楊俊林 曲樂(lè)豐

間充質(zhì)干細(xì)胞治療主動(dòng)脈瘤的研究進(jìn)展

楊俊林 曲樂(lè)豐

主動(dòng)脈瘤（AA）是嚴(yán)重危害人類(lèi)健康的心血管系統(tǒng)疾病，一旦破裂出血，死亡率極高。目前AA的治療主要通過(guò)手術(shù)干預(yù)，但開(kāi)放手術(shù)風(fēng)險(xiǎn)很大；介入治療雖然創(chuàng)傷較小，但也存在諸多局限性，如解剖結(jié)構(gòu)的限制、遠(yuǎn)期管理等。因此，有必要探索新方法在早期進(jìn)行干預(yù)。目前認(rèn)為，AA的發(fā)病主要是由于主動(dòng)脈壁細(xì)胞外基質(zhì)（ECM）合成和降解失衡。慢性炎癥能直接或間接地促進(jìn)該降解過(guò)程，是AA形成的重要因素。間充質(zhì)干細(xì)胞（MSC）具有抗炎和免疫抑制的特性，還能特異性地募集到損傷部位，在治療AA中表現(xiàn)出獨(dú)特的優(yōu)勢(shì)。本文就MSC治療AA的機(jī)制做一綜述。

間質(zhì)干細(xì)胞； 主動(dòng)脈瘤

主動(dòng)脈瘤（aortic aneurysm，AA）是一種嚴(yán)重的心血管系統(tǒng)疾病，一旦破裂出血，死亡率極高。AA起病隱匿，早期缺乏典型的臨床癥狀。通常采用開(kāi)放手術(shù)或介入的方式進(jìn)行治療，但均有局限性：開(kāi)放手術(shù)創(chuàng)傷很大，患者面臨巨大的手術(shù)風(fēng)險(xiǎn)；介入雖然微創(chuàng)，但受限于解剖結(jié)構(gòu)，且存在移植物移位、內(nèi)漏等并發(fā)癥[1]。此外，外科操作對(duì)于尚不符合指征的或處于病變?cè)缙诘那闆r無(wú)能為力。阻止疾病進(jìn)展顯得尤為重要，因此需要新的方法在早期進(jìn)行干預(yù)。目前已有藥物治療、基因治療或細(xì)胞治療等新方法[2]。間充質(zhì)干細(xì)胞（mesenchymal stem cell，MSC）因其獨(dú)特的性質(zhì)，廣泛用于細(xì)胞治療和再生醫(yī)學(xué)。MSC已用于多種疾病的臨床治療，其中應(yīng)用最廣的是心血管系統(tǒng)疾?。〒?jù)clinicaltrils.gov統(tǒng)計(jì)）。本文將對(duì)AA的發(fā)病機(jī)理和MSC治療的機(jī)制做一綜述。

一、疾病概況

心血管系統(tǒng)疾病目前已成為世界范圍內(nèi)首位致死性非傳染疾病。在美國(guó)，AA每年導(dǎo)致10 500例患者死亡[3]。AA發(fā)病機(jī)制尚未完全闡明，流行病學(xué)調(diào)查顯示它跟吸煙、高齡、性別和家族史有密切關(guān)聯(lián)[4-5]。目前研究認(rèn)為，AA的分子機(jī)制可歸結(jié)為主動(dòng)脈壁細(xì)胞外基質(zhì)（extracellular matrices，ECM）的合成和降解失衡；而慢性炎癥反應(yīng)，特別是動(dòng)脈粥樣硬化，在疾病發(fā)生過(guò)程中起重要作用[6]。ECM主要由彈性蛋白和膠原組成，為主動(dòng)脈提供彈性支撐。彈性蛋白是主動(dòng)脈壁的主要纖維成分，其降解將直接導(dǎo)致動(dòng)脈擴(kuò)張[7]。彈性蛋白由血管平滑肌細(xì)胞（smooth muscle cell，SMC）合成[8]，其表達(dá)受 TGF-β1 和 IGF-1 調(diào)控[9-10]。巨噬細(xì)胞是AA疾病過(guò)程中最重要的炎癥細(xì)胞，能在炎癥區(qū)域浸潤(rùn)，能分泌MMP-2和MMP-9，這被認(rèn)為是彈性纖維降解過(guò)程中起作用的最主要的蛋白酶[11-12]?；|(zhì)金屬蛋白酶（matrix metalloproteinases，MMP）的分泌和激活引起ECM降解，進(jìn)一步導(dǎo)致動(dòng)脈壁的薄弱。此外，巨噬細(xì)胞還可分泌多種細(xì)胞因子、趨化因子或蛋白酶，如IL-1β，IL-6，TNF-α，MCP-1[13-15]：這些因子不僅能招募單核細(xì)胞[16]，更重要的是能導(dǎo)致SMC凋亡[17-18]，進(jìn)一步促M(fèi)MP分泌[19]。因此，控制炎癥反應(yīng)以及促進(jìn)ECM合成是治療AA的關(guān)鍵。

抗炎治療成為AA的重要治療靶點(diǎn)，如肥大細(xì)胞脫顆粒抑制劑[20-21]、JNK通路抑制劑[22]、血管緊張素轉(zhuǎn)化酶抑制劑（angiotensin-converting-enzyme inhibitor，ACEI）[23-25]。許多研究的確觀察到了抗炎藥物治療AA的效果，如ACEI類(lèi)和他汀類(lèi)能降低動(dòng)脈瘤破裂風(fēng)險(xiǎn)[26-27]，MMP-9抑制劑（多西環(huán)素）[28]和NSAIDs類(lèi)藥物[29]均能減輕瘤樣擴(kuò)張，JNK抑制劑能改善CaCl2模型小鼠的癥狀[30]。

除藥物治療外，細(xì)胞治療也初顯成效。MSC是細(xì)胞治療中的明星細(xì)胞，跟其他干細(xì)胞相比具有諸多優(yōu)點(diǎn)。胚胎干細(xì)胞（embryonic stem cell，ESC）分化能力最強(qiáng)，但存在難以解決的倫理問(wèn)題；誘導(dǎo)多能干細(xì)胞（induced pluripotent stem cells，iPS）雖無(wú)倫理方面的問(wèn)題，且來(lái)源廣泛，但存在致瘤性。MSC綜合了兩者優(yōu)勢(shì)，不存在倫理問(wèn)題，無(wú)致瘤性，分化能力強(qiáng)，可分泌一系列營(yíng)養(yǎng)因子促進(jìn)組織再生[21]，成為干細(xì)胞治療的明星細(xì)胞。MSC另一個(gè)重要的特征是歸巢（homing），即募集（recruitment）或遷移（migration）能力，可特異性聚集在損傷部位。MSC在AA疾病過(guò)程中也表現(xiàn)出這一特性，有研究認(rèn)為這跟SDF-1/CXCR4有關(guān)[31]。目前已有大量動(dòng)物研究觀察到MSC治療AA的有效性。

二、MSC治療AA的主要機(jī)制

MSC治療AA的機(jī)制可大致分為直接作用和間接作用。直接作用指MSC通過(guò)直接募集到病變的主動(dòng)脈處并分化為血管壁組成細(xì)胞參與血管壁修復(fù)。但目前認(rèn)為MSC主要通過(guò)間接作用（即旁分泌效應(yīng)）起作用，即通過(guò)影響微環(huán)境、免疫細(xì)胞、炎癥反應(yīng)、刺激固有細(xì)胞，直接表現(xiàn)為MSC能降低MMP-2和MMP-9水平、促進(jìn)炎性細(xì)胞因子（IL-6，MCP-1）下調(diào)、促進(jìn)IGF-1和TIMP-2上調(diào)，減少M(fèi)1巨噬細(xì)胞浸潤(rùn)，保護(hù)彈性蛋白[32]。MSC分泌的各種細(xì)胞因子及相互作用是MSC發(fā)揮生物學(xué)效應(yīng)的核心和關(guān)鍵。各種因子及其作用的通路和靶點(diǎn)，有待更深入的研究和進(jìn)一步闡明。MSC主要從抗炎、調(diào)節(jié)SMC和ECM重塑三個(gè)方面對(duì)AA起作用。

（一）抗炎

先前研究發(fā)現(xiàn)，病變的主動(dòng)脈組織有明顯的炎性改變：炎細(xì)胞聚集于主動(dòng)脈外膜，隨后T細(xì)胞、產(chǎn)生MMP降解ECM，導(dǎo)致主動(dòng)脈壁擴(kuò)張。局部炎癥反應(yīng)還造成SMC的表型轉(zhuǎn)化（凋亡），進(jìn)一步導(dǎo)致MMP的產(chǎn)生和ECM降解。因此，抑制過(guò)度的炎癥反應(yīng)是治療的重要靶點(diǎn)，而MSC能降低炎癥反應(yīng)水平。

MSC能抑制淋巴細(xì)胞的功能和活性[33]。MSC通過(guò)表達(dá)吲哚胺2,3-二加氧酶（indoleamine 2,3-dioxygenase，IDO）抑制T細(xì)胞免疫反應(yīng)的激活和增殖，IDO可降解色氨酸、移植T細(xì)胞增殖[34]。MSC抑制Th1細(xì)胞分泌IFN-γ，促進(jìn)Th2細(xì)胞分泌IL-4；而IFN-γ可從多方面調(diào)解免疫應(yīng)答過(guò)程，IL-4在免疫應(yīng)答的負(fù)向調(diào)節(jié)中意義重大。MSC通過(guò)可溶性因子PGE2和TGF-β抑制NK細(xì)胞增殖，通過(guò)減少TNF-α、IFN-γ和IL-12的分泌來(lái)降低DC1細(xì)胞的促炎作用，以及促進(jìn)DC-2分泌IL-10，而PGE2也可以抑制T淋巴細(xì)胞的功能和活性[35]。

MSC還能對(duì)巨噬細(xì)胞起作用。巨噬細(xì)胞存在兩種表型：M1，經(jīng)典活化的促炎表型；M2，抗炎或損傷修復(fù)表型。顯然，M2是治療所需要的表型。MSC分泌的因子能讓巨噬細(xì)胞發(fā)生表型轉(zhuǎn)化，從M1轉(zhuǎn)化為M2[34,36-37]，也能募集和介導(dǎo)巨噬細(xì)胞發(fā)揮損傷修復(fù)的作用[38-39]。

MSC也能影響免疫耐受。AA疾病過(guò)程中，Treg細(xì)胞缺乏，導(dǎo)致Th1功能亢進(jìn)[40]。MSC可促使Th1轉(zhuǎn)化為T(mén)淋巴細(xì)胞，使其免疫耐受性增強(qiáng)。另外，MSC還可促進(jìn)Treg分泌抗炎細(xì)胞因子IL-10，下調(diào)IL-6和MCP-1的表達(dá)，以及降低MMP活性[20]。

（二）調(diào)控SMC

AA發(fā)病時(shí)，一方面，活性氧簇（reactive oxygen species，ROS）介導(dǎo)的凋亡使SMC數(shù)量減少；另一方面，剩余的SMC更多地轉(zhuǎn)化為ECM降解相關(guān)的表型。直接注射移植SMC觀察到了AA的改善[41-43]。有研究認(rèn)為，MSC可分化為有功能的SMC[44-46]，或可用于替代治療[47]；但隨著研究深入，目前主要認(rèn)為MSC主要通過(guò)旁分泌作用來(lái)調(diào)節(jié)剩余SMC功能。研究發(fā)現(xiàn)，在減輕主動(dòng)脈擴(kuò)張、降低MMP-9/TIMP-1水平以及保護(hù)ECM組分方面，MSC比SMC更有效[48]。MSC通過(guò)減輕炎癥反應(yīng)和蛋白分解改善動(dòng)脈壁穩(wěn)態(tài)；或作用于TGFβ-1通路減緩AA進(jìn)展。

MSC可促進(jìn)SMC表達(dá)彈性蛋白[20,49]；MSC也可降低SMC中MMP-2的表達(dá)量，保護(hù)彈性蛋白；MSC可使動(dòng)脈壁中 MMP、IL-6、MCP-1和 TNF-α表達(dá)下降，IGF-1和TIMP-1的表達(dá)上升。這些實(shí)驗(yàn)都說(shuō)明MSC可以逆轉(zhuǎn)SMC的病理表型，抑制AA發(fā)生。

此外，有研究用血小板源性生長(zhǎng)因子-BB刺激鼠肌源性的MSC，觀察到體外分化為SMC樣祖細(xì)胞[50]；Schneider等[48]將MSC腔內(nèi)注射至模型大鼠，可觀察到血管腔的擴(kuò)張被抑制，而且有新生動(dòng)脈組織形成；這些組織表現(xiàn)為SMC陽(yáng)性細(xì)胞聚集、新生的膠原和彈性纖維網(wǎng)絡(luò)和管狀內(nèi)皮細(xì)胞，這說(shuō)明主動(dòng)脈壁的重建也顯著加強(qiáng)了。

（三）重塑ECM

SMC丟失、彈性蛋白和膠原降解導(dǎo)致的主動(dòng)脈壁結(jié)構(gòu)破壞是AA的主要病理生理學(xué)改變。因此，恢復(fù)主動(dòng)脈壁ECM的生理狀態(tài)，是除免疫調(diào)控和SMC調(diào)控之外，AA治療的另一靶點(diǎn)。彈性蛋白和膠原（主要是Ⅰ型和Ⅲ型）是大血管ECM的主要成分；該組分的降解會(huì)導(dǎo)致動(dòng)脈瘤形成。MSC可直接產(chǎn)生多種重要的ECM組分，促進(jìn)主動(dòng)脈壁ECM結(jié)構(gòu)重建。Turnbull等[51]建立了大型動(dòng)物（豬）可操作的模型。之后，Riera等[52]在大型動(dòng)物模型上，聯(lián)合腔內(nèi)治療和細(xì)胞治療觀察了MSC的保護(hù)作用：Darcon補(bǔ)片置入后瘤腔內(nèi)注射MSC，發(fā)現(xiàn)主動(dòng)脈的急性炎癥反應(yīng)被抑制，彈性纖維明顯再生，纖維結(jié)構(gòu)形成以及鈣沉著減少。有意思的是，機(jī)械刺激即可促使MSC合成膠原和彈性蛋白[53]。MSC分泌的ECM組分可作為主動(dòng)脈的重建材料，事實(shí)上，它非常適合用作組織工程學(xué)的支架材料，成為組織工程學(xué)的重要種子細(xì)胞[53]。上文已提及，MSC分泌的ECM組分可通過(guò)激活不同的信號(hào)通路促進(jìn)SMC存活和表型轉(zhuǎn)變[18,54-56]。Ganesh等[57]認(rèn)為AA發(fā)病時(shí)，SMC介導(dǎo)的彈性成分合成降解失衡；他們的研究顯示，MSC可分化為SMC樣細(xì)胞，并分泌一系列營(yíng)養(yǎng)因子，以促進(jìn)ECM組分合成。

四、存在的問(wèn)題

MSC在治療其他心血管系統(tǒng)疾?。ㄈ缧墓＃┮延糜谂R床研究[58-61]，而針對(duì)AA目前僅有動(dòng)物研究。雖然目前已有許多動(dòng)物研究觀察到了MSC治療AA的有效性，但這些效果仍值得進(jìn)一步探討，也存在尚未解決的問(wèn)題。若能進(jìn)一步解決這些問(wèn)題，目前的研究成果轉(zhuǎn)化為臨床治療方案將指日可待。首先，實(shí)驗(yàn)技術(shù)細(xì)節(jié)有待優(yōu)化，給藥途徑應(yīng)在“創(chuàng)傷最小化”和“定位精準(zhǔn)化”兩者之間權(quán)衡。第二，MSC長(zhǎng)期安全性問(wèn)題。臨床研究中MSC難以示蹤，缺乏長(zhǎng)期隨訪(fǎng)數(shù)據(jù)。理論上MSC可在主動(dòng)脈壁處分化為脂肪細(xì)胞、成骨細(xì)胞等，可能會(huì)導(dǎo)致不良后果，如脂質(zhì)沉積和鈣化。第三，動(dòng)物模型的缺陷。無(wú)論動(dòng)物還是細(xì)胞模型都不能完全模擬人體發(fā)病的情況。第四，臨床數(shù)據(jù)不完整。臨床樣本僅能提供疾病末期的病理改變。

有研究通過(guò)質(zhì)譜、蛋白芯片和生物信息學(xué)的方法分析了間充質(zhì)干細(xì)胞條件培養(yǎng)液（mesenchymal stem cellconditioned medium，MSC-CM）成分，鑒定出一系列可能起作用的組分，包括 TGF-β、IGF-1、EGF、FGF、IL、MMPs和TIMPs[62]。MSC-CM本身即可減少心肌細(xì)胞凋亡、減輕氧化應(yīng)激、縮小心梗范圍、增加收縮期和舒張期功能，這是通過(guò)TGF-β通路介導(dǎo)的Smad2磷酸化和凋亡介導(dǎo)的caspase 3活化來(lái)實(shí)現(xiàn)的[63-64]。TGF-β是一種重要的信號(hào)分子，可誘導(dǎo)SMC分化，也可在轉(zhuǎn)錄水平提高SRF表達(dá)量；SRF可通過(guò)調(diào)節(jié)SMC表型轉(zhuǎn)化進(jìn)而控制血管收縮[65]。MSC-CM中，起心臟保護(hù)作用的主要是MSC-CM中大于1 000 kDa的分子片段。這說(shuō)明有多種蛋白參與、而非某一種蛋白在起作用。但尚不清楚哪些因子起最主要的作用，他們之間的交聯(lián)串話(huà)也有待進(jìn)一步研究。雖然注射MSC-CM比注射MSC更簡(jiǎn)便，但由于相關(guān)分子降解很快，效果也是短期的。

MSC為AA治療提供了新的思路和方法。MSC產(chǎn)生的多種生長(zhǎng)因子可介導(dǎo)多種抗炎細(xì)胞因子、蛋白酶抑制劑和促ECM合成刺激物的生成，進(jìn)一步抑制主動(dòng)脈壁的炎癥反應(yīng)和ECM降解。MSC治療AA尚處于初步研究階段，但相信隨著技術(shù)和方法的不斷進(jìn)步以及研究不斷深入，MSC必將對(duì)AA的治療產(chǎn)生深遠(yuǎn)的影響。

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Effect and mechanism of mesenchymal stem cells for aortic aneurysm

Yang Junlin, Qu Lefeng.
Department of Vascular Surgery, Changzheng Hospital, the Second Military Medical University,Shanghai 200003, China

Qu Lefeng, Email: qulefengsubmit@163.com

Aortic aneurysm (AA) is a severe cardiovascular disease endangering human health and has an extremely high mortality rate when rupture occurs. Current treatment for AA is mainly through surgery. However, the risk of open surgery is high. While endovascular treatment is minimally invasive, its use limited due to anatomical complexity and long-term management.Therefore, it is necessary to explore new methods for early interventions. Generally, AA is due to the imbalance of extracellular matrix (ECM) synthesis and degradation in aortic wall. Chronic inflammation especially atherosclerosis can directly or indirectly promote the degradation process,which is an important factor in the pathogenesis of AA. Mesenchymal stem cells (MSC) have antiinflammatory, immunosuppressive properties and homing capacity, ie, migrating to the site of injury,showing unique advantages for AA treatment. This review is about the mechanism of MSC as a treatment for AA.

Mesenchymal stem cell; Aortic aneurysm

2017-02-14）

（本文編輯：陳媛媛）

10.3877/cma.j.issn.2095-1221.2017.03.010

上海市科技人才計(jì)劃(15YF1400500）

200003 上海長(zhǎng)征醫(yī)院血管外科

曲樂(lè)豐，Email：qulefengsubmit@163.com

楊俊林，曲樂(lè)豐.間充質(zhì)干細(xì)胞治療主動(dòng)脈瘤的研究進(jìn)展[J/CD].中華細(xì)胞與干細(xì)胞雜志（電子版），2017，7（3）：173-177.