异种移植人脐带间充质干细胞在大鼠肝切除模型发生病理学反应

异种移植人脐带间充质干细胞在大鼠肝切除模型发生病理学反应 异种移植人脐带间充质干细胞在大鼠肝切除模型发生 病理学反应 暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除模型发生病理学反应 目 录 中 文摘 要 „„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„ „„ „„„ „ „„„ „ „ ? 英 文摘 要 „„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„ „„ „„„ „ „„„ „ „. ? 符 号说 明 „„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„„„ „„„ „ „„„ „?? 正 文 前 言 „„„„„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „ „..01 参 考文 献 „„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „ „„02 第 一部 分 人 脐带间 充质 干细 胞的分 离、 培养与 鉴定前言 „„„„„„„„„„„„„„„„„„ „„„„ „„„„„„ „„„ „ „„„ „ „„„ „.07 材 料和 方法 „„„„„„„„„„„„„„„„„ „„„„ „„„„„ „„„ „„ „„„ „07 结 果 „„„„„„„„„„„„„„„„„„„„„ „„„„ „ „„„„„„„„„ „„„„ „.12 讨 论 „„„„„„„„„„„„„„„„„„„„„ „„„„ „„ „„„„„„„„ „„„„ „.15 结 论 „„„„„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„ „„„ „„„ „ „.17 参 考文 献 „„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„ „„ „„„ „ „..17 第 二部 分 EGFP 标 记 的 人脐 带间充 质干 细胞 行 异种 移植的 可行 性 分析 定性数据统计分析pdf销售业绩分析模板建筑结构震害分析销售进度分析表京东商城竞争战略分析 前 言 „„„„„„„„ „„„„„„„„„„ „„„„ „„„„„„„„„ „ „„„„ „„„„.20 材 料和 方法 „„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „.20 结 果 „„„„„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „..25 讨 论 „„„„„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „..29 结 论 „„„„„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „..31 参 考文 献 „„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „..31 综 述一 „„„„„„„„„„ „„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „.35 综 述二 „„„„„„„„„„ „„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „.43 致 谢 „„„„„„„„„„„„„„„„„„„„„ „„„„ „„„„„„„„„„ „„„„ „..52 附录- ?在校 期间 发 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 的 论文„„„„„„„„„„„„„„„„„„..53 附录- ?附图„„„„„„„„„„„„„„„„„„„„„„„„„54 III暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除模型发生病理学反应 中 文 摘 要 研 究背 景 20 世纪医学界最杰出的成就之一 是人类移植学的发展, 而输血技术则是人 类最早的细胞移植,进入 21 世纪后,临床细 胞移植术进一步发展,其代表性的 成果自然是骨髓移植和同种胰岛移植,近 20 年来,由于临床移植受体的大量增 加, 供体显著短缺, 干细胞移植成为生命科学领域的另一研究热点, 部分学者已 经认为干细胞移植是治疗器官终末期病变的有效手段之一。 细胞移植是指将适量 游 离的具有某种功能的 活 细胞输注到受体的血 管 、体 腔或组织器官内, 由于间充质干细胞具有多向分化潜能、 低免疫原性及免 疫调节 [1] 功能,在 理论上肯定了干细胞移植的优势。Lu 等 发现脐血间充质 干细胞不表达 MHC- ?分子, 低水平表达 MHC- ?分子, ? 类 分 子 是 由 非 共 价 键 连 接 的 两 条 肽 链 组 成 的 糖 蛋 白, 分 布 于 几 乎 所 有 有 核 细 胞 表 面 , 其 重 要 生 理 功 能 是 对 CD8 T 细 胞 的 抗 原 识 别 功 能 起 限 制 性 作 用 , 主 要 介 导 Tc 细 胞 的 细 胞 毒 作 用 , 是 重 要 的 移 植 抗 原 ; ? 类 分 子 的 分 布 比 较 局 限 , 主 要 表 达 于 B 细 胞 、 单 核 - 巨 噬 细 胞 和 树 突 状 细 胞 等 抗 原 递 呈 细 胞 上 , 是 引 起 移 植 排 斥 反 应 的 重 要 靶 抗 原 , 包 括 引 起 宿 主 抗 移 植 物 反 应 (Host versus graft reaction ,hvgr)和 移 植 物 抗 宿 主 反 应 (Graft-versus-host reaction ,gvhr ) ,理论上间充 质干细胞具 有低免疫原性。在过去 10 年里,大量的文 献还反映出间充质干细胞具强大的免 [2] + + 疫抑制作用,Prigione 等 发现间充质干细胞 抑制细胞毒性 CD4 、CD8 T 细胞 的增殖, 减少干扰素的产生, 也一定程度上抑制自然杀伤细胞和 γδT 细胞的增殖 和功能。 鉴于上述特点, 将绿色荧光蛋白标记的人脐带 间充质干细胞移植入与人 类有相似器官 、相近基因的大鼠体内,观察异种移植细胞能否在大鼠体内存活 、 分化 ,为人脐带间充质干细胞的 应用提供实验依据。 本 文 分 两 部 分 , 分 别 探 讨 以 下 问 题 快递公司问题件快递公司问题件货款处理关于圆的周长面积重点题型关于解方程组的题及答案关于南海问题 : (1 ) 研 究 人 脐 带 间 充 质 干 细 胞 分 离 、 培养、 鉴定的方法; (2) 制备大鼠部分肝切除模型, 利用慢病毒载体介导 EGFP 转染人脐带间充质干细胞, 将标记细胞移植入肝损伤大鼠体内, 观察人脐带间充 质干细胞的存活、 分化及再生肝组织病理 、 肝脏功能的 变化, 探讨间充质干细胞 能否用于异种移植。 IV暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除模型发生病理学反应 第 一部 分人 脐 带 间充 质干 细胞 的分 离、 培养 与鉴 定 目的: 研究人脐带 间充 质干细胞的分离、 培养及鉴定方法, 观察其生物学特 性。 方法: 青年健康孕妇足月后行剖宫产术, 术中获得 无菌脐带组织, 应用胶原 酶 ?消化筛选人脐带间充质干细胞, 通过观察细胞形态、 流式细胞仪 检测 工程第三方检测合同工程防雷检测合同植筋拉拔检测方案传感器技术课后答案检测机构通用要求培训 细胞表 面标志物以 及对其进行 成骨、 成脂 诱导分化培养, 对培养的人脐带 间充质干细胞 进行鉴定 。 结 果: 运用胶原酶消化 法可以获得纯化的人 脐带间充质干细胞。 该方法获得 的人脐带血间充质干细胞贴壁生长, 经传代, 呈典型的长梭形, 可涡旋或放射排 列; 流式细胞仪技术检测该细胞的表面标志物, 高度表达 CD90 、CD73 、CD105 , 不表达或低表达 CD34 、CD31 、HLA-DR ;成 脂诱导两周,经油红“O” 染色,镜 下可见脂滴呈红色,成骨诱导 3 周,经茜素红染色,镜下可见深红的钙盐沉淀。 上述结果均符合典型的生物学间充质干细胞特征。 结论 圆锥曲线的二级结论椭圆中二级结论圆锥曲线的二级结论圆锥曲线的二级结论探究欧姆定律实验步骤 : 胶原酶消化法可 以获得高度纯化的人脐带间充质干细胞 , 以供本研究 使用 。 关 键词 :人脐带间充质 干细胞;分离;鉴定 第 二部 分 人 脐带间 充质 干细 胞 异 种移 植的 可行 性分 析 目的: 探讨人脐带间充 质干细胞能否在大鼠体内存活、 分化, 及观察 异种移 植人脐带间充质干细胞对大鼠肝损伤修复的影响。 方法 : 取 生 长 活 跃 的 293T 细胞,以 慢 病 毒 为 载 体 , 增 强 型 绿 色 荧 光 蛋 白 (Enhanced green fluorescent protein ,EGFP ) 为目的基因,以不同 的感染复数 (Multiplicity of infection ,MOI )感染 293T 细胞,收集富含 EGFP 慢病毒颗粒 的细胞上清 , 浓缩后计算病毒浓度, 以 1:100 的感染复数感染人脐带间充质干细 胞, 经激光共聚焦显微镜检测干细胞内 EGFP 的表达; 成功标记后, 人脐带间充 质干细胞经门静脉注入肝部分切除的大鼠体内, 术后 3 个月, 以胶原 酶法分离肝 组织细胞, 同时制作再生肝叶的病理切片, 以确定干细胞的存活、 分化状态及肝 组 织修复情况 ,经腹主动脉抽血检测实验组 、模型组 与对照组的肝功能的差异 。 结果: 转染成功的人脐带间充质干细胞在荧光显微镜下呈绿色梭形, 绿色 荧 V暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除模型发生病理学反应 光充满胞浆; 移植术后 3 个月, 病理切片提示模型 组为正常肝组织, 实验组肝组 织结构较模型 组紊乱, 汇管区炎细胞浸润明显, 肝细胞内淤胆, 血管内有 微栓形 成, 部分坏死的干细胞团栓塞肝内血管, 分离 获得 的部分细胞在共聚焦显微镜下 发出较弱的绿光, 胞核成多核样改变; 模型 组肝功能明显优于实验组 (P0.05)。 结 论 : 异种移植人脐带间充质干细胞在观察期内部分存活于大鼠体内并分 化, 但 实验组病理切片提 示明显的病理学反应, 转氨酶水平也高于其余两组, 结 合异种移植的本质 , 大鼠的肝脏 可能无法给植入的 人间充质干细胞提供完全适宜 增殖和分化的微环境。 关 键词 : 增强型绿色荧 光蛋白;转染;异种移植VI暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除模型发生病理学反应 ABSTRACT Background In 20th century, one of the most outstanding achievements in the modern medicine is the development in the science of human transplantation , while blood transfusion is the earliest technology of human cell transplantation. In 21st century, clinical cell transplantation to be further development, more and more scientists takes attention on cells clinic transplantation, such as: bone marrow transplant and pancreatic islet allografts. Recently, the past 20 years, stem cells transplantation became research hotspots in the field of life science because donor organ shortage and clinical recipients increasing. Some scholars believe that stem cell transplantation is an effective means for the treatment of the organ with end stage disease Cell transplantation is the infusion of the appropriate amount of free living cells those are having a certain function to the receptors in blood vessels, body cavities or tissues and organs. The mesenchymal stem cells having the multiline age differentiation potential, low immunogenicity and immune regulation function, which affirmed the theoretical advantages of stem cell transplantationLu et al [1] found that umbilical cord blood mesenchymal stem cells do not express MHC- ? molecules, and expression of MHC- ?are maintained at a low level, MHC- ? are glycoprotein, which compose of two polypeptide chains connected by a no covalent bond and distribute almost in all nuclear cells surface, their important physiological functions are playing a limiting role in antigen recognition function of CD8T cells, they also mainly mediated cytotoxicity of TC cells, so MHC- ?important antigens in transplantation. Distribution of MHC- ? molecules are more limited, mainly expressed on antigen presenting cells, such as B cells, monocytes - macrophages and dendritic cells, which are target antigens that cause transplant rejection, including host-versus-graft reaction Host versus graft, reaction, HVGR and graft-versus-host reactionGraft-versus-host reaction, GVHR.Therefor, mesenchymal stem cells with low immunogenicity. In VII暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除模 型发生病理学反应 the past 10 years, a lot of literature also reflects that mesenchymal stem cells with powerful immunosuppressive effects, Prigione et al[2] found that the mesen -chymal stem cells inhibit proliferation of cytotoxic CD4 and CD8 T cells, reduce the production of interferon, to some extent, also inhibit proliferation and function of natural killer cells, γδT cells. Given these characteristics, we use green fluorescent protein to label human umbilical cord mesenchymal stem cells, then transplanted labeled human umbilical cord mesenchymal stem cells into the rats, the similar organs similar genes rats, which are with similar genes and genes with human, to observe whether xenograft cells can survive and differentiated in rats, provide experimental basis for the clinical application of human umbilical cord mesenchymal stem cells This paper is divided into two parts, respectively, to discuss the following issues: 1 To research the methods of separation ,culture ,expanding and identification of mesenchymal stem cells MSCs in vitro , the biological characteristics of MSCs ;2 Preparation of rat partial liver resection model, Lentiviral vector-mediated EGFP transfected human umbilical cord mesenchymal stem cells, the labeled cells were transplanted into the damaged liver of rats, to observe human umbilical cord mesenchymal stem cell survival, differentiation and regeneration of liver pathology, investigate whether mesenchymal stem cells are suitable for xenotransplantationPart IIn vitro culture and identification of human umbilical cord mesenchymal stem cells Objective: To study the methods of separation, culture and identification of human umbilical cord mesenchymal stem cells, and to observe the biological characteristics of human umbilical cord mesenchymal stem cellsMethods :Aseptic to get the umbilical cord tissue, Collagenase II digested umbilical cord tissue to screened human umbilical cord mesenchymal stem cells, VIII暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除 模型发生病理学反应 observed the morphous, identify the phenotype of MSCs by flow cytometric, carried osteogenic, adipogenic differentiation culture, cultured human umbilical cord mesenchymal stem cells were identifiedResults: the use of collagenase can obtain purified human mesenchymal stem cells, obtained human umbilical cord mesenchymal stem cells adherent growth, went down to the future generation, the cells were typical long spindle, arranged gyrately or radiantly. Through detection by flow cytometry, were highly to expresse CD90, CD73, CD105, no expression or low expression of CD34, CD31, HLA-DR; Two weeks after adipogenic ,red lipid droplets was visible by oil red O staining. Osteogenic induction has lasted for three weeks; crimson calcium salt precipitation was visible by alizarin red staining. All these results are in line with the typical biological characteristics of mesenchymal stem cellConclusion: Highly purified human umbilical cord mesenchymal stem cells can be harvested by collagenase digestionKeywords: human umbilical cord mesenchymal stem cells; separation; identification Part II. Feasibility analysis of human umbilical cord mesenchymal stem cells xenograft into the rats Objective: To investigate human umbilical cord mesenchymal stem cells whether can survival, differentiate in the rats, and assess the effect of xenograft human umbilical cord mesenchymal stem cells on the repairation of impaired livers in ratsMethods:Cultured 293T cells,which were growing actively , HIV-lentivirus are vectors, enhanced green fluorescent protein Enhanced green fluorescent protein, EGFP is the target gene, 293T cells were infected with different multiplicity of infection Multiplicity of infection, MOI,and then to collect rich the EGFP lentivirus particles from cell supernatants, calculate the concentration of the virus,infect human umbilical cord mesenchymal stem cells with infection IX暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除模 型发生病理学反应 complex infection is 1:100 , expression of eGFP in umbilical cord mesenchymal stem cells was detected by focus microscope fluorescence microscope. Labeled human umbilical cord mesenchymal stem cells were injected into rats via the portal vein, which were partial liver resected, 3 months after surgery, liver tissue cells were isolated by collagenase ?, and producted biopsy of renewable lobe of the liver , to determine the situation just as the survival ,differentiation status of the stem cells, and the reparation of liver tissue Results: The human umbilical cord mesenchymal stem cells were successful transfected were green spindle-shaped under a fluorescence microscope or focus microscope, cytoplasm was full of green the fluorescent. In 3 months after surgery, biopsy showed that control group is normal liver tissue, liver tissue structure of the experimental group are disorder, Lymphocytic infiltration in portal area, Cholestatic in liver cells, thrombosis in the blood vessels, partial necrotic stem cell group embolizated intrahepatic vascular, isolated cells under the confocal microscope give out weaker green, some nucleus of these cells went into multi-core-like changesConclusion: The xenograft of some human umbilical cord mesenchymal stem cells were survivaling in the rats , and differentiate into other cell types, the microenvironment of rat livers cannot be entirely appropriate to the proliferation and differentiation of human stem cells , because of the nature of the xenograftKeywords: enhanced green fluorescent protein; transfection; xenograft X暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除模型 发生病理学反应 符 号 说 明 缩写 英文全 名 中 文全 名 DMSOdimethyl sulphoxide 二 甲基 亚砜 PBS phosphate buffer solution磷 酸盐 缓冲 溶液 FBS fatal bovie serum 胎牛血 清 HUMSCs human umbilical cord mesenchymal stem cells 人 脐带 间充 质 干 细胞 MOI multiple of infection 感 染复 数 EGFP Enhanced green fluorescent protein 增强 型绿色 荧光 蛋白 hvgrHost versus graft reaction 宿主 抗移植 物反 应 gvhrGraft-versus-host reaction 移植 物抗宿 主反 应 h hour 小时 min minute分钟 d day 天 SD sprague dawley SD 大鼠 FITC fluorescein isothiocyanate 异 硫氰酸 荧光 素 CPEcytopathic effect 细胞 病变 效应 OS Osteogenic supplements 成 骨分 化诱 导培 养基 AS Adipogenic supplements 成 脂 诱 导分 化培 养基 ALT alanine transaminase 谷丙转氨酶 AST aspatate aminotransferase 谷草转氨酶 XI异种移 植人脐带间充质干 细胞在大鼠肝切除 模型发生病理学反 应 前言 自我更新和多向分化潜能使间充质干细胞有 望成为治疗人类疾病的重要资 料,据现有的文献报道:间充质干细胞有望用于治疗组织缺损、器官功能不全、 [1,2,3,4] 炎症、肿瘤等疾病 。更重要的是这类细胞具有低免疫原性和 免 疫调节功能 [5,6] [7,8] , 很 可 能 适 用 于 同 种 移 植 , 甚 至 是 异 种 移 植 , 但 其 自 我 更 新 、 多 向 分 化 及 [9] 调 节 免 疫 的 机 制 尚 未 完 全 明了 , 因此,间 充 质 干 细 胞 的 分 离 、 鉴 定 、 分 化 、 免 疫调节、 临床应用等仍是目前研究的热点, 而间充质干细胞能在受体内存活, 是 其能用于临床应用的先决条件。 间充质干细胞可来源于不同组织 , 如胚胎、骨髓、脂肪、脐带血、脐带等 [10,11,12,13,14] , 人脐带间 充质干细胞 也是适用于再生医学的资源, 这与它的多向分 化潜能、 低免疫原性、 低致瘤性、 抗瘤活性等特性密切相关, 该事实在最近的一 [15] 项研究 中再次得到论证: 人脐带间 充质干 细胞和人骨髓 间充质干 细胞生长在乳 腺癌和卵巢癌并存的培养基中 30 天,前者无 明显变化,后者向细长的成纤维细 胞转化, 转化率在持续上升, 而补体表达在下降, 发生转化的人骨髓间充质干细 胞表达肿瘤相关标记因子, 如纤维蛋白裂解产物、 成纤维生长因子、 血管内皮生 长因子、 表皮生 长因子 、 肌糖蛋 白-C 等 。更 令医学界 振奋的 是人脐 带间充质干 细胞对 肿瘤生长有抑制作用, 它不仅抑制乳腺癌细胞的生长, 还可以促进卵巢癌 [16] [17,18] 和骨肉瘤细胞的凋亡 , 其机制与抑制信号通 路密切相关 。 因为 这些特点, 此研究 将人脐带间充质干细胞纳入为此次研究的对象。 近年来, 不少的学者不断改良间充质干细胞的分离方法, 在考虑经济的基础 上, 充分考虑到干细胞的活性、 纯度及收集率。 目前分离间充质干细胞的 常用方 法有 : 免 疫 磁 珠 分 离 法 、 贴壁筛选法、流式细胞仪分离法、密度梯度 离心法等 [19,20,21] 。 上述方法各具特点, 贴壁筛选操作简单但细胞纯度不足, 流式细胞仪筛 选、 磁珠分选均易影响细胞 活性, 密度梯度离心法影响细胞的收集率及纯度。 除 [22,23] 这 些 方 法 外 , 胶 原 酶 消 化 法 已 经 被 广 泛 应 用 , 其 优 点 在 于 : 经 济 , 获 取 的暨南大学硕士学位论文异种移植人脐带间充 质干细胞在大鼠肝切除模型发生病理学反应 细胞纯度相对高,对细胞的损伤小。 [24] 间充质干 细胞 的典型 形 态均呈长 梭形 ,对间充质干细 胞进 行鉴定 , 除了要 把握其独特的形态, 更重要的是细胞的表型及分化能力的测定。 就真核生物而言, 细胞的质膜由脂双层分子和蛋白质构成, 质膜的外侧尚有向外伸出的寡糖链, 质 膜的表面是由这些构成细胞膜糖蛋白、 糖脂的寡糖链形成的一层结构, 称为细胞 外被, 这层结构也就是我们所说的细胞表面, 细胞识别与细胞外被的寡糖链密切 相关, 该寡糖链有一定的排列顺序, 编成细胞表面的密码, 为细胞的识别形成了 分子基础, 也是细胞膜抗原免疫活性特异性的分子基础。 细胞膜抗原多为镶嵌在 细胞膜上的糖蛋白和糖脂, 具有特定的抗原性。 单独的表面抗原难以准确定义间 充质干细胞, 为此, 目前主要联合多个表面抗原如 CD44、CD105 、CD90 、CD73 [25] 去定义 广 义 的 间 充 质 干 细 胞 。另外,倘若间充质干细 胞 具 有 多 向 分 化 能 力 , 那么在适当的条件下, 间充质干细胞能分化为神经 、 骨、 膀胱、 内皮 、 肝细胞等 [26,27,28,29,30] 功能性细胞 ,这为间充质干细胞的鉴定提高了有 力的证据。 细胞移植的提出,最初立于 间充质干细胞具有 低免疫原性和免疫调节属性, [31] 间充质干细胞不表达 MHC- ?分子, 低水平表达 MHC- ?类分子 , 理论上, 同 种移植间充质干细胞不引起免疫反应, 避免快速排斥反应和免疫致敏的产生, 对 治疗免疫性疾病发挥积极的作用。 但异种移植间充质干细胞方面, 国内外报道较 少。 因此, 本研究以 EGFP 标记经成功鉴定的 人脐带间充质干细胞移植入大鼠体 内, 观察其存活、 分化及对肝再生的修复情况 , 为异种移植间充质干细胞的临床 应用间接提供实验依据。 参 考文 献 [1] Peterson B, Zhang J, Iglesias R, et al. 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