RNA干扰cx43基因对培养的人RPE细胞的作用及其蛋白质组学分析
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摘要
背景和目的:实验证明RPE在多种缝隙连接蛋白中主要表达cx43,cx43能够在细胞间形成缝隙连接,从而促进细胞间的信息交流,这种信息交流和连接蛋白本身对RPE的增殖、分化、移形等细胞行为均有影响,而RPE功能和结构的正常是维持视网膜色素上皮层完整性和生理功能的重要因素,其异常与多种眼病的发生有关,因此,我们希望通过RNA干扰的方法研究cx43对RPE的生物学作用,并且通过蛋白质组学方法分析cx43基因被干扰后的蛋白质表达变化,为治疗相关的眼病提供可能的途径或策略。
实验方法:1、培养原代的人RPE细胞,经过细胞角蛋白(ck)、S-100和神经胶质原纤维酸性蛋白(GFAP)免疫细胞化学鉴定后,通过AO/PI染色技术确定培养细胞的存活率,描记其生长曲线,第3-5代用于以下细胞实验2、生物合成针对人cx43基因的三条小干扰RNA和一条阴性RNA通过脂质体转染RPE细胞后,通过RT-PCR的方法确定抑制效率最高的干扰片断3、将该片段以不同浓度通过阳离子脂质体转染培养的人RPE细胞后,采用MTT法观察其对细胞的增殖力的作用;通过流式细胞仪观察其对细胞周期的影响;通过扫描电镜观察其对细胞形态的影响;通过免疫细胞化学和Weston blot观察其对cx43蛋白表达的作用;采用激光共聚焦和荧光淬灭恢复技术观察荧光恢复速率平均百分率,评价其对细胞间通讯功能的影响;通过制作RPE细胞损伤模型,观察其对损伤修复能力的作用4、分离纯化转染siRNA的RPE组和正常对照组RPE细胞的全部蛋白质,应用等电聚焦电泳和SDS-PAGE双向电泳技术,银染显示分离出的蛋白质斑点,经凝胶图像分析软件对两个样本进行胶图分析,寻找差异蛋白点。胶内酶解差异表达的蛋白点,基质辅助电离解析飞行时间质谱(MALDI-TOF-MS)获得肽质量指纹图谱(PMF),搜寻蛋白质数据库并鉴定蛋白质,分析其生物学意义。
结果:1、原代培养的细胞呈多角形,包含大量色素,容易传代,色素随着传代次数逐渐减少。免疫细胞化学染色:ck和S-100抗体染色阳性,阳性细胞率≥94%,GFAP抗体染色阴性,可以确定是高纯度的上皮来源的色素细胞即视网膜色素上皮细胞。AO/PI染色活细胞比率≥96%,细胞生长状态良好,传代后第3、4天细胞处于对数生长期,平均6天传代一次。2、通过RT-PCR证实三条生物合成的siRNA均能抑制人RPE细胞cx43基因的转录,抑制效率最高的是siRNA1,抑制率达到72%。3、siRNA1转染人RPE细胞后,显著促进细胞的增殖,差异有统计学意义(p＜0.01),其促增殖作用有浓度依赖性,浓度为1.25ug/ml时达到饱和,促增殖作用最强,增殖率为146%,细胞平均5天传代一次;抑制cx43基因后,S期细胞比率明显增多,差异有显著性(p＜0.05);细胞的扫描电镜显示转染siRNA后,细胞表型发生变化,细胞体积增大,表面触手增多;免疫细胞化学显示体外培养的人RPE细胞表达cx43,表达部位在细胞膜、细胞质和胞核。转染siRNA24h后,cx43染色变浅,48h后染色明显变。通过计算机图像分析系统显示48h后cx43染色强度降低76%;与Weston blot结果一致,转染24h后,cx43的蛋白表达下降,48h明显抑制cx43的表达,抑制率达到62%;cx43基因被干扰后,细胞荧光恢复速率降低,细胞间通讯功能明显降低;细胞损伤修复能力下降4、通过银染的方法在RPE组三块胶中分离出共有的蛋白质斑点861个,组间匹配率达到92%;转染siRNA组三块胶分离出共有的蛋白质斑点887个,组间匹配率达到93%。经过软件图像分析,发现Volume值改变≥2.0的点共78个。其中上调的16个点,下调的18个点,有19个点在RPE上存在,而转染组不存在,25给在转染组存在而RPE组不存在。随机选取了7个点进行蛋白质谱分析:SP-H抗原、P27BBP、MAPK、IMPDH和HSP70表达上调,β-actin表达下降,VDAC在转染siRNA后出现表达。
结论:RNA干扰是一种高效的特异性基因研究工具。Cx43不仅影响细胞间通讯功能,其正常表达对细胞的增殖、生长周期、损伤修复等多种细胞行为也非常重要,通过蛋白质谱发现其表达异常可以引起多种蛋白的失调,可能对许多眼病的发生起着不可忽视的作用。
Background and aim It is certified that connexin43 is the primary connexin expressed by RPE. Cx43 participates in the formation of gap junctiongap junction, so that it promotes information exchange among cells, and contributes to the proliferation , differentiation and migration of cells. Normal structure and function of RPE play an important role in sustaining the integrity and physiological function of RPE layer, the abnomality of which is related to many eye diseases. Here we investigate the effect of cx43 on RPE by RNA interference and its proteome analysis, to provide probable path to cure eye disease.
Method 1、Primary cultured human RPE cells were identified by ck, S-100 and GFAP through immunocytochemistry method, and the rate of live/dead cells was evaluated by acridine orange/ propidium iodide staining. After the cell growth curves was recorded, RPE cells of the 3-5th passages were utilized. 2、Three different siRNA (siRNAl,siRNA2,siRNA3) targeting against human cx43 gene and one negative control siRNA were designed and transfected into cultured human RPE cells via liposome reagent. The most effective siRNA can be determined by semi-quantitative reverse transcription PCR(RT-PCR. 3、To the most effective siRNA, after transfected into human RPEs with different concentration, the cellular proliferate activities were messured by MTT colorimetry ; the percentages of RPE in different cell circle phase was assayed by FCM; the changes of phenotypical properities were observed with SCM; the protein expression of cx43 was studied through immunocytochemistry stain and Weston blot; the communication intercellular was calculated with FRAP; and the ability of recovery was assessed by using an in vitro wound healing model.4、The total proteins of siRNA1 and RPE were seperated by two-dimensional gel electrophoresis and visualized by silver staining. Proteins with significant expression alterations were selected and their peptide mass fingerprints (PMFs ) were obtained by matrix-assisted laser desorption/ionization time of flying mass spectrometry (MALDI-TOF-MS).The PMFs were used to search NCBInr database by Auto MS-Fit software. The proteins were identity and analysis its biological significence
Results 1、The just digested hRPE cells were polygon , contained large quantity of pigments and easy to passage, but those pigments in the RPE cells decreased along with the cell division. The percentage of cells, with positive of anti-CK、s-100 and negative of anti-GFAP,is up to 94%.according to this, the cultured cells can be identified as highly purified human retinal pigment epithelium cells. The rate of live/dead cell was about 96% through AO/PI staining, the cell grow state in good condition, the cells go into exponential phase of growth after passaged 3-4 days. the cells would be passaged every 6 days. 2、Three pairs of siRNAs were reduced the synthetic of cx43 mRNA in different levels, and the most effective siRNA was siRNA1.the inhibited rate was up to 72% 3、After siRNA1 transfected into human RPE cells, the cellular proliferate activities enhanced significantly in an concentration-dependent manner until it achieved saturate at 1.25ug/ml, and the maximal growth rate was 46%. the cells were passaged every 5 days; the percentate of cells in S phase was increased obviously(p<0.05); the changes of cell phenotype was observed through SCM: the cell volume enlarged and tentacles lie on the surface of cell increased visibly; the protein expression of cx43 was decreased obviously by Immunocytochemistry stain and Weston blot. Cultured RPE cells expressed cx43 in cellular membrane, cytoplasm and nucleus. 24 hours after transfection the protein expression of cx43 was depressed and 48 hours the depression rate was about 76% through image analysis, which was coincidence with the results of Weston blot, its maximal inhibited rate was 62% at 48 hours ; the ability of communication intercellular and recovery form injury were decreased significantly after cx43 gene was interfered. 4、By silver staining, there are 861 protein spots in normal RPE group and 887 protein spots were showed in siRNA1 group. The average matching rate in RPE group and siRNA1 group were 92% and 93% separately. Compared with two groups There were 78 different spots which's volume value changed≥2.0 times. Among them, 16 protein spots increased in abundance and 18 spots showed lower expression. There were 19 protein spots showed in RPE but not in siRNA1 group, and 25 spots showed in siRNA1 but not in RPE group. 10 protein spots were chosen randomly to be performed mass spectrometry analysis, and 7 of them were identified successfully: SP-H antigen, p27BBP protein, voltage-dependent anion channel, mitogen activated protein kinase binding protein 1, heat shock 70kDa protein 8 isoform 1 and inosine monophosphate dehydrogenase 2 were up regulated, while ACTB protein was down regulated.
Conclusion RNA interference is a highly specific effective tool for gene research work. Connexin 43 is not only effect the gap junction-mediated intercellular communication but also very important for some cell behaviors: such as cell growth, cell circle and recovery ability from injury. The abnormal of connexin43 can cause many proteins ' disorder through proteome analysis. Connexin43 may play an important role in many ocular diseases
实验方法:1、培养原代的人RPE细胞,经过细胞角蛋白(ck)、S-100和神经胶质原纤维酸性蛋白(GFAP)免疫细胞化学鉴定后,通过AO/PI染色技术确定培养细胞的存活率,描记其生长曲线,第3-5代用于以下细胞实验2、生物合成针对人cx43基因的三条小干扰RNA和一条阴性RNA通过脂质体转染RPE细胞后,通过RT-PCR的方法确定抑制效率最高的干扰片断3、将该片段以不同浓度通过阳离子脂质体转染培养的人RPE细胞后,采用MTT法观察其对细胞的增殖力的作用;通过流式细胞仪观察其对细胞周期的影响;通过扫描电镜观察其对细胞形态的影响;通过免疫细胞化学和Weston blot观察其对cx43蛋白表达的作用;采用激光共聚焦和荧光淬灭恢复技术观察荧光恢复速率平均百分率,评价其对细胞间通讯功能的影响;通过制作RPE细胞损伤模型,观察其对损伤修复能力的作用4、分离纯化转染siRNA的RPE组和正常对照组RPE细胞的全部蛋白质,应用等电聚焦电泳和SDS-PAGE双向电泳技术,银染显示分离出的蛋白质斑点,经凝胶图像分析软件对两个样本进行胶图分析,寻找差异蛋白点。胶内酶解差异表达的蛋白点,基质辅助电离解析飞行时间质谱(MALDI-TOF-MS)获得肽质量指纹图谱(PMF),搜寻蛋白质数据库并鉴定蛋白质,分析其生物学意义。
结果:1、原代培养的细胞呈多角形,包含大量色素,容易传代,色素随着传代次数逐渐减少。免疫细胞化学染色:ck和S-100抗体染色阳性,阳性细胞率≥94%,GFAP抗体染色阴性,可以确定是高纯度的上皮来源的色素细胞即视网膜色素上皮细胞。AO/PI染色活细胞比率≥96%,细胞生长状态良好,传代后第3、4天细胞处于对数生长期,平均6天传代一次。2、通过RT-PCR证实三条生物合成的siRNA均能抑制人RPE细胞cx43基因的转录,抑制效率最高的是siRNA1,抑制率达到72%。3、siRNA1转染人RPE细胞后,显著促进细胞的增殖,差异有统计学意义(p＜0.01),其促增殖作用有浓度依赖性,浓度为1.25ug/ml时达到饱和,促增殖作用最强,增殖率为146%,细胞平均5天传代一次;抑制cx43基因后,S期细胞比率明显增多,差异有显著性(p＜0.05);细胞的扫描电镜显示转染siRNA后,细胞表型发生变化,细胞体积增大,表面触手增多;免疫细胞化学显示体外培养的人RPE细胞表达cx43,表达部位在细胞膜、细胞质和胞核。转染siRNA24h后,cx43染色变浅,48h后染色明显变。通过计算机图像分析系统显示48h后cx43染色强度降低76%;与Weston blot结果一致,转染24h后,cx43的蛋白表达下降,48h明显抑制cx43的表达,抑制率达到62%;cx43基因被干扰后,细胞荧光恢复速率降低,细胞间通讯功能明显降低;细胞损伤修复能力下降4、通过银染的方法在RPE组三块胶中分离出共有的蛋白质斑点861个,组间匹配率达到92%;转染siRNA组三块胶分离出共有的蛋白质斑点887个,组间匹配率达到93%。经过软件图像分析,发现Volume值改变≥2.0的点共78个。其中上调的16个点,下调的18个点,有19个点在RPE上存在,而转染组不存在,25给在转染组存在而RPE组不存在。随机选取了7个点进行蛋白质谱分析:SP-H抗原、P27BBP、MAPK、IMPDH和HSP70表达上调,β-actin表达下降,VDAC在转染siRNA后出现表达。
结论:RNA干扰是一种高效的特异性基因研究工具。Cx43不仅影响细胞间通讯功能,其正常表达对细胞的增殖、生长周期、损伤修复等多种细胞行为也非常重要,通过蛋白质谱发现其表达异常可以引起多种蛋白的失调,可能对许多眼病的发生起着不可忽视的作用。
Background and aim It is certified that connexin43 is the primary connexin expressed by RPE. Cx43 participates in the formation of gap junctiongap junction, so that it promotes information exchange among cells, and contributes to the proliferation , differentiation and migration of cells. Normal structure and function of RPE play an important role in sustaining the integrity and physiological function of RPE layer, the abnomality of which is related to many eye diseases. Here we investigate the effect of cx43 on RPE by RNA interference and its proteome analysis, to provide probable path to cure eye disease.
Method 1、Primary cultured human RPE cells were identified by ck, S-100 and GFAP through immunocytochemistry method, and the rate of live/dead cells was evaluated by acridine orange/ propidium iodide staining. After the cell growth curves was recorded, RPE cells of the 3-5th passages were utilized. 2、Three different siRNA (siRNAl,siRNA2,siRNA3) targeting against human cx43 gene and one negative control siRNA were designed and transfected into cultured human RPE cells via liposome reagent. The most effective siRNA can be determined by semi-quantitative reverse transcription PCR(RT-PCR. 3、To the most effective siRNA, after transfected into human RPEs with different concentration, the cellular proliferate activities were messured by MTT colorimetry ; the percentages of RPE in different cell circle phase was assayed by FCM; the changes of phenotypical properities were observed with SCM; the protein expression of cx43 was studied through immunocytochemistry stain and Weston blot; the communication intercellular was calculated with FRAP; and the ability of recovery was assessed by using an in vitro wound healing model.4、The total proteins of siRNA1 and RPE were seperated by two-dimensional gel electrophoresis and visualized by silver staining. Proteins with significant expression alterations were selected and their peptide mass fingerprints (PMFs ) were obtained by matrix-assisted laser desorption/ionization time of flying mass spectrometry (MALDI-TOF-MS).The PMFs were used to search NCBInr database by Auto MS-Fit software. The proteins were identity and analysis its biological significence
Results 1、The just digested hRPE cells were polygon , contained large quantity of pigments and easy to passage, but those pigments in the RPE cells decreased along with the cell division. The percentage of cells, with positive of anti-CK、s-100 and negative of anti-GFAP,is up to 94%.according to this, the cultured cells can be identified as highly purified human retinal pigment epithelium cells. The rate of live/dead cell was about 96% through AO/PI staining, the cell grow state in good condition, the cells go into exponential phase of growth after passaged 3-4 days. the cells would be passaged every 6 days. 2、Three pairs of siRNAs were reduced the synthetic of cx43 mRNA in different levels, and the most effective siRNA was siRNA1.the inhibited rate was up to 72% 3、After siRNA1 transfected into human RPE cells, the cellular proliferate activities enhanced significantly in an concentration-dependent manner until it achieved saturate at 1.25ug/ml, and the maximal growth rate was 46%. the cells were passaged every 5 days; the percentate of cells in S phase was increased obviously(p<0.05); the changes of cell phenotype was observed through SCM: the cell volume enlarged and tentacles lie on the surface of cell increased visibly; the protein expression of cx43 was decreased obviously by Immunocytochemistry stain and Weston blot. Cultured RPE cells expressed cx43 in cellular membrane, cytoplasm and nucleus. 24 hours after transfection the protein expression of cx43 was depressed and 48 hours the depression rate was about 76% through image analysis, which was coincidence with the results of Weston blot, its maximal inhibited rate was 62% at 48 hours ; the ability of communication intercellular and recovery form injury were decreased significantly after cx43 gene was interfered. 4、By silver staining, there are 861 protein spots in normal RPE group and 887 protein spots were showed in siRNA1 group. The average matching rate in RPE group and siRNA1 group were 92% and 93% separately. Compared with two groups There were 78 different spots which's volume value changed≥2.0 times. Among them, 16 protein spots increased in abundance and 18 spots showed lower expression. There were 19 protein spots showed in RPE but not in siRNA1 group, and 25 spots showed in siRNA1 but not in RPE group. 10 protein spots were chosen randomly to be performed mass spectrometry analysis, and 7 of them were identified successfully: SP-H antigen, p27BBP protein, voltage-dependent anion channel, mitogen activated protein kinase binding protein 1, heat shock 70kDa protein 8 isoform 1 and inosine monophosphate dehydrogenase 2 were up regulated, while ACTB protein was down regulated.
Conclusion RNA interference is a highly specific effective tool for gene research work. Connexin 43 is not only effect the gap junction-mediated intercellular communication but also very important for some cell behaviors: such as cell growth, cell circle and recovery ability from injury. The abnormal of connexin43 can cause many proteins ' disorder through proteome analysis. Connexin43 may play an important role in many ocular diseases
引文
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