,50(5):841-848

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    • [56] ZHU L P,TIAN T,WANG J Y,et al.Hypoxia ⁃ elicited mesenchymal stem cell⁃derived exosomes facilitates cardi⁃ ac repair through miR ⁃125b ⁃mediated prevention of cell death in myocardial infarction[J].Theranostics,2018,8(22):6163-6177

    • [57] WANG X,CHEN Y,ZHAO Z,et al.Engineered exosomes with ischemic myocardium ⁃targeting peptide for targeted therapy in myocardial infarction[J].J Am Heart Assoc,2018,7(15):e008737

    • [58] WANG Y,DING N,GUAN G,et al.Rapid delivery of hsa⁃ miR⁃590⁃3p using targeted exosomes to treat acute myo⁃ cardial infarction through regulation of the cell cycle[J].J Biomed Nanotechnol,2018,14(5):968-977

    • [59] LIU S,CHEN X,BAO L,et al.Treatment of infarcted heart tissue via the capture and local delivery of circulat⁃ ing exosomes through antibody ⁃ conjugated magnetic nanoparticles[J].Nat Biomed Eng,2020,4(11):1063-1075

    • [60] HAN C,ZHOU J,LIANG C,et al.Human umbilical cord mesenchymal stem cell derived exosomes encapsulated in functional peptide hydrogels promote cardiac repair[J].Biomater Sci,2019,7(7):2920-2933

    • [61] TANG J,VANDERGRIFF A,WANG Z,et al.A regenera⁃ tive cardiac patch formed by spray painting of biomateri⁃ als onto the heart[J].Tissue Eng Part C Methods,2017,23(3):146-155

    • [62] YAO J,HUANG K,ZHU D,et al.A minimally invasive exosome spray repairs heart after myocardial infarction [J].ACS Nano,2021,15(7):11099-11111

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