侯永波 余駿馬 朱海娟
摘要:心肌梗死是致死率較高的疾病之一,且疾病后期進(jìn)展常導(dǎo)致慢性心力衰竭的發(fā)生,探索新的治療方法對(duì)于心肌梗死的預(yù)后十分重要。外泌體是由細(xì)胞或組織液釋放的直徑為30~150 nm的納米級(jí)囊泡,其囊泡內(nèi)攜帶著來(lái)自親代細(xì)胞分泌的特異DNA、RNA、蛋白質(zhì)、脂質(zhì)和代謝廢物等物質(zhì),其作為心肌梗死的潛在治療方法在基礎(chǔ)實(shí)驗(yàn)中早已被證實(shí)。就不同細(xì)胞組織來(lái)源的外泌體、工程化外泌體以及外泌體細(xì)胞膜融合策略在心肌梗死治療中的研究進(jìn)展進(jìn)行綜述,為外泌體在臨床上的應(yīng)用提供科學(xué)證據(jù)。
關(guān)鍵詞:心肌梗死;外泌體;間質(zhì)干細(xì)胞;成纖維細(xì)胞;巨噬細(xì)胞;膜融合;微RNAs
中圖分類號(hào):R541文獻(xiàn)標(biāo)志碼:ADOI:10.11958/20230440
New research progress of exosomes in the treatment of myocardial infarction
HOU Yongbo YU Junma ZHU Haijuan
1 College of Anesthesiology-Wannan Medical College, Wuhu 241002, China; 2 Department of Anesthesiology, the Third Affiliated Hospital of Anhui Medical University, Hefei First People's Hospital; 3 Department of Anesthesiology,
Maternal and Child Health Hospital Affiliated to Anhui Medical University
Corresponding Author E-mail: 35880762@qq.com
Abstract: Myocardial infarction is one of the most lethal diseases, and the progression of the disease often leads to the occurrence of chronic heart failure. Therefore, it is very important to explore new treatment methods for the prognosis of myocardial infarction. Exosomes are nanoscale vesicles with a diameter of 30-150 nm released from cells or tissue fluid. The vesicles carry specific DNA, RNA, proteins, lipids, metabolic waste and other substances secreted by parental cells. As a potential treatment for myocardial infarction, it has long been confirmed in basic experiments. This article reviews the latest research progress of exosomes from different cells and tissues, engineered exosomes and exosome cell membrane fusion strategies in the treatment of myocardial infarction, and provides scientific evidence for the clinical application of exosomes.
Key words: myocardial infarction; exosomes; mesenchymal stem cells; fibroblasts; macrophages; membrane fusion; microRNAs
急性心肌梗死(AMI)可造成心肌細(xì)胞永久性死亡和組織繼發(fā)性纖維化瘢痕,嚴(yán)重影響患者生存質(zhì)量。盡管臨床上再灌注治療獲得了一定療效,但由于心室重構(gòu)的原因,部分患者最終進(jìn)展為慢性心力衰竭。因此探索新的治療藥物和技術(shù)對(duì)于心肌梗死治療具有重要意義。外泌體是一類細(xì)胞外囊泡,由Johnstone于1983年從綿羊的網(wǎng)織紅細(xì)胞中發(fā)現(xiàn)。起初研究者認(rèn)為外泌體僅作為細(xì)胞代謝過(guò)程中的“垃圾袋”這一角色存在。隨著對(duì)外泌體的深入研究,發(fā)現(xiàn)其還具有細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)、組織發(fā)育與修復(fù)、免疫調(diào)節(jié)等多個(gè)重要的病理生理作用[1]。機(jī)體多種細(xì)胞均可分泌外泌體,其攜帶的獨(dú)特蛋白質(zhì)和遺傳物質(zhì)基于親代細(xì)胞類型及細(xì)胞生理狀態(tài)而存在差異[2]。不同細(xì)胞來(lái)源的外泌體以不同機(jī)制在缺血心肌處發(fā)揮保護(hù)效應(yīng)。此外,通過(guò)構(gòu)建工程化外泌體和外泌體細(xì)胞膜融合策略,提高了外泌體靶向能力和治療效率,為外泌體生物制劑開(kāi)發(fā)提供了新的方向。
1 不同細(xì)胞來(lái)源外泌體的心肌保護(hù)作用
1.1 間充質(zhì)干細(xì)胞(mesenchymal stem cell,MSCs)源性外泌體 MSCs是一種多能干細(xì)胞,具有自我更新和多向分化的潛能。近年來(lái),越來(lái)越多的研究證明MSCs衍生的外泌體通過(guò)遞送囊泡內(nèi)信號(hào)分子至缺血心肌,對(duì)受損的心肌細(xì)胞同樣具有保護(hù)能力[3-5]。Tang等[3]發(fā)現(xiàn),間充質(zhì)干細(xì)胞源性外泌體(mesenchymal stem cell-derived exosomes,MSC-exos)可通過(guò)遞送miR-320b至受體細(xì)胞,下調(diào)受體細(xì)胞中的NOD樣受體熱蛋白結(jié)構(gòu)域相關(guān)蛋白3(NLRP3)蛋白表達(dá),抑制大鼠梗死區(qū)心肌細(xì)胞焦亡,減小心肌梗死面積。在另一項(xiàng)研究中,MSC-exos來(lái)源的miR-486-5p通過(guò)抑制H9C2心肌細(xì)胞缺氧狀態(tài)中磷酸酶基因(PTEN)的表達(dá),從而激活下游磷脂酰肌醇3-激酶/磷酸激酶B(PI3K/AKT)通路,最終誘導(dǎo)H9C2心肌細(xì)胞增殖并減少其凋亡[4]。此外,MSC-exos還可通過(guò)基因修飾使外泌體富集特定基因,來(lái)調(diào)節(jié)受體細(xì)胞的生物學(xué)行為。Sun等[5]將過(guò)表達(dá)缺氧誘導(dǎo)因子-1α(HIF-1α)慢病毒載體轉(zhuǎn)染至MSCs中,將過(guò)表達(dá)HIF-1α的MSC-exos經(jīng)尾靜脈血管注入到心肌梗死大鼠體循環(huán)中,28 d后發(fā)現(xiàn)梗死心肌纖維化程度降低,心室重構(gòu)減輕,同時(shí)超聲結(jié)果顯示大鼠左心室收縮末期內(nèi)徑和右心室舒張末期內(nèi)徑降低,左心室射血分?jǐn)?shù)和左心室短軸縮短率提高,保護(hù)了心臟泵功能,對(duì)心肌梗死起到明顯治療作用。
1.2 心臟祖細(xì)胞源性外泌體(cardiac progenitor cells,CPCs-exos) 祖細(xì)胞也稱前體細(xì)胞,分化程度處于干細(xì)胞和成體細(xì)胞兩者之間,擁有向心肌、心臟血管等心臟組織結(jié)構(gòu)分化的潛能[6]。CPCs-exos通過(guò)調(diào)節(jié)蛋白質(zhì)或靶基因的表達(dá),修復(fù)受損心肌和實(shí)現(xiàn)心臟保護(hù)效應(yīng)。Youn等[7]利用生物合成技術(shù)構(gòu)建高表達(dá)具有促血管生成作用的miR-322的CPCs-exos,與單獨(dú)注射CPCs-exos相比,高表達(dá)的miR-322通過(guò)煙酰胺腺嘌呤二核苷酸磷酸氧化酶2(NOX2)調(diào)節(jié)內(nèi)皮細(xì)胞遷移和刺激毛細(xì)血管生成,促進(jìn)心肌修復(fù)。除促血管生成作用外,CPCs-exos中的一些miRNA也可通過(guò)降低心肌細(xì)胞缺血缺氧狀態(tài)下的氧化應(yīng)激來(lái)發(fā)揮心肌保護(hù)效應(yīng)。Xiao等[8]研究發(fā)現(xiàn),心肌缺血再灌注期間,缺血心肌處活性氧大量生成,受氧化應(yīng)激刺激的CPCs分泌高表達(dá)miR-21的外泌體,旁分泌的外泌體通過(guò)與鄰近細(xì)胞膜融合傳遞miR-21,抑制靶細(xì)胞中的程序性細(xì)胞死亡因子4(PDCD4)的表達(dá),從而減少心肌細(xì)胞氧化應(yīng)激繼發(fā)的細(xì)胞凋亡。
1.3 血漿源性外泌體 除了干細(xì)胞來(lái)源之外,一些研究發(fā)現(xiàn)循環(huán)血液中的一些外泌體同樣具有心肌保護(hù)效應(yīng)。Vicencio等[9]研究證實(shí)血漿來(lái)源的外泌體其囊泡膜表面的熱休克蛋白(HSP70)通過(guò)調(diào)控Toll樣受體4-細(xì)胞外調(diào)節(jié)蛋白激酶1/2-P38絲裂原活化蛋白激酶(TLR4-ERK1/2-P38 MAPK)信號(hào)軸,使HSP27磷酸化,從而產(chǎn)生心肌保護(hù)效應(yīng)。此外,當(dāng)慢性心力衰竭的心肌經(jīng)歷缺血時(shí),血漿來(lái)源的外泌體對(duì)心肌也同樣具有保護(hù)作用。Luo等[10]通過(guò)永久性結(jié)扎大鼠心臟冠狀動(dòng)脈28 d構(gòu)建梗死后慢性心力衰竭模型,于心肌缺血前輸注缺血預(yù)處理后的供體大鼠血漿外泌體,發(fā)現(xiàn)心肌缺血面積顯著降低,同時(shí)乳酸脫氫酶、肌鈣蛋白,以及肌酸激酶同工酶指標(biāo)均優(yōu)于對(duì)照組。但血漿來(lái)源的外泌體并非全部具有保護(hù)作用,不同疾病狀態(tài)下的外泌體因內(nèi)容物含量差異而發(fā)揮不同的病理生理作用。研究發(fā)現(xiàn),健康志愿者血漿中的外泌體所包含的miR-342-3p能分別靶向心肌細(xì)胞中的SRY-box轉(zhuǎn)錄因子6(SOX6)和轉(zhuǎn)錄因子EB(TFEB)基因,抑制心肌細(xì)胞的凋亡和自噬,然而處于急性心肌梗死康復(fù)期(梗死后3~7 d)患者的血漿外泌體中miR-342-3p的含量是顯著下調(diào)的,對(duì)心臟修復(fù)不利[11]。因此,血漿源性的外泌體對(duì)缺血心肌的作用可能是多方面復(fù)雜的,還需要進(jìn)一步探究。
1.4 心肌細(xì)胞源性外泌體 不同微環(huán)境下的心肌細(xì)胞分泌的外泌體內(nèi)容物會(huì)有所差異,從而發(fā)揮出不同的心肌修復(fù)能力。此外,心肌細(xì)胞與心臟中其他細(xì)胞(如內(nèi)皮細(xì)胞、成纖維細(xì)胞、巨噬細(xì)胞等)間的細(xì)胞通訊和心臟功能關(guān)系密切且重要。Turner等[12]通過(guò)對(duì)左心室肥大和正常左心室人群樣本的人誘導(dǎo)多功能干細(xì)胞源性心肌細(xì)胞(hiPSC-CMs)及其各自分泌的外泌體RNA種類測(cè)序,發(fā)現(xiàn)兩者之間細(xì)胞和外泌體中RNA種類和數(shù)量呈現(xiàn)明顯不同的表達(dá)模式,接著將兩組外泌體分別和人誘導(dǎo)多功能干細(xì)胞源性內(nèi)皮細(xì)胞共孵育后,發(fā)現(xiàn)左心室肥大組外泌體促進(jìn)了內(nèi)皮細(xì)胞增殖,但血管生成和遷移減少,血管生成功能失調(diào),表明不同環(huán)境中外泌體的功能會(huì)受到調(diào)節(jié),且外泌體作為細(xì)胞間信息通信介質(zhì)的重要作用。
1.5 心臟成纖維細(xì)胞源性外泌體 心肌梗死后長(zhǎng)時(shí)間缺血過(guò)程中,心肌細(xì)胞陸續(xù)死亡,后期成纖維細(xì)胞增多,分泌膠原外纖維促進(jìn)瘢痕組織的形成,大量的瘢痕組織會(huì)代替正常的心臟結(jié)構(gòu),導(dǎo)致心臟收縮舒張功能受損,影響全身供血。但在心肌梗死期間心臟成纖維細(xì)胞分泌的外泌體中的miRNA表達(dá)異常,產(chǎn)生心肌保護(hù)作用。Liu等[13]研究表明,在SD大鼠心肌梗死模型中,心肌成纖維細(xì)胞分泌的外泌體中miR-133a表達(dá)異常升高,其通過(guò)靶向結(jié)合心肌細(xì)胞內(nèi)的ELAV樣RNA結(jié)合蛋白1(ELAVL1)基因,抑制心肌細(xì)胞焦亡。Luo等[14]通過(guò)建立細(xì)胞缺氧復(fù)氧和動(dòng)物缺血再灌注模型,用富含miR-423-3p的心臟成纖維細(xì)胞源性外泌體干預(yù),發(fā)現(xiàn)其靶向下游基因RAP2C,減輕了細(xì)胞凋亡,縮小了梗死面積,提示RAP2C作為一種新型靶向治療的可能性。
1.6 巨噬細(xì)胞源性外泌體 炎癥調(diào)控在心肌梗死后心室重構(gòu)的過(guò)程發(fā)揮重要作用,并與心肌梗死繼發(fā)的各種病理生理過(guò)程密切相關(guān)。巨噬細(xì)胞是機(jī)體固有免疫細(xì)胞,根據(jù)炎癥微環(huán)境的改變表現(xiàn)出促炎M1表型或抗炎M2表型。研究表明,在心肌梗死后M1型巨噬細(xì)胞浸潤(rùn)梗死心肌,隨后表型動(dòng)態(tài)改變?yōu)镸2表型,有助于從炎癥向修復(fù)的轉(zhuǎn)變[15],這一作用可能是通過(guò)巨噬細(xì)胞來(lái)源的外泌體來(lái)調(diào)控的。Wang等[16]發(fā)現(xiàn),心肌梗死后M1型巨噬細(xì)胞分泌高表達(dá)miR-155的M1型-外泌體(M1-exos),并可從巨噬細(xì)胞轉(zhuǎn)移到心肌成纖維細(xì)胞,基因敲除miR-155的小鼠心肌梗死后心臟破裂的發(fā)生率降低,心功能改善,而給予M1-exos或miR-155模擬物后,心臟破裂發(fā)生率增加、炎癥反應(yīng)也會(huì)加劇。Liu等[17]發(fā)現(xiàn),心肌梗死后多個(gè)促炎miRNAs在M1-exos中高表達(dá),包括上述的miR-155,其被轉(zhuǎn)移到內(nèi)皮細(xì)胞,通過(guò)下調(diào)沉默信息調(diào)節(jié)因子1/腺苷酸活化蛋白激酶α2(Sirt1/AMPKα2)-內(nèi)皮型NO合酶,抑制內(nèi)皮細(xì)胞血管生成。Dai等[18]發(fā)現(xiàn),M2型巨噬細(xì)胞來(lái)源外泌體(M2-exos)通過(guò)呈遞miR-148a至心肌細(xì)胞,下調(diào)靶基因硫氧還蛋白相互作用蛋白(TXNIP),通過(guò)調(diào)控Toll4樣受體/核因子κB/NOD樣受體熱蛋白結(jié)構(gòu)域相關(guān)蛋白3(TLR4/NF-κB/NLRP3)炎癥信號(hào)通路來(lái)減輕心肌缺血再灌注損傷。另一項(xiàng)研究發(fā)現(xiàn),靜脈注射M2-exos至心肌梗死后小鼠可將miR-1271-5p傳遞給心肌細(xì)胞,下調(diào)轉(zhuǎn)錄子編碼基因SOX6表達(dá),減少心肌細(xì)胞凋亡,保護(hù)心臟功能[19]。
此外,心肌細(xì)胞源性外泌體[20]、骨髓間充質(zhì)干細(xì)胞源性外泌體[21]、脂肪源性間充質(zhì)干細(xì)胞外泌體[22]及人臍帶間充質(zhì)干細(xì)胞源性外泌體[15]等均可通過(guò)調(diào)控巨噬細(xì)胞極化及其遷移來(lái)減輕炎癥和心肌損傷,促進(jìn)巨噬細(xì)胞極化可能是不同細(xì)胞來(lái)源外泌體發(fā)揮炎癥調(diào)控作用、改善心肌梗死后重構(gòu)的關(guān)鍵環(huán)節(jié)。
2 工程化外泌體和外泌體-細(xì)胞膜融合
外泌體是天然生物膜包被的直徑在30~150 nm的納米級(jí)囊泡,因囊泡膜具有與親代細(xì)胞相似的蛋白和脂質(zhì)組成,能被親代細(xì)胞優(yōu)先特異性攝?。?3]。在動(dòng)物實(shí)驗(yàn)中,外泌體主要通過(guò)心肌注射、冠狀動(dòng)脈注射和外周靜脈注射途徑給藥。雖然心肌注射效果更佳,但臨床實(shí)踐中操作困難、風(fēng)險(xiǎn)大、難以推廣,外周靜脈給藥后進(jìn)入循環(huán)中的外泌體會(huì)隨著血流進(jìn)入其他非特異性器官,如血流豐富的肝、肺、脾、腎等,心肌組織攝取量較少[24],且容易被免疫系統(tǒng)清除及補(bǔ)體系統(tǒng)破壞[25],導(dǎo)致體內(nèi)存留半衰期短。因此需要尋求新的方法來(lái)提高外泌體的免疫相容性和對(duì)心肌組織靶向特性。目前具有前景的研究是構(gòu)建工程化外泌體和外泌體-細(xì)胞膜融合策略。
2.1 工程化外泌體 當(dāng)來(lái)自于同源異體的外泌體進(jìn)入實(shí)驗(yàn)動(dòng)物的全身血管循環(huán)系統(tǒng)內(nèi)時(shí),滯留時(shí)間越長(zhǎng),越有利于外泌體在體內(nèi)的組織分布及提高治療效果[26]。Wei等[27]將分離純化的高表達(dá)CD47外泌體經(jīng)尾靜脈注射入大鼠體內(nèi)120 min后仍能在血漿中被檢測(cè)到,遠(yuǎn)遠(yuǎn)超過(guò)低于30 min檢測(cè)上限的對(duì)照組外泌體。該現(xiàn)象可能是由于外泌體中高表達(dá)的CD47減緩了自身在循環(huán)血液?jiǎn)魏送淌杉?xì)胞系統(tǒng)中清除速率。Yao等[28]利用微型雙管注射器將外泌體-纖維蛋白原混合液和凝血酶通過(guò)微創(chuàng)胸壁切口噴灑到Y(jié)orkshire 豬心臟表面,形成包含外泌體的凝膠涂層;隨后發(fā)現(xiàn),與直接將外泌體心肌注射相比,此種方法可延長(zhǎng)外泌體在心臟的滯留時(shí)間,且對(duì)于心肌梗死的保護(hù)作用更優(yōu)。
2.2 外泌體-細(xì)胞膜融合 Li等[29]將細(xì)胞外囊泡(extracellular vesicles,EVs)與血小板膜囊泡(platelet membrane vesicles,PMVs)通過(guò)0.4 μm和0.2 μm聚碳酸酯膜反復(fù)擠壓融合,形成血小板細(xì)胞外囊泡雜化膜(P-EVs),隨后經(jīng)熒光標(biāo)記后和EVs共同由尾靜脈注入心肌梗死大鼠模型中,24 h后將大鼠心臟、肝、肺、脾、腎、腦組織取出進(jìn)行體外熒光成像觀察,發(fā)現(xiàn)P-EVs較EVs更多地滯留到缺血受損的心肌組織,考慮可能是因?yàn)檠“逯饕ㄟ^(guò)血小板表面糖蛋白GPIbα與活化內(nèi)皮分泌的血管性血友病因子結(jié)合而粘附在受損血管壁上[30-31]。同時(shí)P-EVs與低氧誘導(dǎo)的人臍靜脈內(nèi)皮細(xì)胞共孵育后發(fā)現(xiàn),P-EVs增強(qiáng)了內(nèi)皮細(xì)胞增殖、遷移以及血管生成能力。在Zhang等[32]的研究中,間充質(zhì)干細(xì)胞來(lái)源的細(xì)胞外囊泡與單核細(xì)胞孵育后采用聚碳酸酯膜擠壓融合的方法制備單核細(xì)胞模擬仿生的間充質(zhì)干細(xì)胞源性外泌體(monocyte mimic-bioinspired MSC-Evs,Mon-Exos);Mon-Exos借助梗死后心肌組織對(duì)單核細(xì)胞的募集作用而靶向聚集在缺血受損心肌處,隨后旁分泌囊泡內(nèi)容物,促進(jìn)內(nèi)皮細(xì)胞成熟并調(diào)節(jié)巨噬細(xì)胞向M2型極化,減輕了大鼠缺血心肌處的炎癥反應(yīng)。
3 小結(jié)與展望
外泌體作為細(xì)胞間通信的重要信使,參與調(diào)節(jié)急性心肌梗死的病理生理過(guò)程,不同細(xì)胞來(lái)源的外泌體由于其包含生物活性分子的差異,使其能通過(guò)不同的信號(hào)通路發(fā)揮各種心肌保護(hù)效應(yīng)。雖已有大量的研究去探索外泌體生物功能,但是目前對(duì)外泌體的生物發(fā)生、分泌、靶向受體細(xì)胞的作用機(jī)制還沒(méi)有完全詮釋。且外泌體體積小,如何分離純化高效制備外泌體仍需深入研究。將外泌體與其他細(xì)胞融合形成雜化膜,可繼承雙方特性,提高外泌體對(duì)缺血心肌的靶向能力和治療效率,為外泌體在心肌梗死方面的治療開(kāi)辟了新方向。后續(xù)開(kāi)發(fā)新的融合技術(shù),將外泌體與其他細(xì)胞膜融合或融合后的雜化膜作為藥物遞送載體可能是未來(lái)的研究方向。
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(2023-03-27收稿 2023-04-19修回)
(本文編輯 李志蕓)