HO-1基因转染脂肪间充质干细胞在支气管哮喘中的作用及机制研究
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摘要
第一部分：脂肪间充质干细胞的分离、培养及鉴定
目的：分离、培养小鼠脂肪间充质干细胞（Adipose-derived mesenchymal stemcells，ADSCs），通过流式细胞技术和干细胞多能分化诱导技术对干细胞进行鉴定，掌握体外干细胞培养技术，了解干细胞的生物学特性。
材料与方法：用无菌技术切取6-8w的BALB/c小鼠腹股沟及腹部脂肪组织，用I型胶原酶消化获得ADSCs，将细胞培养在含10%胎牛血清（Fetal bovine serum，FBS）的L-Dulbeeo改良的eagle培养液（Dulbeco’s modified eagle medium，DMEM）培养基中，采用单纯贴壁法对鼠ADSCs进行分离，并在体外进行ADSCs传代培养、纯化。用倒置显微镜每天观察细胞生长，计算细胞贴壁率，绘制ADSCs的生长曲线，用流式细胞仪对ADSCs表面标志物CD90、CD44、CD11b、CD45进行鉴定，然后用不同的诱导液诱导ADSCs向成脂肪、成骨、成软骨细胞分化，并采用油红O染色、改良Gomori钙钴法、Von Kossa染色、阿尔新蓝染色等方法进行鉴定。
结果：接种后第2d，细胞开始稀疏地贴附于培养瓶的表面，呈纺锤形，少数呈三角形、多角形。在第3d换液时，发现大多数细胞均已贴壁。至第5d左右，细胞呈集落样生长，形态呈成纤维细胞样梭形细胞。至第9-10d，细胞集落生长至80%融合，细胞呈均一的梭形，成旋涡状排列，2w左右，细胞可长满瓶底。传代细胞以均匀分布的方式生长，5-7d就几乎完全融合，1w左右即可以传代一次。细胞接种后2h左右，即有部分细胞出现贴壁，贴壁率为29.4%±1.3%，24h的贴壁率97.3%±1.8%。接种后第1d即有细胞生长，但前3d细胞生长比较缓慢，第4-8d细胞生长显著加快，至第8d，细胞生长接近融合。传至3代后，细胞的形态呈现均一的长梭形、成纤维状。经测定CD90、CD44阳性细胞达到96.6%和85.3%；CD11b、CD45阳性细胞均为0.5%，在不同的诱导环境下，可分化为成脂肪细胞、成骨细胞、成软骨细胞。表明所得细胞为ADSCs。
结论：通过I型胶原酶和单纯贴壁法可以体外获得大量ADSCs，具有较强的增殖能力，细胞表面标志CD90、CD44阳性，CD11b、CD45阴性，体外具有很强的多向分化潜能。
第二部分：携带HO-1基因慢病毒的包装和ADSCs的转染
目的：制备携带血红素氧化酶-1（Heme oxygenase-1，HO-1）基因的慢病毒载体，并对其进行测序鉴定，在293T细胞中进行慢病毒包装，得到高滴度的携带HO-1基因的慢病毒，进行ADSCs的转染。
材料与方法：从新鲜脾脏组织中抽提出小鼠总RNA，将总RNA反转录合成cDNA。根据小鼠HO-1基因（GeneBank序号：NM_010442.2），设计并合成HO-1基因引物，利用人工合成的引物，采用RT-PCR技术钓取目的基因HO-1的cDNA片段，再将目的基因片段与pMD18T载体连接，再将酶切线性化的pMD18T-HO-1与酶切线性化的pCDH-MCS-EF1-GFP-Puro载体连接，其产物转化感受态细菌XL10-gold。对长出的克隆先进行菌落鉴定，挑取符合预期的阳性克隆进行测序。然后在293T细胞内，进行慢病毒的包装，收集、浓缩病毒颗粒并检测病毒滴度，最后将携带HO-1基因的慢病毒转染ADSCs，并运用RT-qPCR和Western-Blot的方法检测ADSCs的HO-1mRNA和HO-1蛋白的表达情况。
结果：琼脂糖电泳及测序证实成功构建了重组pCDH-CMV-HO-1载体，HO-1基因被成功导入pCDH-CMV-MCS-EF1-GFP-Puro载体，在293T细胞内，成功地包装成携有HO-1基因的慢病毒，病毒滴度为3×108TU/ml。成功地将携有HO-1基因的慢病毒转染至ADSCs，运用RT-qPCR和Western-Blot的方法能在ADSCs检测到高水平HO-1mRNA和HO-1蛋白的表达。
结论：成功构建了携带HO-1基因的慢病毒，并成功地转染到ADSCs中，为下一步的小鼠哮喘模型体内实验提供优质的、HO-1基因修饰的ADSCs来源。
第三部分：转HO-1基因的ADSCs治疗支气管哮喘的实验研究
目的：以支气管哮喘小鼠为模型，研究转HO-1基因的ADSCs在支气管哮喘中的治疗作用，及其对参与哮喘发病的细胞因子的影响，比较单用ADSCs和转HO-1基因的ADSCs在哮喘中的作用，确定HO-1在哮喘肺部的抗炎作用，评估基因疗法在支气管哮喘治疗中的可行性。
材料与方法：选用雌性BALB/c小鼠32只，体重18-22g，随机将小鼠分为：对照组、哮喘组、ADSCs/HO-1组和ADSCs组。哮喘组运用卵清蛋白（Ovalbumin，OVA）致敏并激发，制作小鼠哮喘动物模型，在实验d0、d7、d14天，给哮喘组小鼠注射OVA致敏液200μl，从d21天到d27天给予小鼠吸入3%的OVA溶液，每次30min，每天一次，在d20天，哮喘组经尾静脉注入0.1ml生理盐水。治疗组致敏、激发同哮喘组，在d20天，治疗组经尾静脉注入0.1ml2×106个ADSCs/HO-1和ADSCs。对照组以生理盐水代替OVA，实验方法同哮喘组，在d20天，哮喘组经尾静脉注入0.1ml生理盐水。在d28天，各组小鼠在测定肺功能后，进行肺泡灌洗，再收集肺组织观察各组肺部病理变化情况，检测支气管肺泡灌洗液（Bronchoaleolarlavage fluid，BALF）中炎症细胞和细胞因子的变化情况，并检测HO-1在肺组织中的表达情况。
结果：成功建立支气管哮喘小鼠模型。肺组织冰冻切片可以检测到绿色荧光蛋白的表达。与对照组相比，哮喘组肺功能为气道阻力增高、肺的顺应性下降，肺泡灌洗液中细胞总数明显升高，分类中嗜酸粒细胞也明显升高，细胞因子IL-4、IL-5、IL-13、TNF-明显升高而细胞因子IFN-γ、IL-10明显降低，肺组织切片HE染色示气道周围有大量炎性细胞浸润，PAS染色示气道黏膜有较多杯状细胞增生，免疫组化染色示HO-1表达增加。治疗组能降低气道阻力、增加肺的顺应性，减少肺泡灌洗液中细胞总数和嗜酸粒细胞数，减少细胞因子IL-4、IL-5、IL-13、TNF-，增加细胞因子IFN-γ、IL-10，减少气道周围炎性细胞浸润和气道黏膜的杯状细胞，增加肺组织HO-1的表达，与ADSCs组相比， ADSCs/HO-1组作用更明显，各组间差异有统计学意义。
结论：用OVA致敏和激发可以成功建立小鼠哮喘模型。经尾静脉途径注入的小鼠ADSCs可以在小鼠肺部炎症的趋化下，迁移并定植于小鼠肺部。转染HO-1基因的ADSCs和单独注入ADSCs均能减轻小鼠的气道高反应、气管周围的炎性细胞浸润、气管黏膜杯状细胞增生，调节BALF中多种炎症介质如IL-4、IL-5、IL-10、IL-13、IFN-γ、TNF-的产生，对支气管哮喘均有治疗作用，但转染HO-1基因的ADSCs作用更显著，HO-1在哮喘肺部具有抗炎作用。基因疗法治疗支气管哮喘是可行的。
Part Ⅰ: Isolation, cultivation and identification of mice adipose-derive mesenchymal stem cells in vitro
Objective: To isolate, culture murine adipose-derived mesenchymal stem cells(ADSCs), to identify ADSCs by flow cytometry and stem cell pluripotent differentiationtechnology，to master stem cells culture techniques in vitro and understand the biologicalcharacteristics of ADSCs,
Material and methods: To take inguinal and abdomen adipose tissue of BALB/cmice aged6-8weeks by sterile technique. Adipose tissue was digested with type Icollagenase and got ADSCs, the cells were cultured in Dulbeco’s modified eaglemedium(DMEM) containing10%fetal bovine serum(FBS), ADSCs were isolated byadherent, ADSCs were subcultured and purified in vitro. Cell growth was observed usingan inverted microscope every day. Cell adhesion rate was calculated and growth curve ofADSCs was draw. Stem cell surface markers CD90, CD44, CD11b and CD45wereidentified using flow cytometry. ADSCs were induced into adipocyte, osteocyte,chondrocyte using different induction medium. ADSCs were identified using oil red Ostaining, modified Gomori calcium cobalt method, Von Kossa staining, Alcian bluestaining method.
Results: The cells sparsely attached to the surface of the flask as fusiform, a fewtriangular, polygon on the second day after inoculation. When the medium was changed onthe third day, most cells were adherent. On the fifth day, cells were colony-like growth, theshape of cells were the fibroblast-like spindle. On the ninth-tenth day, cell colonies were about80%confluence, cells were uniform spindle-shaped and spirally arrange. About twoweeks later, the cells could cover the bottom. Passaged cells grow in a uniformlydistributed manner, cells were almost completely confluent on the fifth-seventh day, aweek later cells could be subcultured one time. About2hours after cell inoculation, somecells were adherent, adherent rate was29.4%±1.3%, it was97.3%±1.8%24hours later.Cells began to grow on the first day after inoculation, but cell growth is relatively slowduring the first3days, cell growth was accelerated during the fourth-eighth day, cells werealmost confluent on the eighth day. Cell morphology showed uniform long spindle orfibrous until three generations. The determination of CD90, CD44-positive cells reached96.6%and85.3%, CD11b, CD45positive cells were reached0.5%, they could differentiateinto adipocytes, osteoblasts, and chondrocytes in different medium. It indicated that thecells were ADSCs
Conclusion: we could get lots of adipose-derived mesenchymal stem cells by type Icollagenase and adherent in vitro, cell surface markers CD90, CD44were positive andCD11b, CD45were negative, the cells were with multipotent differentiation in vitro.
Part2: Establishment of lentiviral vector with HO-1gene andtransfection for adipose-derived mesenchymal stem cells
Objective: To prepare the lentiviral vector with HO-1gene and the HO-1genesequence was tested; lentiviruses were packed in293T cells, the high titer lentivirus withHO-1gene were obtained, ADSCs were transfected by lentivirus with HO-1gene.
Material and methods: Total RNA was obtained from fresh spleen tissues of mice,total RNA was reversely transcribed to cDNA. According to mouse HO-1gene (GeneBanknumber: NM_010442.2), the primer of HO-1was designed and synthesized, the cDNAfragment of HO-1gene was obtained using RT-PCR technology and connected with thepMD18T vector. The pMD18T-HO-1was obtained. And then it was connected with thepCDH-MCS-EF1-GFP vector linearized by digestion, the product transformed thecompetent cells XL10-gold. The clone was identified; the positive clones were selected to be sequenced. Lentiviruses were packaged in293T cells, lentiviruses were collected andconcentrated, the titer of virus was determined. Finally ADSCs were transfected bylentiviruses with HO-1gene. The expression of HO-1on ADSCs was determined inRT-qPCR and Western-Blot way.
Results: Agarose gel electrophoresis and sequencing confirmed that the recombinantVector pCDH-CMV-HO-1was successfully constructed; HO-1gene wassuccessfully introduced into the pCDH-CMV-MCS-EF1-GFP-Puro vector. Lentiviruseswith HO-1gene were successfully packaged in293T cells, the virus titer was3×108TU/ml. Lentiviruses with HO-1gene was successfully transfected into ADSCs, HO-1wasabundantly expressed in ADSCs.
Conclusion: Lentiviruses with HO-1gene was successfully constructed, and ADSCswere successfully transfected with lentiviruses with HO-1gene.The high qualified ADSCswith HO-1gene were provided for the animal experiment.
Part3: Experimental study about transplantation ofADSCs with HO-1gene in the treatment of asthma
Objective: Mice were as models of asthma, the effect was researched about ADSCswith HO-1gene in the treatment of bronchial asthma, and the impact on cytokinesinvolved in the pathogenesis of asthma was discussed. The effect was compared betweenADSCs and ADSCs with HO-1gene in asthma. The feasibility of gene therapy in asthmawas evaluated.
Material and methods:32female BALB/c mice were chosen, weight is18-22g,and animal model of asthma was established via OVA sensitization and challenging. Micewere divided into four groups: control group, asthma group, HO-1/ADSCs group andADSCs group. Mice were sensitized with200μl OVA on d0,7,14and challenged viainhaling3%OVA solution from d21to d27,30minutes every time, once a day. On thetwentieth day, the asthma group was injected with0.1ml natural saline through tail vein.The procedure of ADSCs group and HO-1/ADSCs group were same as that in the asthma group, but on the twentieth day, they were injected with0.1ml2×106ADSCs or ADSCswith HO-1gene. Control group received saline instead of OVA, the procedure is same asthat in the asthma group. On the twenty-eighth day, mice were sacrificed after spirometrytest to observe the changes of lung tissue, inflammatory cells, cytokines in BALF andexpression of HO-1in lung tissue.
Results: Mice model of asthma was successfully established. Compared with thecontrol group, in asthma group airway resistance was increased, lung compliance wasdecreased, the total number of cells and eosinophils were significantly increased in BALF,cytokines like IL-4, IL-5, IL-13,TNF-were significantly increased and the cytokine likeIL-10, IFN-γ was significantly decreased. HE staining of lung tissue shows inflammatorycells infiltration around the airway, PAS staining showed mucus cells were increased inairway mucosa, expression of HO-1was increased through immune-histochemistrystaining. In treatment groups airway resistance could be reduced, lung compliance could beincreased, the total number of cells and eosinophils in BALF could be reduced, cytokineslike IL-4、IL-5、IL-13、TNF-could be reduced, cytokines like IFN-γ、IL-10could beincreased, infiltration of inflammatory cells around the airways and mucus cells in airwaymucosa could be reduced, HO-1expression in lung tissue could be increased. The effect inHO-1/ADSCs group was better than that in ADSCs group; the difference between thegroups was statistically significant.
Conclusion: ADSCs with HO-1gene and ADSCs had therapeutic effect on asthma,but the effect in ADSCs with HO-1gene was better than that in ADSCs, the gene therapywas feasible in the treatment of asthma.
目的：分离、培养小鼠脂肪间充质干细胞（Adipose-derived mesenchymal stemcells，ADSCs），通过流式细胞技术和干细胞多能分化诱导技术对干细胞进行鉴定，掌握体外干细胞培养技术，了解干细胞的生物学特性。
材料与方法：用无菌技术切取6-8w的BALB/c小鼠腹股沟及腹部脂肪组织，用I型胶原酶消化获得ADSCs，将细胞培养在含10%胎牛血清（Fetal bovine serum，FBS）的L-Dulbeeo改良的eagle培养液（Dulbeco’s modified eagle medium，DMEM）培养基中，采用单纯贴壁法对鼠ADSCs进行分离，并在体外进行ADSCs传代培养、纯化。用倒置显微镜每天观察细胞生长，计算细胞贴壁率，绘制ADSCs的生长曲线，用流式细胞仪对ADSCs表面标志物CD90、CD44、CD11b、CD45进行鉴定，然后用不同的诱导液诱导ADSCs向成脂肪、成骨、成软骨细胞分化，并采用油红O染色、改良Gomori钙钴法、Von Kossa染色、阿尔新蓝染色等方法进行鉴定。
结果：接种后第2d，细胞开始稀疏地贴附于培养瓶的表面，呈纺锤形，少数呈三角形、多角形。在第3d换液时，发现大多数细胞均已贴壁。至第5d左右，细胞呈集落样生长，形态呈成纤维细胞样梭形细胞。至第9-10d，细胞集落生长至80%融合，细胞呈均一的梭形，成旋涡状排列，2w左右，细胞可长满瓶底。传代细胞以均匀分布的方式生长，5-7d就几乎完全融合，1w左右即可以传代一次。细胞接种后2h左右，即有部分细胞出现贴壁，贴壁率为29.4%±1.3%，24h的贴壁率97.3%±1.8%。接种后第1d即有细胞生长，但前3d细胞生长比较缓慢，第4-8d细胞生长显著加快，至第8d，细胞生长接近融合。传至3代后，细胞的形态呈现均一的长梭形、成纤维状。经测定CD90、CD44阳性细胞达到96.6%和85.3%；CD11b、CD45阳性细胞均为0.5%，在不同的诱导环境下，可分化为成脂肪细胞、成骨细胞、成软骨细胞。表明所得细胞为ADSCs。
结论：通过I型胶原酶和单纯贴壁法可以体外获得大量ADSCs，具有较强的增殖能力，细胞表面标志CD90、CD44阳性，CD11b、CD45阴性，体外具有很强的多向分化潜能。
第二部分：携带HO-1基因慢病毒的包装和ADSCs的转染
目的：制备携带血红素氧化酶-1（Heme oxygenase-1，HO-1）基因的慢病毒载体，并对其进行测序鉴定，在293T细胞中进行慢病毒包装，得到高滴度的携带HO-1基因的慢病毒，进行ADSCs的转染。
材料与方法：从新鲜脾脏组织中抽提出小鼠总RNA，将总RNA反转录合成cDNA。根据小鼠HO-1基因（GeneBank序号：NM_010442.2），设计并合成HO-1基因引物，利用人工合成的引物，采用RT-PCR技术钓取目的基因HO-1的cDNA片段，再将目的基因片段与pMD18T载体连接，再将酶切线性化的pMD18T-HO-1与酶切线性化的pCDH-MCS-EF1-GFP-Puro载体连接，其产物转化感受态细菌XL10-gold。对长出的克隆先进行菌落鉴定，挑取符合预期的阳性克隆进行测序。然后在293T细胞内，进行慢病毒的包装，收集、浓缩病毒颗粒并检测病毒滴度，最后将携带HO-1基因的慢病毒转染ADSCs，并运用RT-qPCR和Western-Blot的方法检测ADSCs的HO-1mRNA和HO-1蛋白的表达情况。
结果：琼脂糖电泳及测序证实成功构建了重组pCDH-CMV-HO-1载体，HO-1基因被成功导入pCDH-CMV-MCS-EF1-GFP-Puro载体，在293T细胞内，成功地包装成携有HO-1基因的慢病毒，病毒滴度为3×108TU/ml。成功地将携有HO-1基因的慢病毒转染至ADSCs，运用RT-qPCR和Western-Blot的方法能在ADSCs检测到高水平HO-1mRNA和HO-1蛋白的表达。
结论：成功构建了携带HO-1基因的慢病毒，并成功地转染到ADSCs中，为下一步的小鼠哮喘模型体内实验提供优质的、HO-1基因修饰的ADSCs来源。
第三部分：转HO-1基因的ADSCs治疗支气管哮喘的实验研究
目的：以支气管哮喘小鼠为模型，研究转HO-1基因的ADSCs在支气管哮喘中的治疗作用，及其对参与哮喘发病的细胞因子的影响，比较单用ADSCs和转HO-1基因的ADSCs在哮喘中的作用，确定HO-1在哮喘肺部的抗炎作用，评估基因疗法在支气管哮喘治疗中的可行性。
材料与方法：选用雌性BALB/c小鼠32只，体重18-22g，随机将小鼠分为：对照组、哮喘组、ADSCs/HO-1组和ADSCs组。哮喘组运用卵清蛋白（Ovalbumin，OVA）致敏并激发，制作小鼠哮喘动物模型，在实验d0、d7、d14天，给哮喘组小鼠注射OVA致敏液200μl，从d21天到d27天给予小鼠吸入3%的OVA溶液，每次30min，每天一次，在d20天，哮喘组经尾静脉注入0.1ml生理盐水。治疗组致敏、激发同哮喘组，在d20天，治疗组经尾静脉注入0.1ml2×106个ADSCs/HO-1和ADSCs。对照组以生理盐水代替OVA，实验方法同哮喘组，在d20天，哮喘组经尾静脉注入0.1ml生理盐水。在d28天，各组小鼠在测定肺功能后，进行肺泡灌洗，再收集肺组织观察各组肺部病理变化情况，检测支气管肺泡灌洗液（Bronchoaleolarlavage fluid，BALF）中炎症细胞和细胞因子的变化情况，并检测HO-1在肺组织中的表达情况。
结果：成功建立支气管哮喘小鼠模型。肺组织冰冻切片可以检测到绿色荧光蛋白的表达。与对照组相比，哮喘组肺功能为气道阻力增高、肺的顺应性下降，肺泡灌洗液中细胞总数明显升高，分类中嗜酸粒细胞也明显升高，细胞因子IL-4、IL-5、IL-13、TNF-明显升高而细胞因子IFN-γ、IL-10明显降低，肺组织切片HE染色示气道周围有大量炎性细胞浸润，PAS染色示气道黏膜有较多杯状细胞增生，免疫组化染色示HO-1表达增加。治疗组能降低气道阻力、增加肺的顺应性，减少肺泡灌洗液中细胞总数和嗜酸粒细胞数，减少细胞因子IL-4、IL-5、IL-13、TNF-，增加细胞因子IFN-γ、IL-10，减少气道周围炎性细胞浸润和气道黏膜的杯状细胞，增加肺组织HO-1的表达，与ADSCs组相比， ADSCs/HO-1组作用更明显，各组间差异有统计学意义。
结论：用OVA致敏和激发可以成功建立小鼠哮喘模型。经尾静脉途径注入的小鼠ADSCs可以在小鼠肺部炎症的趋化下，迁移并定植于小鼠肺部。转染HO-1基因的ADSCs和单独注入ADSCs均能减轻小鼠的气道高反应、气管周围的炎性细胞浸润、气管黏膜杯状细胞增生，调节BALF中多种炎症介质如IL-4、IL-5、IL-10、IL-13、IFN-γ、TNF-的产生，对支气管哮喘均有治疗作用，但转染HO-1基因的ADSCs作用更显著，HO-1在哮喘肺部具有抗炎作用。基因疗法治疗支气管哮喘是可行的。
Part Ⅰ: Isolation, cultivation and identification of mice adipose-derive mesenchymal stem cells in vitro
Objective: To isolate, culture murine adipose-derived mesenchymal stem cells(ADSCs), to identify ADSCs by flow cytometry and stem cell pluripotent differentiationtechnology，to master stem cells culture techniques in vitro and understand the biologicalcharacteristics of ADSCs,
Material and methods: To take inguinal and abdomen adipose tissue of BALB/cmice aged6-8weeks by sterile technique. Adipose tissue was digested with type Icollagenase and got ADSCs, the cells were cultured in Dulbeco’s modified eaglemedium(DMEM) containing10%fetal bovine serum(FBS), ADSCs were isolated byadherent, ADSCs were subcultured and purified in vitro. Cell growth was observed usingan inverted microscope every day. Cell adhesion rate was calculated and growth curve ofADSCs was draw. Stem cell surface markers CD90, CD44, CD11b and CD45wereidentified using flow cytometry. ADSCs were induced into adipocyte, osteocyte,chondrocyte using different induction medium. ADSCs were identified using oil red Ostaining, modified Gomori calcium cobalt method, Von Kossa staining, Alcian bluestaining method.
Results: The cells sparsely attached to the surface of the flask as fusiform, a fewtriangular, polygon on the second day after inoculation. When the medium was changed onthe third day, most cells were adherent. On the fifth day, cells were colony-like growth, theshape of cells were the fibroblast-like spindle. On the ninth-tenth day, cell colonies were about80%confluence, cells were uniform spindle-shaped and spirally arrange. About twoweeks later, the cells could cover the bottom. Passaged cells grow in a uniformlydistributed manner, cells were almost completely confluent on the fifth-seventh day, aweek later cells could be subcultured one time. About2hours after cell inoculation, somecells were adherent, adherent rate was29.4%±1.3%, it was97.3%±1.8%24hours later.Cells began to grow on the first day after inoculation, but cell growth is relatively slowduring the first3days, cell growth was accelerated during the fourth-eighth day, cells werealmost confluent on the eighth day. Cell morphology showed uniform long spindle orfibrous until three generations. The determination of CD90, CD44-positive cells reached96.6%and85.3%, CD11b, CD45positive cells were reached0.5%, they could differentiateinto adipocytes, osteoblasts, and chondrocytes in different medium. It indicated that thecells were ADSCs
Conclusion: we could get lots of adipose-derived mesenchymal stem cells by type Icollagenase and adherent in vitro, cell surface markers CD90, CD44were positive andCD11b, CD45were negative, the cells were with multipotent differentiation in vitro.
Part2: Establishment of lentiviral vector with HO-1gene andtransfection for adipose-derived mesenchymal stem cells
Objective: To prepare the lentiviral vector with HO-1gene and the HO-1genesequence was tested; lentiviruses were packed in293T cells, the high titer lentivirus withHO-1gene were obtained, ADSCs were transfected by lentivirus with HO-1gene.
Material and methods: Total RNA was obtained from fresh spleen tissues of mice,total RNA was reversely transcribed to cDNA. According to mouse HO-1gene (GeneBanknumber: NM_010442.2), the primer of HO-1was designed and synthesized, the cDNAfragment of HO-1gene was obtained using RT-PCR technology and connected with thepMD18T vector. The pMD18T-HO-1was obtained. And then it was connected with thepCDH-MCS-EF1-GFP vector linearized by digestion, the product transformed thecompetent cells XL10-gold. The clone was identified; the positive clones were selected to be sequenced. Lentiviruses were packaged in293T cells, lentiviruses were collected andconcentrated, the titer of virus was determined. Finally ADSCs were transfected bylentiviruses with HO-1gene. The expression of HO-1on ADSCs was determined inRT-qPCR and Western-Blot way.
Results: Agarose gel electrophoresis and sequencing confirmed that the recombinantVector pCDH-CMV-HO-1was successfully constructed; HO-1gene wassuccessfully introduced into the pCDH-CMV-MCS-EF1-GFP-Puro vector. Lentiviruseswith HO-1gene were successfully packaged in293T cells, the virus titer was3×108TU/ml. Lentiviruses with HO-1gene was successfully transfected into ADSCs, HO-1wasabundantly expressed in ADSCs.
Conclusion: Lentiviruses with HO-1gene was successfully constructed, and ADSCswere successfully transfected with lentiviruses with HO-1gene.The high qualified ADSCswith HO-1gene were provided for the animal experiment.
Part3: Experimental study about transplantation ofADSCs with HO-1gene in the treatment of asthma
Objective: Mice were as models of asthma, the effect was researched about ADSCswith HO-1gene in the treatment of bronchial asthma, and the impact on cytokinesinvolved in the pathogenesis of asthma was discussed. The effect was compared betweenADSCs and ADSCs with HO-1gene in asthma. The feasibility of gene therapy in asthmawas evaluated.
Material and methods:32female BALB/c mice were chosen, weight is18-22g,and animal model of asthma was established via OVA sensitization and challenging. Micewere divided into four groups: control group, asthma group, HO-1/ADSCs group andADSCs group. Mice were sensitized with200μl OVA on d0,7,14and challenged viainhaling3%OVA solution from d21to d27,30minutes every time, once a day. On thetwentieth day, the asthma group was injected with0.1ml natural saline through tail vein.The procedure of ADSCs group and HO-1/ADSCs group were same as that in the asthma group, but on the twentieth day, they were injected with0.1ml2×106ADSCs or ADSCswith HO-1gene. Control group received saline instead of OVA, the procedure is same asthat in the asthma group. On the twenty-eighth day, mice were sacrificed after spirometrytest to observe the changes of lung tissue, inflammatory cells, cytokines in BALF andexpression of HO-1in lung tissue.
Results: Mice model of asthma was successfully established. Compared with thecontrol group, in asthma group airway resistance was increased, lung compliance wasdecreased, the total number of cells and eosinophils were significantly increased in BALF,cytokines like IL-4, IL-5, IL-13,TNF-were significantly increased and the cytokine likeIL-10, IFN-γ was significantly decreased. HE staining of lung tissue shows inflammatorycells infiltration around the airway, PAS staining showed mucus cells were increased inairway mucosa, expression of HO-1was increased through immune-histochemistrystaining. In treatment groups airway resistance could be reduced, lung compliance could beincreased, the total number of cells and eosinophils in BALF could be reduced, cytokineslike IL-4、IL-5、IL-13、TNF-could be reduced, cytokines like IFN-γ、IL-10could beincreased, infiltration of inflammatory cells around the airways and mucus cells in airwaymucosa could be reduced, HO-1expression in lung tissue could be increased. The effect inHO-1/ADSCs group was better than that in ADSCs group; the difference between thegroups was statistically significant.
Conclusion: ADSCs with HO-1gene and ADSCs had therapeutic effect on asthma,but the effect in ADSCs with HO-1gene was better than that in ADSCs, the gene therapywas feasible in the treatment of asthma.
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