间充质干细胞治疗主动脉瘤的研究进展

杨俊林 曲乐丰

间充质干细胞治疗主动脉瘤的研究进展

杨俊林 曲乐丰

主动脉瘤（AA）是严重危害人类健康的心血管系统疾病，一旦破裂出血，死亡率极高。目前AA的治疗主要通过手术干预，但开放手术风险很大；介入治疗虽然创伤较小，但也存在诸多局限性，如解剖结构的限制、远期管理等。因此，有必要探索新方法在早期进行干预。目前认为，AA的发病主要是由于主动脉壁细胞外基质（ECM）合成和降解失衡。慢性炎症能直接或间接地促进该降解过程，是AA形成的重要因素。间充质干细胞（MSC）具有抗炎和免疫抑制的特性，还能特异性地募集到损伤部位，在治疗AA中表现出独特的优势。本文就MSC治疗AA的机制做一综述。

间质干细胞； 主动脉瘤

主动脉瘤（aortic aneurysm，AA）是一种严重的心血管系统疾病，一旦破裂出血，死亡率极高。AA起病隐匿，早期缺乏典型的临床症状。通常采用开放手术或介入的方式进行治疗，但均有局限性：开放手术创伤很大，患者面临巨大的手术风险；介入虽然微创，但受限于解剖结构，且存在移植物移位、内漏等并发症[1]。此外，外科操作对于尚不符合指征的或处于病变早期的情况无能为力。阻止疾病进展显得尤为重要，因此需要新的方法在早期进行干预。目前已有药物治疗、基因治疗或细胞治疗等新方法[2]。间充质干细胞（mesenchymal stem cell，MSC）因其独特的性质，广泛用于细胞治疗和再生医学。MSC已用于多种疾病的临床治疗，其中应用最广的是心血管系统疾病（据clinicaltrils.gov统计）。本文将对AA的发病机理和MSC治疗的机制做一综述。

一、疾病概况

心血管系统疾病目前已成为世界范围内首位致死性非传染疾病。在美国，AA每年导致10 500例患者死亡[3]。AA发病机制尚未完全阐明，流行病学调查显示它跟吸烟、高龄、性别和家族史有密切关联[4-5]。目前研究认为，AA的分子机制可归结为主动脉壁细胞外基质（extracellular matrices，ECM）的合成和降解失衡；而慢性炎症反应，特别是动脉粥样硬化，在疾病发生过程中起重要作用[6]。ECM主要由弹性蛋白和胶原组成，为主动脉提供弹性支撑。弹性蛋白是主动脉壁的主要纤维成分，其降解将直接导致动脉扩张[7]。弹性蛋白由血管平滑肌细胞（smooth muscle cell，SMC）合成[8]，其表达受 TGF-β1 和 IGF-1 调控[9-10]。巨噬细胞是AA疾病过程中最重要的炎症细胞，能在炎症区域浸润，能分泌MMP-2和MMP-9，这被认为是弹性纤维降解过程中起作用的最主要的蛋白酶[11-12]。基质金属蛋白酶（matrix metalloproteinases，MMP）的分泌和激活引起ECM降解，进一步导致动脉壁的薄弱。此外，巨噬细胞还可分泌多种细胞因子、趋化因子或蛋白酶，如IL-1β，IL-6，TNF-α，MCP-1[13-15]：这些因子不仅能招募单核细胞[16]，更重要的是能导致SMC凋亡[17-18]，进一步促MMP分泌[19]。因此，控制炎症反应以及促进ECM合成是治疗AA的关键。

抗炎治疗成为AA的重要治疗靶点，如肥大细胞脱颗粒抑制剂[20-21]、JNK通路抑制剂[22]、血管紧张素转化酶抑制剂（angiotensin-converting-enzyme inhibitor，ACEI）[23-25]。许多研究的确观察到了抗炎药物治疗AA的效果，如ACEI类和他汀类能降低动脉瘤破裂风险[26-27]，MMP-9抑制剂（多西环素）[28]和NSAIDs类药物[29]均能减轻瘤样扩张，JNK抑制剂能改善CaCl2模型小鼠的症状[30]。

除药物治疗外，细胞治疗也初显成效。MSC是细胞治疗中的明星细胞，跟其他干细胞相比具有诸多优点。胚胎干细胞（embryonic stem cell，ESC）分化能力最强，但存在难以解决的伦理问题；诱导多能干细胞（induced pluripotent stem cells，iPS）虽无伦理方面的问题，且来源广泛，但存在致瘤性。MSC综合了两者优势，不存在伦理问题，无致瘤性，分化能力强，可分泌一系列营养因子促进组织再生[21]，成为干细胞治疗的明星细胞。MSC另一个重要的特征是归巢（homing），即募集（recruitment）或迁移（migration）能力，可特异性聚集在损伤部位。MSC在AA疾病过程中也表现出这一特性，有研究认为这跟SDF-1/CXCR4有关[31]。目前已有大量动物研究观察到MSC治疗AA的有效性。

二、MSC治疗AA的主要机制

MSC治疗AA的机制可大致分为直接作用和间接作用。直接作用指MSC通过直接募集到病变的主动脉处并分化为血管壁组成细胞参与血管壁修复。但目前认为MSC主要通过间接作用（即旁分泌效应）起作用，即通过影响微环境、免疫细胞、炎症反应、刺激固有细胞，直接表现为MSC能降低MMP-2和MMP-9水平、促进炎性细胞因子（IL-6，MCP-1）下调、促进IGF-1和TIMP-2上调，减少M1巨噬细胞浸润，保护弹性蛋白[32]。MSC分泌的各种细胞因子及相互作用是MSC发挥生物学效应的核心和关键。各种因子及其作用的通路和靶点，有待更深入的研究和进一步阐明。MSC主要从抗炎、调节SMC和ECM重塑三个方面对AA起作用。

（一）抗炎

先前研究发现，病变的主动脉组织有明显的炎性改变：炎细胞聚集于主动脉外膜，随后T细胞、产生MMP降解ECM，导致主动脉壁扩张。局部炎症反应还造成SMC的表型转化（凋亡），进一步导致MMP的产生和ECM降解。因此，抑制过度的炎症反应是治疗的重要靶点，而MSC能降低炎症反应水平。

MSC能抑制淋巴细胞的功能和活性[33]。MSC通过表达吲哚胺2,3-二加氧酶（indoleamine 2,3-dioxygenase，IDO）抑制T细胞免疫反应的激活和增殖，IDO可降解色氨酸、移植T细胞增殖[34]。MSC抑制Th1细胞分泌IFN-γ，促进Th2细胞分泌IL-4；而IFN-γ可从多方面调解免疫应答过程，IL-4在免疫应答的负向调节中意义重大。MSC通过可溶性因子PGE2和TGF-β抑制NK细胞增殖，通过减少TNF-α、IFN-γ和IL-12的分泌来降低DC1细胞的促炎作用，以及促进DC-2分泌IL-10，而PGE2也可以抑制T淋巴细胞的功能和活性[35]。

MSC还能对巨噬细胞起作用。巨噬细胞存在两种表型：M1，经典活化的促炎表型；M2，抗炎或损伤修复表型。显然，M2是治疗所需要的表型。MSC分泌的因子能让巨噬细胞发生表型转化，从M1转化为M2[34,36-37]，也能募集和介导巨噬细胞发挥损伤修复的作用[38-39]。

MSC也能影响免疫耐受。AA疾病过程中，Treg细胞缺乏，导致Th1功能亢进[40]。MSC可促使Th1转化为T淋巴细胞，使其免疫耐受性增强。另外，MSC还可促进Treg分泌抗炎细胞因子IL-10，下调IL-6和MCP-1的表达，以及降低MMP活性[20]。

（二）调控SMC

AA发病时，一方面，活性氧簇（reactive oxygen species，ROS）介导的凋亡使SMC数量减少；另一方面，剩余的SMC更多地转化为ECM降解相关的表型。直接注射移植SMC观察到了AA的改善[41-43]。有研究认为，MSC可分化为有功能的SMC[44-46]，或可用于替代治疗[47]；但随着研究深入，目前主要认为MSC主要通过旁分泌作用来调节剩余SMC功能。研究发现，在减轻主动脉扩张、降低MMP-9/TIMP-1水平以及保护ECM组分方面，MSC比SMC更有效[48]。MSC通过减轻炎症反应和蛋白分解改善动脉壁稳态；或作用于TGFβ-1通路减缓AA进展。

MSC可促进SMC表达弹性蛋白[20,49]；MSC也可降低SMC中MMP-2的表达量，保护弹性蛋白；MSC可使动脉壁中 MMP、IL-6、MCP-1和 TNF-α表达下降，IGF-1和TIMP-1的表达上升。这些实验都说明MSC可以逆转SMC的病理表型，抑制AA发生。

此外，有研究用血小板源性生长因子-BB刺激鼠肌源性的MSC，观察到体外分化为SMC样祖细胞[50]；Schneider等[48]将MSC腔内注射至模型大鼠，可观察到血管腔的扩张被抑制，而且有新生动脉组织形成；这些组织表现为SMC阳性细胞聚集、新生的胶原和弹性纤维网络和管状内皮细胞，这说明主动脉壁的重建也显著加强了。

（三）重塑ECM

SMC丢失、弹性蛋白和胶原降解导致的主动脉壁结构破坏是AA的主要病理生理学改变。因此，恢复主动脉壁ECM的生理状态，是除免疫调控和SMC调控之外，AA治疗的另一靶点。弹性蛋白和胶原（主要是Ⅰ型和Ⅲ型）是大血管ECM的主要成分；该组分的降解会导致动脉瘤形成。MSC可直接产生多种重要的ECM组分，促进主动脉壁ECM结构重建。Turnbull等[51]建立了大型动物（猪）可操作的模型。之后，Riera等[52]在大型动物模型上，联合腔内治疗和细胞治疗观察了MSC的保护作用：Darcon补片置入后瘤腔内注射MSC，发现主动脉的急性炎症反应被抑制，弹性纤维明显再生，纤维结构形成以及钙沉着减少。有意思的是，机械刺激即可促使MSC合成胶原和弹性蛋白[53]。MSC分泌的ECM组分可作为主动脉的重建材料，事实上，它非常适合用作组织工程学的支架材料，成为组织工程学的重要种子细胞[53]。上文已提及，MSC分泌的ECM组分可通过激活不同的信号通路促进SMC存活和表型转变[18,54-56]。Ganesh等[57]认为AA发病时，SMC介导的弹性成分合成降解失衡；他们的研究显示，MSC可分化为SMC样细胞，并分泌一系列营养因子，以促进ECM组分合成。

四、存在的问题

MSC在治疗其他心血管系统疾病（如心梗）已用于临床研究[58-61]，而针对AA目前仅有动物研究。虽然目前已有许多动物研究观察到了MSC治疗AA的有效性，但这些效果仍值得进一步探讨，也存在尚未解决的问题。若能进一步解决这些问题，目前的研究成果转化为临床治疗方案将指日可待。首先，实验技术细节有待优化，给药途径应在“创伤最小化”和“定位精准化”两者之间权衡。第二，MSC长期安全性问题。临床研究中MSC难以示踪，缺乏长期随访数据。理论上MSC可在主动脉壁处分化为脂肪细胞、成骨细胞等，可能会导致不良后果，如脂质沉积和钙化。第三，动物模型的缺陷。无论动物还是细胞模型都不能完全模拟人体发病的情况。第四，临床数据不完整。临床样本仅能提供疾病末期的病理改变。

有研究通过质谱、蛋白芯片和生物信息学的方法分析了间充质干细胞条件培养液（mesenchymal stem cellconditioned medium，MSC-CM）成分，鉴定出一系列可能起作用的组分，包括 TGF-β、IGF-1、EGF、FGF、IL、MMPs和TIMPs[62]。MSC-CM本身即可减少心肌细胞凋亡、减轻氧化应激、缩小心梗范围、增加收缩期和舒张期功能，这是通过TGF-β通路介导的Smad2磷酸化和凋亡介导的caspase 3活化来实现的[63-64]。TGF-β是一种重要的信号分子，可诱导SMC分化，也可在转录水平提高SRF表达量；SRF可通过调节SMC表型转化进而控制血管收缩[65]。MSC-CM中，起心脏保护作用的主要是MSC-CM中大于1 000 kDa的分子片段。这说明有多种蛋白参与、而非某一种蛋白在起作用。但尚不清楚哪些因子起最主要的作用，他们之间的交联串话也有待进一步研究。虽然注射MSC-CM比注射MSC更简便，但由于相关分子降解很快，效果也是短期的。

MSC为AA治疗提供了新的思路和方法。MSC产生的多种生长因子可介导多种抗炎细胞因子、蛋白酶抑制剂和促ECM合成刺激物的生成，进一步抑制主动脉壁的炎症反应和ECM降解。MSC治疗AA尚处于初步研究阶段，但相信随着技术和方法的不断进步以及研究不断深入，MSC必将对AA的治疗产生深远的影响。

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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）

（本文编辑：陈媛媛）

10.3877/cma.j.issn.2095-1221.2017.03.010

上海市科技人才计划(15YF1400500）

200003 上海长征医院血管外科

曲乐丰，Email：qulefengsubmit@163.com

杨俊林，曲乐丰.间充质干细胞治疗主动脉瘤的研究进展[J/CD].中华细胞与干细胞杂志（电子版），2017，7（3）：173-177.