Cx43基因修饰骨髓间充质干细胞移植对心肌梗死大鼠心功能及电生理影响的实验研究
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摘要
背景:骨髓间充质干细胞(Mesenchymal Stem Cells,MSCs)移植能改善梗死后心功能,但移植细胞在损伤心肌中存活很少,严重地削弱其心肌保护效应。同时,细胞移植的潜在致心律失常风险一直是心血管领域不可忽视的问题。连接蛋白43(Connexin43,Cx43)在MSCs中表达量很少,在心肌微环境下可以逐渐升高并促进细胞间的电传导; MSCs中的Cx43参与细胞生长调节和细胞间信息传递。
目的:探讨MSCs中Cx43蛋白表达对移植后细胞存活及其治疗效应的影响,同时观察MSCs移植对心脏电生理的影响及其机制,为MSCs移植治疗急性心肌梗死及其安全性提供理论依据。
方法:采用全骨髓细胞贴壁培养的方法分离纯化MSCs,流式细胞技术测定细胞表面抗原,成骨、成脂、成心肌分化鉴定MSCs多向分化能力。构建携带Cx43全长基因或其siRNA干扰基因的质粒载体并转染雄性大鼠骨髓MSCs,以细胞免疫荧光染色和免疫印迹确定Cx43表达及其持续时间。将上述MSCs及其试验对照注射到急性冠脉前降支结扎的雌性大鼠左心室前壁,移植4天观察MSCs在梗死心脏中定位与存活;两周后以超声心动图评价心功能,以程序电刺激(Programmed Electrical Stimulation,PES)测定心室有效不应期(Effective Refractory Period,ERP)、室颤阈值(Ventricular Fibrillation Threshold,VFT)以及室性心律失常(Ventricular Arrhythmias,VAs)诱发率;以心外膜电图测定左心室非梗死区、梗死周边区(Infarcted Border Zone, IBZ)及梗死区单相动作电位时程(Action Potential Duration ,APD)、心肌激动时间(Activation Time ,AT);通过Real-time定量PCR检测雄性染色体Sry-1在雌性受体内的含量以评估移植细胞存活率;通过Masson染色测定心脏梗死面积、组织纤维化,以Collagen I表达和分布检测评估心脏胶原沉积,以血管内皮细胞和平滑肌细胞染色检测血管增生和成熟;同时观察心脏中Cx43蛋白表达及其分布,心肌细胞短暂外向钾电流(Ito)编码基因Kv4.2蛋白表达。
结果:1.贴壁分离的细胞表达CD4(494.5%)、CD2(990.7%)、CD10(573.5%),很少表达CD34(3.3%)、CD14(1.2%)、CD45(5.2%)。在合适的培养条件下可以诱导分化成脂肪细胞、骨细胞以及心肌样细胞。Cx43过表达或干扰质粒瞬时转染MSCs可以显著上调(2倍左右)或下调(70%)Cx43蛋白表达,并维持一周左右。2.增强MSCs中Cx43蛋白(MSCs-Cx43组)使移植细胞存活显著高于空载体组(MSCs-vector组);而削弱Cx43的MSCs(MSCs-SiCx43组)存活率则显著降低。与PBS组比较,MSCs移植显著缩小梗死面积,MSCs-Cx43组梗死面积进一步缩小,而MSCs-SiCx43与MSCs-vector治疗组之间无显著差别。MSCs移植可以显著减低I型胶原含量,其中MSCs-Cx43治疗组抑制最明显。MSCs移植提高梗死后大鼠左心室射血分数(LVEF)和短轴缩短率(LVSF),其中MSCs-Cx43治疗组效果最佳。MSCs移植促进心脏梗死区和梗死周边区血管再生和成熟,其中MSCs-Cx43组新生血管显著高于MSCs-vector组和MSCs-SiCx43组。3.心肌梗死后2周,心脏室颤阈值降低,VAs诱发率增加,QT间期延长,梗死周边区APD90缩短,心肌AT延长;MSCs移植改善这些电生理参数,但MSCs组间差别没有统计学意义。心肌梗死后Kv4.2蛋白表达下降,Cx43表达降低,分布紊乱,MSCs移植部分纠正这些异常,但MSCs组之间没有统计学差异。
结论:1.质粒介导的Cx43基因转染能够短暂地调节MSCs的Cx43表达;2.提高MSCs的Cx43蛋白表达促进MSCs在梗死心肌内的存活,进一步缩小梗死面积、改善心功能、降低纤维化并促进血管新生与成熟;3. MSCs移植减少VAs诱发率,提高VFT、降低心肌复极离散、改善局部电传导,提高心肌组织中Cx43和Kv4.2蛋白表达,改善其分布,但短暂增强Cx43没有进一步的影响。
Backgrounds: Bone marrow mesenchymal stem cells (MSCs) transplantation has been reported to improve cardiac pump function after acute myocardial infarction (MI). However, poor homing, engraftment and survival of donor cells in damaged heart tissue compromise the efficacy of cell therapy. Moreover, concern that intramyocardial delivery of cells could cause potentially life-threatening ventricular arrhythmias has been repeatedly raised. Connexin 43 (Cx43), low expressed in MSCs and increased progressively under cardiac micro-environments, was involved in regulating cell growth and integrating with host tissue.
Objectives: to investigate the role of Cx43 in cell survival and therapeutic effects of intramyocardial bone marrow MSCs injection in rats with AMI, to assess the electrophysiological and arrhythmogenic effects and provide efficacy and safety evidences for MSCs therapy in AMI .
Methods: We genetically modified male MSCs with plasmids with full-length cDNA or a siRNA sequence of rat Cx43 and evaluated Cx43 protein expression and sustained time by Western blots and immunofluorescence. Four days after intracardiac injection into a female rat left anterior descending (LAD) ligation model, cell survival and engraftment were identified by GFP immunofluorescence. Two weeks after transplantation, cardiac function, effective refractory period(ERP), ventricular arrhythmias (VAs)inducibility and ventricular fibrillation threshold (VFT) were assessed by echocardiography and programmed electrical stimulation(PES), respectively. Epicardial monophasic action potential (MAP) recordings were obtained from the infarcted zone, infarcted border zone(IBZ) and none infarcted zone(NIZ) of left ventricular epicardium. Action potential duration (APD) and activation time (AT) were calculated. Cell survival was quantitative detected Sry-1 in host heart by Real-time PCR. Histological analysis was used to observe infarct size, collagen deposition and distribution, blood vessel density and maturity, Cx43 distribution in heart tissue. Quantitative analysis of Cx43, collagen I and Kv4.2 (transient outward Potassium Current) were determined by immunoblots.
Results:
1. MSCs were negative for haemopoietic markers CD34,CD14 and CD45 and positive for CD29, CD44, and CD105. MSCs cultured in differentiation medium led to Oil red-O-positive or Alizarin Red positive. Part of 5-azacytidine treated MSCs expressed cardiac marker troponin T, myosin light chain 2a and Cx43. Cx43 protein expression increased significantly in MSCs-Cx43 but decreased greatly in MSCs-SiCx43 compared with MSCs-vector and wild MSCs after 2 days transfection. The regulating effects could be sustained for one weeks.
2. Cx43 overexpressed in MSCs resulted in about three fold cell survival compared with MSCs-vector transfected MSCs. There were significantly reduced infarct size, increased blood vessel density and maturity, and markedly improved left ventricular ejection fraction (LVEF) and shortening fraction (LVSF) compared with control MSCs treated animals. Furthermore, cardiac fibrosis was attenuated mostly in MSCs-Cx43 group, although the difference between MSCs groups have not reach statistical significance.
3. MSCs injection led to significantly reduced VFT,inducibility of VAs, prolonged APD and shortened AT in IBZ compared with PBS group. MSCs improve protein expression of Kv4.2 and Cx43 in left ventricular tissue. Moreover, Cx43 distribution in the IBZ was significantly improved by MSCs injection. However, Cx43 regulation in MSCs has no significant further effects on these electrophysiological parameters.
Conclusions:
1. Cx43 in MSCs could be regulated by plasmids vector mediated gene modification.
2. Cx43 promotes engraftment and survival of injected MSCs in infarcted tissue,which further reduce infarcted size and fibrosis, improve angiogenesis and preserve heart function.
3. MSCs injection decreases inducibility of VAs and focal dispersion of APD, increase VFT and conductive velocity. Moreover, MSCs transplantation improve protein expression and distribution of Kv4.2 and Cx43 in infarcted border zone of the hearts. However, Cx43 overexpression has no further electrophysiological benefits.
目的:探讨MSCs中Cx43蛋白表达对移植后细胞存活及其治疗效应的影响,同时观察MSCs移植对心脏电生理的影响及其机制,为MSCs移植治疗急性心肌梗死及其安全性提供理论依据。
方法:采用全骨髓细胞贴壁培养的方法分离纯化MSCs,流式细胞技术测定细胞表面抗原,成骨、成脂、成心肌分化鉴定MSCs多向分化能力。构建携带Cx43全长基因或其siRNA干扰基因的质粒载体并转染雄性大鼠骨髓MSCs,以细胞免疫荧光染色和免疫印迹确定Cx43表达及其持续时间。将上述MSCs及其试验对照注射到急性冠脉前降支结扎的雌性大鼠左心室前壁,移植4天观察MSCs在梗死心脏中定位与存活;两周后以超声心动图评价心功能,以程序电刺激(Programmed Electrical Stimulation,PES)测定心室有效不应期(Effective Refractory Period,ERP)、室颤阈值(Ventricular Fibrillation Threshold,VFT)以及室性心律失常(Ventricular Arrhythmias,VAs)诱发率;以心外膜电图测定左心室非梗死区、梗死周边区(Infarcted Border Zone, IBZ)及梗死区单相动作电位时程(Action Potential Duration ,APD)、心肌激动时间(Activation Time ,AT);通过Real-time定量PCR检测雄性染色体Sry-1在雌性受体内的含量以评估移植细胞存活率;通过Masson染色测定心脏梗死面积、组织纤维化,以Collagen I表达和分布检测评估心脏胶原沉积,以血管内皮细胞和平滑肌细胞染色检测血管增生和成熟;同时观察心脏中Cx43蛋白表达及其分布,心肌细胞短暂外向钾电流(Ito)编码基因Kv4.2蛋白表达。
结果:1.贴壁分离的细胞表达CD4(494.5%)、CD2(990.7%)、CD10(573.5%),很少表达CD34(3.3%)、CD14(1.2%)、CD45(5.2%)。在合适的培养条件下可以诱导分化成脂肪细胞、骨细胞以及心肌样细胞。Cx43过表达或干扰质粒瞬时转染MSCs可以显著上调(2倍左右)或下调(70%)Cx43蛋白表达,并维持一周左右。2.增强MSCs中Cx43蛋白(MSCs-Cx43组)使移植细胞存活显著高于空载体组(MSCs-vector组);而削弱Cx43的MSCs(MSCs-SiCx43组)存活率则显著降低。与PBS组比较,MSCs移植显著缩小梗死面积,MSCs-Cx43组梗死面积进一步缩小,而MSCs-SiCx43与MSCs-vector治疗组之间无显著差别。MSCs移植可以显著减低I型胶原含量,其中MSCs-Cx43治疗组抑制最明显。MSCs移植提高梗死后大鼠左心室射血分数(LVEF)和短轴缩短率(LVSF),其中MSCs-Cx43治疗组效果最佳。MSCs移植促进心脏梗死区和梗死周边区血管再生和成熟,其中MSCs-Cx43组新生血管显著高于MSCs-vector组和MSCs-SiCx43组。3.心肌梗死后2周,心脏室颤阈值降低,VAs诱发率增加,QT间期延长,梗死周边区APD90缩短,心肌AT延长;MSCs移植改善这些电生理参数,但MSCs组间差别没有统计学意义。心肌梗死后Kv4.2蛋白表达下降,Cx43表达降低,分布紊乱,MSCs移植部分纠正这些异常,但MSCs组之间没有统计学差异。
结论:1.质粒介导的Cx43基因转染能够短暂地调节MSCs的Cx43表达;2.提高MSCs的Cx43蛋白表达促进MSCs在梗死心肌内的存活,进一步缩小梗死面积、改善心功能、降低纤维化并促进血管新生与成熟;3. MSCs移植减少VAs诱发率,提高VFT、降低心肌复极离散、改善局部电传导,提高心肌组织中Cx43和Kv4.2蛋白表达,改善其分布,但短暂增强Cx43没有进一步的影响。
Backgrounds: Bone marrow mesenchymal stem cells (MSCs) transplantation has been reported to improve cardiac pump function after acute myocardial infarction (MI). However, poor homing, engraftment and survival of donor cells in damaged heart tissue compromise the efficacy of cell therapy. Moreover, concern that intramyocardial delivery of cells could cause potentially life-threatening ventricular arrhythmias has been repeatedly raised. Connexin 43 (Cx43), low expressed in MSCs and increased progressively under cardiac micro-environments, was involved in regulating cell growth and integrating with host tissue.
Objectives: to investigate the role of Cx43 in cell survival and therapeutic effects of intramyocardial bone marrow MSCs injection in rats with AMI, to assess the electrophysiological and arrhythmogenic effects and provide efficacy and safety evidences for MSCs therapy in AMI .
Methods: We genetically modified male MSCs with plasmids with full-length cDNA or a siRNA sequence of rat Cx43 and evaluated Cx43 protein expression and sustained time by Western blots and immunofluorescence. Four days after intracardiac injection into a female rat left anterior descending (LAD) ligation model, cell survival and engraftment were identified by GFP immunofluorescence. Two weeks after transplantation, cardiac function, effective refractory period(ERP), ventricular arrhythmias (VAs)inducibility and ventricular fibrillation threshold (VFT) were assessed by echocardiography and programmed electrical stimulation(PES), respectively. Epicardial monophasic action potential (MAP) recordings were obtained from the infarcted zone, infarcted border zone(IBZ) and none infarcted zone(NIZ) of left ventricular epicardium. Action potential duration (APD) and activation time (AT) were calculated. Cell survival was quantitative detected Sry-1 in host heart by Real-time PCR. Histological analysis was used to observe infarct size, collagen deposition and distribution, blood vessel density and maturity, Cx43 distribution in heart tissue. Quantitative analysis of Cx43, collagen I and Kv4.2 (transient outward Potassium Current) were determined by immunoblots.
Results:
1. MSCs were negative for haemopoietic markers CD34,CD14 and CD45 and positive for CD29, CD44, and CD105. MSCs cultured in differentiation medium led to Oil red-O-positive or Alizarin Red positive. Part of 5-azacytidine treated MSCs expressed cardiac marker troponin T, myosin light chain 2a and Cx43. Cx43 protein expression increased significantly in MSCs-Cx43 but decreased greatly in MSCs-SiCx43 compared with MSCs-vector and wild MSCs after 2 days transfection. The regulating effects could be sustained for one weeks.
2. Cx43 overexpressed in MSCs resulted in about three fold cell survival compared with MSCs-vector transfected MSCs. There were significantly reduced infarct size, increased blood vessel density and maturity, and markedly improved left ventricular ejection fraction (LVEF) and shortening fraction (LVSF) compared with control MSCs treated animals. Furthermore, cardiac fibrosis was attenuated mostly in MSCs-Cx43 group, although the difference between MSCs groups have not reach statistical significance.
3. MSCs injection led to significantly reduced VFT,inducibility of VAs, prolonged APD and shortened AT in IBZ compared with PBS group. MSCs improve protein expression of Kv4.2 and Cx43 in left ventricular tissue. Moreover, Cx43 distribution in the IBZ was significantly improved by MSCs injection. However, Cx43 regulation in MSCs has no significant further effects on these electrophysiological parameters.
Conclusions:
1. Cx43 in MSCs could be regulated by plasmids vector mediated gene modification.
2. Cx43 promotes engraftment and survival of injected MSCs in infarcted tissue,which further reduce infarcted size and fibrosis, improve angiogenesis and preserve heart function.
3. MSCs injection decreases inducibility of VAs and focal dispersion of APD, increase VFT and conductive velocity. Moreover, MSCs transplantation improve protein expression and distribution of Kv4.2 and Cx43 in infarcted border zone of the hearts. However, Cx43 overexpression has no further electrophysiological benefits.
引文
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