腺病毒介导的突变型人胰岛素原基因转染人脐带间充质干细胞
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摘要
研究背景:目前糖尿病已成为仅次于心脑血管病症和癌症的第三大死亡疾病,它是一种影响体内胰岛素和糖含量的疾病,共有两种主要类型,分别为Ⅰ型和Ⅱ型,其共同特征是胰岛β细胞损伤或不能产生足够的胰岛素或机体不能有效的利用胰岛素,所以胰岛素就被作为治疗糖尿病的特效药应用于临床。由于随时需要注射胰岛素,给患者带来了极大的不便,目前国际上对糖尿病患者进行胰岛移植和基因治疗研究成为了热点。但面临的主要问题是供体不足,免疫排斥,胰岛素基因的转染效率和表达调控等。人脐带来源的间充质干细胞可以较易获得和纯化,并且易于基因修饰,可以将外源性基因转染间充质干细胞,建立一种安全的基因治疗的“细胞载体”。研究表明间充质干细胞还有免疫抑制功能,它不但在体外可以抑制T淋巴细胞增殖反应,在体内实验中也表现出了类似免疫抑制剂的作用,所以利用它作为细胞载体可以避免免疫排斥问题。并且我们利用基因重组的方法将胰岛素原基因进行改造,使其可以在非β细胞(间充质干细胞)中高效表达。相信我们的研究可以为Ⅰ型糖尿病的治疗提供一些有力的实验依据。目的:将人胰岛素原基因进行两个部位的突变,通过腺病毒介导将其转染到人脐带间充质干细胞中,研究其表达分泌人胰岛素的能力。方法:应用RT-PCR的方法从健康流产胎儿胰腺组织中扩增pINS的cDNA序列,利用重叠延伸PCR方法对pINS基因在A链-C肽和C肽-B链的连接处进行两个部位的突变,产生Furin蛋白酶酶切位点。采用AdEasy~(TM)系统构建重组腺病毒pAdINS、pAdINS-M2和pAdGFP。分离培养人脐带间充质干细胞,并对其生长特性,免疫表型,分化能力及Furin蛋白酶的表达进行鉴定。pAdINS、pAdINS-M2和pAdGFP感染人脐带间充质干细胞后,利用荧光显微镜和流式细胞仪检测它们的感染效率,并确定最佳的感染复数(multiplicities of infection,MOI)。以感染复数为100的pAdINS、pAdINS-M2或pAdGFP感染人脐带间充质干细胞1、3、5、7、10天后,RT-PCR检测人胰岛素原基因在人脐带间充质干细胞中表达;Western blot检测成熟人胰岛素和人C-肽在人脐带间充质干细胞中的表达;免疫荧光实验检测感染后48小时人胰岛素在人脐带间充质干细胞中的表达:ELISA实验检测感染后1、3、5、7、10天人胰岛素和人C-肽的分泌。结果:自健康流产胎儿胰腺组织中扩增出364 bp的pINS cDNA,连接入穿梭质粒中,构建重组腺病毒。pAdINS-M2经扩增纯化后滴度达到2.57×10~(10) PFU/mL,pAdINS的滴度为1.25×10~(10)PFU/mL,对照病毒AdGFP为4.85×10~9 PFU/mL。成功的从脐带组织中分离培养出间充质干细胞,绘制生长曲线,约3天扩增一代。细胞周期检测,大部分细胞都处于G0-G1期(占94.39%),小部分处于G2-M期(4.15%)和S期(1.45%)。在合适的诱导培养条件下,分离培养的人脐带间充质干细胞能够分化为脂肪细胞和成骨细胞。应用RT-PCR方法在人脐带间充质干细胞中检测到了Furin蛋白酶的存在,表明我们构建的含Furin蛋白酶酶切位点的人胰岛素原基因在此细胞中可以被切割产生成熟的人胰岛素。通过重组腺病毒pAdINS、pAdINS-M2和pAdGFP以不同感染复数感染人脐带间充质干细胞,利用荧光显微镜和流式细胞仪检测感染效率,确定MOI 100为最佳的感染复数。以MOI=100的pAdINS、pAdINS-M2或pAdGFP感染人脐带间充质干细胞1、3、5、7、10天后,RT-PCR方法检测到在pAdINS和pAdINS-M2感染的UC-MSCs中人胰岛素原基因都有表达;Western blot的结果显示pAdINS感染的UC-MSCs表达人胰岛素原,而pAdINS-M2感染的UC-MSCs中检测到了人胰岛素和C.肽,pAdGFP感染的UC-MSCs中两者都没有检测到表达。免疫荧光也检测了pAdINS-M2感染后48小时人胰岛素和C-肽在人脐带间充质干细胞胞浆中表达:ELISA检测感染后1、3、5、7、10天培养上清中人胰岛素和C-肽的浓度。结果显示,自感染后24小时目的基因就开始表达,第3-5天表达量达高峰,一周后表达有所下降。与RT-PCR和Western blot结果一致。结论:成功构建含有Furin蛋白酶切位点的人胰岛素原基因腺病毒重组体(pAdINS-M2);分离培养了人脐带源间充质干细胞,并对其进行了鉴定;重组腺病毒pAdINS-M2感染人脐带间充质干细胞后,表达分泌成熟人胰岛素和C-肽。可以为Ⅰ型糖尿病的治疗提供一些有力的实验依据。
Background:At present,diabetes already has become being the third big death diseases only inferior to the heart blood vessel of brain illness and cancer.It is a disease affecting insulin and sugar content,divided into two main species types:type 1 and type 2.Their common characteristic is the pancreatic beta cells loss or the body can not produce enough insulin or effectively use insulin.Type 1 diabetes is an insulin-dependent,autoimmune disorder in which the insulin producing beta cells of the pancreatic islets are selectively destroyed.Islet transplant is considered as the optimal treatment for typeⅠdiabetes.However,because of the need to provide a large number of donor islet sufficient to achieve the purpose of clinical diabetes,after transplantation at the same time,also has the immune rejection problems,these to some extent have hindered its development.Objective:Our study was based on the characteristics of diabetes,using human umbilical cord-derived mesenchymal stem cell characteristics,mutative human proinsulin gene transfected into human umbilical cord-derived mesenchymal stem cells,caused it to express the mature human insulin. Methods and Results:A novel approach to produce insulin-secreting cell products using human umbilical cord-derived mesenchymal stem cells(UC-MSCs) carrying a human proinsulin gene was developed in the present study.In this study,we first constructed an adenovirus vector with a mutated human proinsulin gene and then transfected UC-MSCs with the vector.The transfected UC-MSCs were analyzed for their biological characteristics including the immune phenotype,the ability of differentiation and the expression of furin protease in comparison with normal UC-MSCs.Transcription and expression of the proinsulin gene in transfected UC-MSCs were detected by RT-PCR,western blot and immunofluorescence.And the secretion of mature insulin and C-peptide was examined by ELISA.Conclusion:We generated the human proinsulin gene containing the recognition site of the furin protease,and then constructed it to the adenovirus vector system(pAdINS-M2).After pAdINS-M2 infected the UC-MSCs,human mature insulin and C-peptide were express.It may be provide some powerful experiment basis for the treatment of typeⅠdiabetes.
Background:At present,diabetes already has become being the third big death diseases only inferior to the heart blood vessel of brain illness and cancer.It is a disease affecting insulin and sugar content,divided into two main species types:type 1 and type 2.Their common characteristic is the pancreatic beta cells loss or the body can not produce enough insulin or effectively use insulin.Type 1 diabetes is an insulin-dependent,autoimmune disorder in which the insulin producing beta cells of the pancreatic islets are selectively destroyed.Islet transplant is considered as the optimal treatment for typeⅠdiabetes.However,because of the need to provide a large number of donor islet sufficient to achieve the purpose of clinical diabetes,after transplantation at the same time,also has the immune rejection problems,these to some extent have hindered its development.Objective:Our study was based on the characteristics of diabetes,using human umbilical cord-derived mesenchymal stem cell characteristics,mutative human proinsulin gene transfected into human umbilical cord-derived mesenchymal stem cells,caused it to express the mature human insulin. Methods and Results:A novel approach to produce insulin-secreting cell products using human umbilical cord-derived mesenchymal stem cells(UC-MSCs) carrying a human proinsulin gene was developed in the present study.In this study,we first constructed an adenovirus vector with a mutated human proinsulin gene and then transfected UC-MSCs with the vector.The transfected UC-MSCs were analyzed for their biological characteristics including the immune phenotype,the ability of differentiation and the expression of furin protease in comparison with normal UC-MSCs.Transcription and expression of the proinsulin gene in transfected UC-MSCs were detected by RT-PCR,western blot and immunofluorescence.And the secretion of mature insulin and C-peptide was examined by ELISA.Conclusion:We generated the human proinsulin gene containing the recognition site of the furin protease,and then constructed it to the adenovirus vector system(pAdINS-M2).After pAdINS-M2 infected the UC-MSCs,human mature insulin and C-peptide were express.It may be provide some powerful experiment basis for the treatment of typeⅠdiabetes.
引文
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