SCI 干细胞国际 1687 - 9678 1687 - 966 x Hindawi 10.1155 / 2017/6294717 6294717 研究文章 间充质干细胞促进转移的肺癌细胞表达下调全身抗肿瘤免疫反应 Gazdic 玛丽娜 1 Simovic·马尔科维奇 走 2 Jovicic 维 3 Misirkic-Marjanovic 穿着俗艳的美女 4 Djonov 瓦伦汀 5 http://orcid.org/0000 - 0002 - 0071 - 8376 Jakovljevic 弗拉基米尔• 6 Arsenijevic 梅 2 陆基克 踩踏L。 2 http://orcid.org/0000 - 0001 - 5948 - 9902 Volarevic 弗拉季斯拉夫• 2 Fagioli 语言 1 部门的遗传学 医学科学学院 Kragujevac大学 34000年Kragujevac 塞尔维亚 kg.ac.rs 2 微生物学和免疫学 分子医学和干细胞研究中心 医学科学学院 Kragujevac大学 马·马尔科维奇街69号 34000年Kragujevac 塞尔维亚 kg.ac.rs 3 组织学与胚胎学 医学科学学院 Kragujevac大学 34000年Kragujevac 塞尔维亚 kg.ac.rs 4 微生物学和免疫学研究所 医学院的 贝尔格莱德大学 11000年贝尔格莱德 塞尔维亚 bg.ac.rs 5 解剖学研究所 伯尔尼大学 3000年伯尔尼9 瑞士 unibe.ch 6 生理学系 医学科学学院 Kragujevac大学 34000年Kragujevac 塞尔维亚 kg.ac.rs 2017年 16 7 2017年 2017年 09年 03 2017年 04 06 2017年 05年 06 2017年 16 7 2017年 2017年 版权©2017滨Gazdic et al。 这是一个开放的文章在知识共享归属许可下发布的,它允许无限制的使用,分布和繁殖在任何媒介,提供最初的工作是正确的引用。

由于大多数系统管理的间充质干细胞(msc)成为禁锢在肺部,我们使用转移性肺癌模型,静脉注射引起的路易斯肺癌1 (LLC1)细胞,探讨分子机制参与MSC-mediated调制的转移。msc显著增强肺癌转移,减弱促炎细胞因子(TNF -的浓度 α、IL-17)和增加免疫抑制il - 10的水平,一氧化氮和犬尿氨酸LLC1-treated小鼠的血清。msc深刻地减少了巨噬细胞的浸润,肿瘤坏死因子- α第树突状细胞(dc)、肿瘤坏死因子- α和IL-17-producing CD4 + T细胞,但增加IL-10-producing CD4 + T淋巴细胞在肺部肿瘤的动物。lung-infiltrated总数、细胞毒性FasL perforin-expressing, TNF - α和IL-17-producing CD8 + T淋巴细胞,NKG2D-expressing自然杀伤(NK)细胞显著减少LLC1 + MSC-treated老鼠。细胞毒性抑制NK细胞的MSC-conditioned媒介。这种现象被废除的抑制剂诱导一氧化氮合酶(间接宾语)和吲哚胺2,3-dioxygenase (IDO),表明伊诺的重要性和被罩MSC-mediated抑制NK细胞的抗肿瘤细胞毒性。该研究提供了证据,msc促进肺癌转移通过抑制抗肿瘤免疫反应有关的安全担忧MSC-based治疗患者为恶性疾病遗传易感性。 Kragujevac大学医学科学学院 MP01/12 MP01/14 塞尔维亚科学 ON175103 ON175069 瑞士国家科学基金会 IZ73Z0_152454/1 菲利普莫里斯和领导力发展中心 启动对科学 1。介绍<gydF4y2Ba/title> <p>间充质干细胞(msc) self-renewable成人干细胞呈形态,可以发现在几乎所有产后组织(<gydF4y2Baxref ref-type="bibr" rid="B1"> 1<gydF4y2Ba/xref>]。msc目前使用广泛的临床试验由于其multilineage分化潜力和免疫调节的特点。msc分化为中胚层来源的细胞在体外和体内,但最近公布的数据表明,在特定的文化条件下,msc的塑性应扩展到nonmesenchymal血统的neuroectodermal(神经元、星形胶质细胞和少突胶质细胞)或内胚层的(肝细胞)起源<gydF4y2Baxref ref-type="bibr" rid="B2"> 2<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>msc可以促进血管生成分化转移到内皮细胞,通过生产几个proangiogenic因素(肝细胞生长因子(HGF)、血管内皮生长因子(VEGF)、转化生长因子β(TGF -<gydF4y2Baitalic> β<gydF4y2Ba/italic>)和白介素- 6 (IL)) (<gydF4y2Baxref ref-type="bibr" rid="B3"> 3<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>msc抑制免疫反应衰减迁移和成熟的树突状细胞(dc),促进替代激活巨噬细胞,并减少核扩散,激活,和B和T淋巴细胞的效应函数,自然杀伤(NK)细胞和自然杀伤T (NKT) (<gydF4y2Baxref ref-type="bibr" rid="B1"> 1<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>尽管proangiogenic msc是有益的和免疫抑制特性退化性和自身免疫性疾病的治疗,他们可以代表一个严重的问题,如果病人收到msc原发性或转移性肿瘤。因此,安全性MSC-based治疗仍然是一个有争议的问题。主要关心的是潜在的恶性转变管理msc。最近的一项荟萃分析部分向科学界显示,恶性肿瘤在MSC-treated注意到患者发生只在以前或现在恶性肿瘤患者,在没有形成新创肿瘤(<gydF4y2Baxref ref-type="bibr" rid="B4"> 4<gydF4y2Ba/xref>]。然而,骨髓间充质促进新血管形成和抑制抗肿瘤免疫的潜力仍然是现有的重大关切有关MSC-based安全的疗法,应进一步探索在临床前和临床研究。<gydF4y2Ba/p> <p>msc至少有三个函数能够促进肿瘤转移:导航网站组织受损,包括转移性损伤、免疫调节因子的生产,和proangiogenic分泌细胞因子和生长因子,促进新血管形成使肿瘤细胞的转移<gydF4y2Baxref ref-type="bibr" rid="B1"> 1<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B4"> 4<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>Lung-infiltrated细胞以及他们的产品有助于肿瘤逃逸机制和宿主免疫抑制是成为重要的介质在促进肺癌生长和转移(<gydF4y2Baxref ref-type="bibr" rid="B5"> 5<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B6"> 6<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>因为绝大多数静脉注射msc最初成为裹入肺中msc与tumor-infiltrated免疫细胞(<gydF4y2Baxref ref-type="bibr" rid="B1"> 1<gydF4y2Ba/xref>),我们使用转移性肺癌小鼠模型来研究分子和细胞机制MSC-mediated调制的抗肿瘤免疫反应和肺癌转移的进展。<gydF4y2Ba/p> <p>因此,我们表明,静脉应用程序msc在肿瘤的老鼠明显抑制全身抗肿瘤免疫反应,减少lung-infiltrated DCs的总数、巨噬细胞、CD4 + T淋巴细胞,ctl, NK细胞,减抗肿瘤的细胞毒性ctl和NK细胞产生的转移性肺部病变的扩张。<gydF4y2Ba/p> </sec> <sec id="sec2"> <title>2。材料和方法<gydF4y2Ba/title> <sec id="sec2.1"> <title>2.1。细胞<gydF4y2Ba/title> <p>C57BL / 6小鼠骨髓msc隔绝买来Gibco(目录号码s1502 - 100)。修改完成杜尔贝科的鹰的细胞培养介质(DMEM)包含heat-inactivated 10%胎牛血清的边后卫,100国际单位/毫升青霉素G和100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>g / mL链霉素(Sigma-Aldrich,慕尼黑,德国),37°C的5%的股份有限公司<gydF4y2Basub>2<gydF4y2Ba/sub>孵化器。msc在通道3在整个实验。<gydF4y2Ba/p> <p>小鼠肺癌细胞系(Lewis肺癌LLC1) (3 ll, H2b),源自C57BL小鼠肺内植入卢(刘易斯)肺癌,从美国购买类型文化集合(写明ATCC)(目录号码crl - 1642™)。细胞通常生长在悬挂在完整的DMEM培养基,在37°C公司5%<gydF4y2Basub>2<gydF4y2Ba/sub>孵化器。LLC1细胞通道3使用整个实验。<gydF4y2Ba/p> </sec> <sec id="sec2.2"> <title>2.2。代MSC-Conditioned介质(MSC-CM)<gydF4y2Ba/title> <p>msc被播种密度的10000细胞/厘米<gydF4y2Basup>2<gydF4y2Ba/sup>。为了收集MSC-CM, msc第一次培养血清完全培养基和孵化37°C在潮湿的气氛中有5%的公司<gydF4y2Basup>2<gydF4y2Ba/sup>。80%的融合,细胞被洗两次1 x磷酸盐(PBS,英杰公司),和介质改为无血清培养基。48小时后,中收集,离心机13000×<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"> <mml:mi> g<gydF4y2Ba/mml:mi> </mml:math> </inline-formula>在4°C 10分钟,储存在−80°C到使用(<gydF4y2Baxref ref-type="bibr" rid="B7"> 7<gydF4y2Ba/xref>]。<gydF4y2Ba/p> </sec> <sec id="sec2.3"> <title>2.3。药物抑制吲哚胺2,3-Dioxygenase (IDO)和诱导一氧化氮合酶(间接宾语)<gydF4y2Ba/title> <p>msc在培养基培养48 h 1-methyltryptophan包含1毫米,(1-MT Sigma-Aldrich,圣路易斯,密苏里州),IDO酶活性的抑制剂(<gydF4y2Baxref ref-type="bibr" rid="B8"> 8<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>阻止伊诺活动,msc是培养48 h的1毫米伊诺的抑制剂,L-N<gydF4y2Basup>G<gydF4y2Ba/sup>柠檬酸单甲精氨酸(L-NMMA Sigma-Aldrich,圣路易斯,密苏里州)(<gydF4y2Baxref ref-type="bibr" rid="B9"> 9<gydF4y2Ba/xref>]。<gydF4y2Ba/p> </sec> <sec id="sec2.4"> <title>2.4。动物<gydF4y2Ba/title> <p>6-8-week-old C57Bl / 6雄性老鼠。所有动物受到人类保健和所有的实验都通过,按照指南进行动物伦理委员会的医学科学学院Kragujevac大学的塞尔维亚。老鼠被安置在12小时的光暗周期温度控制的环境中,与标准的实验室管理食物和水随意<gydF4y2Baitalic> 。<gydF4y2Ba/italic></p> </sec> <sec id="sec2.5"> <title>2.5。诱导实验性转移和系统性应用msc<gydF4y2Ba/title> <p>实验转移引起的静脉注射5×10<gydF4y2Basup>4<gydF4y2Ba/sup>LLC1细胞(<gydF4y2Baxref ref-type="bibr" rid="B10"> 10<gydF4y2Ba/xref>]。小鼠静脉注射收到5×10<gydF4y2Basup>5<gydF4y2Ba/sup>msc或生理盐水注射后一周LLC1细胞。老鼠牺牲28天的实验,如前所述[<gydF4y2Baxref ref-type="bibr" rid="B5"> 5<gydF4y2Ba/xref>]。<gydF4y2Ba/p> </sec> <sec id="sec2.6"> <title>2.6。组织病理学分析<gydF4y2Ba/title> <p>所有老鼠都牺牲在大气饱和乙醚(β哼哼,贝尔格莱德)和肺组织病理学分析孤立转移性肿瘤诱导后殖民地28天。<gydF4y2Ba/p> <p>孤立肺在10%福尔马林固定石蜡和嵌入式,和连续4<gydF4y2Baitalic> μ<gydF4y2Ba/italic>m组织部分安装在幻灯片。部分被苏木精和伊红染色())和低功耗下检查(100 x)光microscopy-equipped数码相机(蔡司Axioskop 40,耶拿,德国)。转移验证了光学显微镜(放大10倍和40 x)特征褐黑色色素“热点”与巨大的多核细胞明显受限于周围肺组织。<gydF4y2Ba/p> </sec> <sec id="sec2.7"> <title>2.7。免疫组织化学<gydF4y2Ba/title> <p>免疫组织化学染色,石蜡包埋部分(4<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米)的小鼠肺组织。在柠檬酸缓冲Heat-mediated抗原检索(pH = 6.0)。Deparaffinized组织切片与初级孵化鼠标anti-CD3 (sc - 20047,圣克鲁斯生物技术),anti-CD4 (ab183685 Abcam) anti-CD68 (ab49777 Abcam) anti-TNF -<gydF4y2Baitalic> α<gydF4y2Ba/italic>抗体(ab6671 Abcam)和anti-IL-17 (ab79056 Abcam)。染色被使用鼠标具体合/民建联可视化检测包含IHC工具包(CD3和CD68 ab64259 Abcam)和兔特定合/原子能委员会包含IHC检测设备(ab94361 Abcam) CD4, TNF -<gydF4y2Baitalic> α<gydF4y2Ba/italic>,IL-17。部分和迈耶的苏木精复染色。部分是显微照片与数码相机安装在光学显微镜(日本奥林巴斯BX51)、数字化、和分析。<gydF4y2Ba/p> </sec> <sec id="sec2.8"> <title>2.8。隔离Lung-Infiltrated免疫细胞<gydF4y2Ba/title> <p>肺,获得控制,LLC1和LLC1 + MSC-treated 28天的小鼠实验中,用无菌磷酸盐(PBS)洗净,放置在培养皿DMEM补充10%的边后卫。解剖肺组织孵化在介质中含有胶原酶IV型(0.5毫克/毫升)和IV型牛胰脏DNAse(罗氏诊断;1毫克/毫升)37°C 45分钟。这些细胞被过滤100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>m细胞尼龙滤网清洁50毫升锥形管。然后,细胞颗粒状通过离心法在300×10分钟<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"> <mml:mi> g<gydF4y2Ba/mml:mi> </mml:math> </inline-formula>,10°C。耗尽了红细胞裂解缓冲(NH4Cl 0.144米,0.0169米三基地,pH值7.4)在37°C公司5%<gydF4y2Basub>2<gydF4y2Ba/sub>大气为5分钟(<gydF4y2Baxref ref-type="bibr" rid="B11"> 11<gydF4y2Ba/xref>]。<gydF4y2Ba/p> </sec> <sec id="sec2.9"> <title>2.9。流式细胞术分析细胞内染色Lung-Infiltrated免疫细胞<gydF4y2Ba/title> <p>Lung-infiltrated免疫细胞筛选各种细胞表面和细胞内标记流式细胞术。简单地说,1×10<gydF4y2Basup>6<gydF4y2Ba/sup>细胞孵化与anti-mouse CD45 F4/80, CD4, CD8, CD11c, CD11b, CD49b, FasL, CD107,穿孔素,NKG2D单克隆抗体结合与异硫氰酸荧光素(FITC),藻红蛋白(PE), peridinin叶绿素蛋白质(PerCP),或allophycocyanin (APC)(都来自BD生物科学,圣何塞、钙、美国)后,制造商的指示。免疫细胞来源于肺则同时染色的细胞内内容TNF -<gydF4y2Baitalic> α<gydF4y2Ba/italic>、il - 10和IL-17使用固定/透化作用工具包和anti-mouse单克隆抗体结合与异硫氰酸荧光素(FITC),藻红蛋白(PE), peridinin叶绿素蛋白质(PerCP)和allophycocyanin (APC) (BD生物科学)。细胞内细胞因子染色,细胞被刺激50 ng / mL PMA和500 ng / mL ionomycin 5 h,和GolgiStop (BD生物科学)补充道。细胞被固定在Cytofix / Cytoperm,洋溢着0.1%皂素,染上荧光Abs。流仪分析了BD生物科学的FACSCalibur和使用流动分析软件分析程序。<gydF4y2Ba/p> </sec> <sec id="sec2.10"> <title>2.10。测量血清细胞因子和生长因子的肿瘤的老鼠<gydF4y2Ba/title> <p>水平的肿瘤坏死因子-<gydF4y2Baitalic> α<gydF4y2Ba/italic>IL-17, il - 10,在鼠标血清HGF 14日21日和28日天的实验测量使用ELISA试剂盒特定的老鼠细胞因子(研发系统,明尼阿波利斯,美国)根据制造商的指示。<gydF4y2Ba/p> <p>血清一氧化氮(NO)浓度测定在格里斯试剂而活动以来的犬尿氨酸通过分光光度测量油催化新陈代谢的色氨酸犬尿氨酸(<gydF4y2Baxref ref-type="bibr" rid="B12"> 12<gydF4y2Ba/xref>]。没有和犬尿氨酸的浓度测定小鼠血清在14日21日和28日天的实验。<gydF4y2Ba/p> </sec> <sec id="sec2.11"> <title>2.11。隔离的NK细胞磁性细胞分选<gydF4y2Ba/title> <p>28天的实验中,脾脏NK细胞被孤立的LLC1和LLC1 + MSC-treated老鼠通过磁性细胞排序根据制造商的指示。单细胞悬浮体的单核细胞来自于脾脏被贴上单克隆anti-mouse CD49b抗体,抗体和单克隆anti-biotin配共轭微(Miltenyi研究)。标记细胞被分离在随后耗尽mac列(Miltenyi研究),这是放置在磁场的mac分离器(Miltenyi研究)。孤立的NK细胞被用于coculture纯化NK细胞实验和细胞毒性试验。<gydF4y2Ba/p> </sec> <sec id="sec2.12"> <title>2.12。细胞毒性试验<gydF4y2Ba/title> <p>的DP版本xCELLigence系统(罗氏)用于本研究测定NK细胞的细胞毒性。DP版本包含一个测量单元内安置一个标准组织文化孵化器3站,每个需要E16天板(每个E16天板有16井)。100年<gydF4y2Baitalic> μ<gydF4y2Ba/italic>L的完全培养基添加到每个好,和背景阻抗板测量xCELLigence RTCA DP仪器在37°C和5%的公司<gydF4y2Basub>2<gydF4y2Ba/sub>。LLC1细胞NK细胞作为目标。播种密度4×10<gydF4y2Basup>4<gydF4y2Ba/sup>LLC1细胞/被认为是最优的,用于所有化验。效应的目标比(E: T比值)10:1使用[<gydF4y2Baxref ref-type="bibr" rid="B13"> 13<gydF4y2Ba/xref>]。LLC1细胞在DMEM resuspended FCS在4×10 10%<gydF4y2Basup>5<gydF4y2Ba/sup>细胞每毫升。总共有100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>L肿瘤细胞被添加到每个E16天板的,当时放在xCELLigence RTCA DP。NK细胞,分离出LLC1和LLC1 + MSC-treated 28天的小鼠实验中,被数和resuspended 4×10的浓度<gydF4y2Basup>6<gydF4y2Ba/sup>细胞在DMEM + 10% FCS媒体每毫升。然后,100年<gydF4y2Baitalic> μ<gydF4y2Ba/italic>L NK细胞或媒体就被添加到各自的井。E-plate 16是放在xCELLigence RTCA DP,和阻抗测量每15分钟记录24小时37°C和5%的公司<gydF4y2Basub>2<gydF4y2Ba/sub>。NK细胞介导肿瘤细胞的死亡是实时监控和减少表明细胞指数。数据分析与RTCA软件1.2(究其生物科学)。<gydF4y2Ba/p> </sec> <sec id="sec2.13"> <title>2.13。统计分析<gydF4y2Ba/title> <p>使用学生结果进行了分析<gydF4y2Baitalic> t<gydF4y2Ba/italic>以及。所有的数据都在本研究中被表示为平均值±标准平均误差(SEM)。的值<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>被视为具有统计学意义。<gydF4y2Ba/p> </sec> </sec> <sec id="sec3"> <title>3所示。结果<gydF4y2Ba/title> <sec id="sec3.1"> <title>3.1。静脉注射的msc显著增强肺癌转移<gydF4y2Ba/title> <p>首先,我们调查了系统性应用msc能否调节自发LLC1肿瘤细胞转移到肺部。我们观察到LLC1 + MSC-treated肿瘤小鼠肺转移的数量增加(图展出<gydF4y2Baxref rid="fig1a" ref-type="fig"> 1(一)<gydF4y2Ba/xref>动物只有LLC1细胞相比)。显著提高肿瘤细胞的多形性原子核,安排在聚合形式,注意到在肺部MSC-treated肿瘤的实验动物在28日的一天。虽然肿瘤细胞的血管周的渗透也注意到在肺部隔绝LLC1-treated老鼠,这些老鼠恶性组织的扩张相比,明显降低LLC1 + MSCs-treated动物肺组织和肿瘤细胞(图几乎完全取代<gydF4y2Baxref rid="fig1a" ref-type="fig"> 1(一)<gydF4y2Ba/xref>)。肺组织广泛证实恶性肿瘤的组织学得分LLC1-treated小鼠静脉注射获得msc(图<gydF4y2Baxref rid="fig1b" ref-type="fig"> 1 (b)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> <fig-group id="fig1"> <label>图1<gydF4y2Ba/label> <p>msc促进肺癌转移。(a)代表)彩色老鼠肺部获得28天的实验。他走时染色肝组织样本的图像显示在同一放大(×100)。(b)组织学得分的28天肺组织确定的实验。(c)血清TNF浓度-<gydF4y2Baitalic> α<gydF4y2Ba/italic>,(d) IL-17 (e) il - 10,和(f) HGF测量14日21日和28日天的实验。(g)的犬尿氨酸(h)没有在小鼠血清14日21日和28日天的实验。数据呈现意味着±扫描电镜;<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 10<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>每个实验小鼠组。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Ba/p> <fig id="fig1a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.001a"></graphic> </fig> <fig id="fig1b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.001b"></graphic> </fig> <fig id="fig1c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.001c"></graphic> </fig> <fig id="fig1d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.001d"></graphic> </fig> <fig id="fig1e"> <label>(e)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.001e"></graphic> </fig> <fig id="fig1f"> <label>(f)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.001f"></graphic> </fig> <fig id="fig1g"> <label>(g)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.001g"></graphic> </fig> <fig id="fig1h"> <label>(h)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.001h"></graphic> </fig> </fig-group> </sec> <sec id="sec3.2"> <title>3.2。msc改变血清水平的细胞因子和生长因子,在抗肿瘤免疫反应中发挥了重要作用<gydF4y2Ba/title> <p>为了探索是否MSC-dependent肺转移病灶的扩张是其对系统的影响免疫反应的结果,细胞因子在肿瘤动物的血清浓度测定在14日21日和28日天的实验。根据组织学分析,msc大大改变血清细胞因子和生长因子的抗肿瘤免疫反应中扮演重要的角色在所有时间点测量。抗肿瘤细胞因子TNF -的浓度<gydF4y2Baitalic> α<gydF4y2Ba/italic>(图<gydF4y2Baxref rid="fig1c" ref-type="fig"> 1 (c)<gydF4y2Ba/xref>)和IL-17(图<gydF4y2Baxref rid="fig1d" ref-type="fig"> 1 (d)<gydF4y2Ba/xref>)的浓度显著降低,而免疫抑制il - 10(图<gydF4y2Baxref rid="fig1" ref-type="fig"> 1 (e)<gydF4y2Ba/xref>)、犬尿氨酸(图<gydF4y2Baxref rid="fig1g" ref-type="fig"> 1 (g)<gydF4y2Ba/xref>),没有(图<gydF4y2Baxref rid="fig1h" ref-type="fig"> 1 (h)<gydF4y2Ba/xref>)都明显高于血清LLC1-treated老鼠收到msc。没有任何显著差异实验组之间血清的免疫调节HGF水平(图<gydF4y2Baxref rid="fig1f" ref-type="fig"> 1 (f)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> </sec> <sec id="sec3.3"> <title>3.3。msc显著降低DCs的总数、巨噬细胞、CD4 +辅助T细胞在肺部LLC1-Treated老鼠和改变他们的细胞因子<gydF4y2Ba/title> <p>接下来,我们分析了细胞构成的肺部肿瘤注射后28天为了确定细胞目标LLC1-treated MSC-mediated抑制抗肿瘤免疫反应的动物。msc深刻CD45 +白细胞的浸润到肺实质(<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>;图<gydF4y2Baxref rid="fig2a" ref-type="fig"> 2(一个)<gydF4y2Ba/xref>)。流式细胞仪分析显示的总数CD45 + F4/80 +巨噬细胞(图<gydF4y2Baxref rid="fig2b" ref-type="fig"> 2 (b)<gydF4y2Ba/xref>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)、CD45 + CD11c + CD11b +炎症DCs(图<gydF4y2Baxref rid="fig2c" ref-type="fig"> 2 (c)<gydF4y2Ba/xref>左面板,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)和CD4 +辅助T细胞(图<gydF4y2Baxref rid="fig2d" ref-type="fig"> 2 (d)<gydF4y2Ba/xref>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)显著降低肺肿瘤的老鼠获得msc。<gydF4y2Ba/p> <fig-group id="fig2"> <label>图2<gydF4y2Ba/label> <p>MSC治疗减少涌入的DCs、巨噬细胞和CD4 + T细胞在转移性肺癌模型,改变他们的细胞因子。(一)CD45 +总体数量、(b) CD45 + F4/80 +, (c) CD45 + CD11c + CD11b +,和CD11c + TNF -<gydF4y2Baitalic> α<gydF4y2Ba/italic>+细胞在肺部的控制、LLC1和LLC1 + MSC-treated 28天的小鼠实验。(d)和代表总数流式细胞术点块CD4 +, TNF -<gydF4y2Baitalic> α<gydF4y2Ba/italic>和IL-17-producing CD4 +细胞在28天的实验。(e)的总数lung-infiltrating CD4 +细胞il - 10 + 28天的实验。值意味着±SEM (<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M12"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 10<gydF4y2Ba/mml:mn> <mml:mtext> </mml:mtext> <mml:mtext> </mml:mtext> <mml:mi mathvariant="normal"> p<gydF4y2Ba/mml:mi> <mml:mi mathvariant="normal"> e<gydF4y2Ba/mml:mi> <mml:mi mathvariant="normal"> r<gydF4y2Ba/mml:mi> <mml:mtext> </mml:mtext> <mml:mtext> </mml:mtext> <mml:mi mathvariant="normal"> g<gydF4y2Ba/mml:mi> <mml:mi mathvariant="normal"> r<gydF4y2Ba/mml:mi> <mml:mi mathvariant="normal"> o<gydF4y2Ba/mml:mi> <mml:mi mathvariant="normal"> u<gydF4y2Ba/mml:mi> <mml:mi mathvariant="normal"> p<gydF4y2Ba/mml:mi> </mml:math> </inline-formula>)。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M13"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M14"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Ba/p> <fig id="fig2a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.002a"></graphic> </fig> <fig id="fig2b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.002b"></graphic> </fig> <fig id="fig2c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.002c"></graphic> </fig> <fig id="fig2d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.002d"></graphic> </fig> <fig id="fig2e"> <label>(e)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.002e"></graphic> </fig> </fig-group> <p>细胞内染色显示,系统性的TNF - msc的应用减少了渗透<gydF4y2Baitalic> α<gydF4y2Ba/italic>第DCs(图<gydF4y2Baxref rid="fig2c" ref-type="fig"> 2 (c)<gydF4y2Ba/xref>右面板,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M15"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)、肿瘤坏死因子-<gydF4y2Baitalic> α<gydF4y2Ba/italic>第(图<gydF4y2Baxref rid="fig2d" ref-type="fig"> 2 (d)<gydF4y2Ba/xref>中间面板,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M16"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>),IL-17-producing CD4 +辅助T细胞(图<gydF4y2Baxref rid="fig2d" ref-type="fig"> 2 (d)<gydF4y2Ba/xref>右面板,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M17"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)和增加CD4 + T细胞的存在产生免疫抑制il - 10(图<gydF4y2Baxref rid="fig2e" ref-type="fig"> 2 (e)<gydF4y2Ba/xref>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M18"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)。<gydF4y2Ba/p> <p>免疫组织化学分析证实了这些发现。静脉注射的msc减少CD3 + T淋巴细胞(图的存在<gydF4y2Baxref rid="fig3a" ref-type="fig"> 3(一个)<gydF4y2Ba/xref>(图),CD4 + T辅助细胞<gydF4y2Baxref rid="fig3b" ref-type="fig"> 3 (b)<gydF4y2Ba/xref>)、CD68 +巨噬细胞(图<gydF4y2Baxref rid="fig3c" ref-type="fig"> 3 (c)<gydF4y2Ba/xref>)、肿瘤坏死因子-<gydF4y2Baitalic> α<gydF4y2Ba/italic>第(图<gydF4y2Baxref rid="fig3d" ref-type="fig"> 3 (d)<gydF4y2Ba/xref>(图),IL-17-producing细胞<gydF4y2Baxref rid="fig3e" ref-type="fig"> 3 (e)<gydF4y2Ba/xref>)在肺部LLC1-treated小鼠肿瘤诱导后28天。<gydF4y2Ba/p> <fig-group id="fig3"> <label>图3<gydF4y2Ba/label> <p>系统性的msc可以减少注射免疫细胞和炎性细胞因子在LLC1-treated小鼠的肺。代表图像CD3、CD4、CD68 TNF -<gydF4y2Baitalic> α<gydF4y2Ba/italic>肺,IL-17免疫组织化学染色石蜡包埋组织切片获得28天的实验(××20日40)。(一)CD3 +细胞、CD4 +细胞(b)和(c) CD68 +肺巨噬细胞存在于更高的数字在LLC1-treated老鼠LLC1 + msc和对照组相比。(d) TNF的表达<gydF4y2Baitalic> α<gydF4y2Ba/italic>和(e) IL-17肺的肺组织高LLC1-treated老鼠LLC1 + MSC和对照组相比。<gydF4y2Ba/p> <fig id="fig3a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.003a"></graphic> </fig> <fig id="fig3b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.003b"></graphic> </fig> <fig id="fig3c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.003c"></graphic> </fig> <fig id="fig3d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.003d"></graphic> </fig> <fig id="fig3e"> <label>(e)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.003e"></graphic> </fig> </fig-group> </sec> <sec id="sec3.4"> <title>3.4。msc减少渗透肺部的ctl LLC1-Treated老鼠和减毒的FasL的表达,穿孔素,CD107表面<gydF4y2Ba/title> <p>静脉注射的msc显著降低细胞毒性CD8 + ctl总数(图<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(一),<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M19"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)在肺部LLC1-treated 28天的小鼠实验。此外,分析细胞毒性分子参与CTL-mediated抗肿瘤免疫反应(FasL、穿孔素和CD107)表明,msc设法减弱涌入FasL + ctl(图<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(b),<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M20"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>),穿孔素+ ctl(图<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(c),<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M21"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>),CD107 + ctl(图<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(d),<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M22"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)在肺部肿瘤的动物。<gydF4y2Ba/p> <fig id="fig4"> <label>图4<gydF4y2Ba/label> <p>msc减少渗透肺部的ctl LLC1-treated老鼠和减弱的FasL的表达,穿孔素,CD107表面。总数(a) CD8 +、CD8 + FasL + (b), (c) CD8 +穿孔素+,(d) CD8 + CD107 +、CD8 + TNF - (e)<gydF4y2Baitalic> α<gydF4y2Ba/italic>+,(f) CD8 + IL-17 +细胞在肺部的控制,LLC1,和LLC1 + MSC-treated 28天的小鼠实验中,伴随着代表点的情节。数据呈现意味着±扫描电镜;<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M23"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 10<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>每个实验小鼠组。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M24"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M25"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Ba/p> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.004"></graphic> </fig> <p>细胞内染色显示系统的应用msc减弱ctl的能力产生抗肿瘤细胞因子(数字<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(e) -<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(f))。有显著降低TNF -的数量<gydF4y2Baitalic> α<gydF4y2Ba/italic>第(图<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(e),<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M26"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)和IL-17-producing ctl(图<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(f),<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M27"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)在MSC + LLC1-treated老鼠相比LLC1-only对待动物。<gydF4y2Ba/p> </sec> <sec id="sec3.5"> <title>3.5。抗肿瘤的细胞毒性NK细胞明显减毒在MSC + LLC1-Treated老鼠旁分泌,不,和IDO-Dependent的方式<gydF4y2Ba/title> <p>由流式细胞术,后28天肿瘤诱导,CD49b + NK细胞的存在显著降低了LLC1 + MSC-treated老鼠相比LLC1-only对待动物(图<gydF4y2Baxref rid="fig5a" ref-type="fig"> 5(一个)<gydF4y2Ba/xref>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M28"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)。<gydF4y2Ba/p> <fig-group id="fig5"> <label>图5<gydF4y2Ba/label> <p>msc减弱的NK细胞抗肿瘤细胞毒性伊诺和IDO-dependent方式。(a)的总数CD49b +和(b) CD49b + NKG2D +细胞在肺部的控制,LLC1, LLC1 + MSC-treated 28天的小鼠实验。(c - d)。由xCELLigence系统获得的结果显示细胞毒性对LLC1靶细胞NK细胞的活性。数据呈现意味着±扫描电镜;<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M29"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 10<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>每个实验小鼠组。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M30"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M31"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M32"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Ba/p> <fig id="fig5a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.005a"></graphic> </fig> <fig id="fig5b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.005b"></graphic> </fig> <fig id="fig5c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.005c"></graphic> </fig> <fig id="fig5d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2017/6294717.fig.005d"></graphic> </fig> </fig-group> <p>此外,NK细胞的总数,激活受体NKG2D表达,参与抗肿瘤免疫反应,明显降低肺部的肿瘤小鼠获得msc(图<gydF4y2Baxref rid="fig5b" ref-type="fig"> 5 (b)<gydF4y2Ba/xref>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M33"> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)。因此,xCELLigence实时监测系统获得的结果表明NK细胞毒性隔绝LLC1 + MSC-treated老鼠大大减少细胞毒性对LLC1细胞NK细胞与动物,只有LLC1细胞(图<gydF4y2Baxref rid="fig5c" ref-type="fig"> 5 (c)<gydF4y2Ba/xref>),这表明静脉注射的msc显著降低抗肿瘤NK细胞的细胞毒性。<gydF4y2Ba/p> <p>直接表明可溶性因子,而不是细胞细胞负责MSC-mediated接触抑制NK细胞的细胞毒性与LLC1细胞,MSC-CM的影响进行评估。因为它是图所示<gydF4y2Baxref rid="fig5d" ref-type="fig"> 5 (d)<gydF4y2Ba/xref>对LLC1 MSC-CM显著抑制NK细胞的细胞毒性细胞。这种现象在伊诺抑制剂的存在完全废除(L-NMMA)或被罩抑制剂(1-MT),表明伊诺我作为重要因素MSC-mediated抑制NK细胞的抗肿瘤细胞毒性(图<gydF4y2Baxref rid="fig5d" ref-type="fig"> 5 (d)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> </sec> </sec> <sec id="sec4"> <title>4所示。讨论<gydF4y2Ba/title> <p>众所周知,msc天生tumor-homing细胞,几个小时全身注射后,迁移在肺部(<gydF4y2Baxref ref-type="bibr" rid="B14"> 14<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B15"> 15<gydF4y2Ba/xref>]。许多受体、细胞外基质蛋白和可溶性tumor-derived因素已报告影响肿瘤趋向性的静脉注射msc (<gydF4y2Baxref ref-type="bibr" rid="B15"> 15<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B16"> 16<gydF4y2Ba/xref>]。最近,这是表明巨噬细胞移动抑制因子(MIF) / CXCR4和单核细胞化学引诱物蛋白1 (MCP-1) / CCR2通路负责迁移msc在肺部的肿瘤微环境<gydF4y2Baxref ref-type="bibr" rid="B15"> 15<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B16"> 16<gydF4y2Ba/xref>]。MIF从肿瘤细胞分泌吸引msc CXCR4-dependent方式到肺部。击倒的趋化因子受体CXCR4或MIF废除MSC归航以体内肿瘤肺转移模型(<gydF4y2Baxref ref-type="bibr" rid="B15"> 15<gydF4y2Ba/xref>]。同样,msc的归巢能力压制后推倒MCP-1的表达在肺癌细胞表面或阻塞CCR2表示msc、指示的重要作用MCP-1 / CCR2轴取向的msc肺肿瘤(<gydF4y2Baxref ref-type="bibr" rid="B16"> 16<gydF4y2Ba/xref>]。后立即移植,msc与tumor-infiltrated免疫细胞相互作用,影响抗肿瘤免疫反应(<gydF4y2Baxref ref-type="bibr" rid="B17"> 17<gydF4y2Ba/xref>]。因此,发现MSC-based调制相关的抗肿瘤免疫msc的可能对临床应用有重要影响。<gydF4y2Ba/p> <p>在这里,我们提供的证据表明,系统性应用msc tumorbearing动物促进扩张肺转移的抑制抗肿瘤免疫反应的抑制先天(DCs, NK细胞)和自适应(CD4 + T辅助,CD8 + ctl)免疫力。<gydF4y2Ba/p> <p>显著降低巨噬细胞的数量(数字<gydF4y2Baxref rid="fig2b" ref-type="fig"> 2 (b)<gydF4y2Ba/xref>和<gydF4y2Baxref rid="fig3c" ref-type="fig"> 3 (c)<gydF4y2Ba/xref>),DCs(图<gydF4y2Baxref rid="fig2c" ref-type="fig"> 2 (c)<gydF4y2Ba/xref>)、效应CD4 +辅助T细胞(数字<gydF4y2Baxref rid="fig2d" ref-type="fig"> 2 (d)<gydF4y2Ba/xref>和<gydF4y2Baxref rid="fig3b" ref-type="fig"> 3 (b)<gydF4y2Ba/xref>)和CD8 + ctl(数字<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(一),<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(b),<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(c),<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(d),<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(e)<gydF4y2Baxref rid="fig4" ref-type="fig"> 4<gydF4y2Ba/xref>(f))以及NK细胞数量和细胞毒性的降低(图<gydF4y2Baxref rid="fig5" ref-type="fig"> 5<gydF4y2Ba/xref>)表明,系统性应用msc感应和影响效应阶段的抗肿瘤免疫反应。<gydF4y2Ba/p> <p>静脉注射的msc抑制,几乎瞬间,迁移的DCs引流淋巴结显著影响DCs的能力对CD4 + T细胞抗原呈递和cross-presentation CD8 + T细胞(<gydF4y2Baxref ref-type="bibr" rid="B18"> 18<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B19"> 19<gydF4y2Ba/xref>]。因此,显著降低CD11c + CD11b + DCs(图<gydF4y2Baxref ref-type="fig" rid="fig2c"> 2 (c)<gydF4y2Ba/xref>)是伴随着减少数量的CD4 +(数字<gydF4y2Baxref ref-type="fig" rid="fig2d"> 2 (d)<gydF4y2Ba/xref>和<gydF4y2Baxref ref-type="fig" rid="fig3b"> 3 (b)<gydF4y2Ba/xref>)和CD8 + T细胞(图<gydF4y2Baxref ref-type="fig" rid="fig3a"> 3(一个)<gydF4y2Ba/xref>)在肺部LLC1-treated老鼠收到msc。<gydF4y2Ba/p> <p>DC的成熟也受msc (<gydF4y2Baxref ref-type="bibr" rid="B20"> 20.<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B21"> 21<gydF4y2Ba/xref>]。直流接触tnf和msc未能上调成熟标记(<gydF4y2Baxref ref-type="bibr" rid="B19"> 19<gydF4y2Ba/xref>]。转,不成熟的DCs强烈阻碍的能力产生TNF -<gydF4y2Baitalic> α<gydF4y2Ba/italic>和其他促炎细胞因子,抑制肿瘤的生长和转移<gydF4y2Baxref ref-type="bibr" rid="B22"> 22<gydF4y2Ba/xref>]。符合这些观察,血清TNF的表达下调<gydF4y2Baitalic> α<gydF4y2Ba/italic>(图<gydF4y2Baxref ref-type="fig" rid="fig1c"> 1 (c)<gydF4y2Ba/xref>)是伴随着低数量的TNF -<gydF4y2Baitalic> α<gydF4y2Ba/italic>第DCs在肺部LLC1 + MSCs-treated老鼠相比LLC1-only对待动物(图<gydF4y2Baxref ref-type="fig" rid="fig2c"> 2 (c)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> <p>除了抑制幼稚T细胞活化,msc能够诱导效应的抑制CD4 + T辅助细胞主要是通过生产可溶性介导因素包括语言,不,il - 10,前列腺素E2 (PGE2)、胶质瘤、TGF -<gydF4y2Baitalic> β<gydF4y2Ba/italic>(<gydF4y2Baxref ref-type="bibr" rid="B23"> 23<gydF4y2Ba/xref>]。因此,静脉注射的msc与更高的血清il - 10水平(图了<gydF4y2Baxref ref-type="fig" rid="fig1e"> 1 (e)<gydF4y2Ba/xref>)、犬尿氨酸(图<gydF4y2Baxref ref-type="fig" rid="fig1g"> 1 (g)<gydF4y2Ba/xref>),没有(图<gydF4y2Baxref ref-type="fig" rid="fig1h"> 1 (h)<gydF4y2Ba/xref>),其次是减少数量的lung-infiltrated效应CD4 + T细胞(数字<gydF4y2Baxref ref-type="fig" rid="fig2d"> 2 (d)<gydF4y2Ba/xref>和<gydF4y2Baxref ref-type="fig" rid="fig3b"> 3 (b)<gydF4y2Ba/xref>),产生抗肿瘤细胞因子TNF -<gydF4y2Baitalic> α<gydF4y2Ba/italic>和IL-17(图<gydF4y2Baxref ref-type="fig" rid="fig2d"> 2 (d)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> <p>进步的炎性疾病,包括肿瘤、相关的损失IL-17-producing CD4 + Th17细胞和互惠的分数增加免疫抑制IL-10-producing CD4 + T淋巴细胞在外周血和发炎组织(<gydF4y2Baxref ref-type="bibr" rid="B24"> 24<gydF4y2Ba/xref>]。MSC-derived被罩是一种酶,具有强大的免疫调节作用,导致其酶活性,从而导致分解代谢的必需氨基酸色氨酸L-kynurenine (<gydF4y2Baxref ref-type="bibr" rid="B25"> 25<gydF4y2Ba/xref>]。代谢物的L-kynurenine通路已经被证明作为关键分子开关刺激IL-10producing T细胞的免疫抑制特性和同步块重组成IL-17-producing效应T细胞(<gydF4y2Baxref ref-type="bibr" rid="B26"> 26<gydF4y2Ba/xref>]。因此,在这里,我们表明,注入msc增加血清犬尿氨酸水平LLC1-treated老鼠(图<gydF4y2Baxref ref-type="fig" rid="fig1g"> 1 (g)<gydF4y2Ba/xref>),伴随着IL-10-producing CD4 + T淋巴细胞数量的增加和减少的数量IL-17-producing Th17细胞(图<gydF4y2Baxref ref-type="fig" rid="fig2d"> 2 (d)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> <p>如上所述,msc的直流衰减能力cross-presentation和CD8 + T细胞的活化<gydF4y2Baxref ref-type="bibr" rid="B18"> 18<gydF4y2Ba/xref>]。此外,msc抑制ctl的增殖和抑制表面分子的表达参与CTL-mediated细胞毒性对肿瘤细胞(<gydF4y2Baxref ref-type="bibr" rid="B27"> 27<gydF4y2Ba/xref>]。符合这些发现,显著降低lung-infiltrated CD8 + ctl FasL表达(图<gydF4y2Baxref ref-type="fig" rid="fig4"> 4<gydF4y2Ba/xref>(b)和穿孔素(图)<gydF4y2Baxref ref-type="fig" rid="fig4"> 4<gydF4y2Ba/xref>(c))被发现在MSC + LLC1-treated老鼠相比LLC1-only对待动物表明系统性管理MSC抑制穿孔素和FasL-mediated ctl的抗肿瘤细胞毒性机制。<gydF4y2Ba/p> <p>msc抑制NK细胞的增殖和细胞毒性,以及[<gydF4y2Baxref ref-type="bibr" rid="B28"> 28<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref ref-type="bibr" rid="B30"> 30.<gydF4y2Ba/xref>]。这种抑制作用的msc与激活NK细胞受体表达下调表达,如NKG2D,主要是由被罩,PGE2, TGF -<gydF4y2Baitalic> β<gydF4y2Ba/italic>1 (<gydF4y2Baxref ref-type="bibr" rid="B29"> 29日<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B30"> 30.<gydF4y2Ba/xref>]。在这里,我们表明,msc减少的总数lung-infiltrated NKG2D-expressing LLC1-treated小鼠NK细胞(图<gydF4y2Baxref ref-type="fig" rid="fig5b"> 5 (b)<gydF4y2Ba/xref>)和显著减弱他们对肺癌细胞的细胞毒性体外(图<gydF4y2Baxref ref-type="fig" rid="fig5c"> 5 (c)<gydF4y2Ba/xref>)。伊诺和被罩抑制剂设法几乎完全恢复细胞毒性对LLC1 NK细胞的活性细胞体外(图<gydF4y2Baxref ref-type="fig" rid="fig5d"> 5 (d)<gydF4y2Ba/xref>),这表明伊诺和语言信号的重要性MSC-mediated抑制NK细胞毒性抗肿瘤。众所周知,炎性细胞因子,如肿瘤坏死因子-<gydF4y2Baitalic> α<gydF4y2Ba/italic>骨髓间充质使用iNOS-dependent机制,引发不生产(<gydF4y2Baxref ref-type="bibr" rid="B9"> 9<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B31"> 31日<gydF4y2Ba/xref>]。MSC-derived没有可以直接抑制淋巴细胞的增殖或可能增加被罩活动可能导致的衰减NK细胞的细胞毒性(<gydF4y2Baxref ref-type="bibr" rid="B9"> 9<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B31"> 31日<gydF4y2Ba/xref>]。<gydF4y2Ba/p> </sec> <sec id="sec5"> <title>5。结论<gydF4y2Ba/title> <p>我们的研究提供的证据表明,系统性应用msc可以促进转移的肺癌细胞抑制抗肿瘤免疫反应。这些发现引起严重担忧关于安全的静脉应用msc的患者为恶性疾病遗传易感性。<gydF4y2Ba/p> </sec> <back> <sec> 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