hUC-MSC_S/hHGF基因修饰的hUC-MSC_S移植在心肌损伤修复中的实验研究
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摘要
目的：
本实验选用广西巴马小型猪,通过外科手术建立急性心肌梗死模型,将体外培养的人脐带间充质干细胞(Human umbilical cord mesenchymal stem cells, hUC-MSCs)经心外膜植入心肌梗死区,观察hUC-MSCs移植对缺血性心肌损伤的修复作用并探讨其机制。同时比较人肝细胞生长因子(Human hepatocyte growth factor, hHGF)基因修饰的hUC-MSCs移植与单纯的hUC-MSCs移植在同一急性心肌梗死模型中的心肌损伤修复作用有无差别并探讨其可能的机制。
方法：
无菌条件下采集足月儿的脐带后,hUC-MSCs经体外分离、培养、扩增至第五代。用携带hHGF基因的重组腺病毒基因表达载体以150的感染强度转染hUC-MSCs,获得hHGF基因修饰的hUC-MSCs。两种干细胞均在术前以CM-Dil标记备用。采用外科手术方法于中、远端1/3交界处结扎冠状动脉前降支制成小型猪急性心肌梗死模型。随机将实验动物分为4组,每组6只。A组空白对照组(只造模而不做任何干预)；B组PBS组；C组hUC-MSCs移植组；D组hHGF基因修饰的hUC-MSCs移植组。C组与D组中每只动物分别接受总计2×107的hUC-MSCs或(?)hHGF基因修饰的hUC-MSCs,分成9-10个点经心外膜注入梗死后缺血的心肌；PBS组则注入同等体积的无菌PBS。6周后,采用静息核素心肌灌注显像与经胸超声心动图评价梗死区血流灌注与局部收缩功能的变化。实验动物处死后采集梗死区域的心肌标本,采用RT-PCR、免疫荧光与免疫组化、Masson和TUNEL染色的方法观察干细胞的植入、增殖及分化,血管新生,存活心肌、细胞凋亡的情况,以揭示可能的作用机制。
结果：
(1)术后6周与空白对照组和PBS组相比,hUC-MSCs移植组与hHGF基因修饰的hUC-MSCs移植组经静息核素心肌灌注显像检测的灌注质量缺损百分率变化显著改善(P<0.001)；经胸超声心动图观察到的局部梗死区室壁舒张末期厚度与收缩期增厚率显著改善(P<0.001)。免疫荧光检查发现hUC-MSCs与hHGF基因修饰的hUC-MSC这两种干细胞移植后6周,原梗死区域仍可见所移植的干细胞存活,其中部分向心肌和血管内皮细胞分化。同时亦可见固有心脏干细胞的募集与分化。与空白对照组和PBS组相比,hUC-MSCs移植组与hHGF基因修饰的hUC-MSCs移植组的vWF免疫组化染色结果显示新生血管密度显著增加(P<0.001), Masson染色结果显示存活心肌明显增多而纤维组织明显减少(P<0.001), TUNEL染色结果显示细胞凋亡明显减少(P<0.001),血管内皮生长因子(Vascular endothelial growth factor, VEGF)、肝细胞生长因子(Hepatocyte growth factor, HGF)、转化生长因子β3(Transforming growth factor-β3, TGF-β3)、血管性血友病因子(Von Willebrand Factor, vWF)、基质细胞衍生因子(Stromal cell-derived factor-1, SDF-1)和CXC族细胞因子受体4(CXC chemokine receptor4, CXCR4) mRNA的表达明显上调(P<0.001)。
(2)干细胞移植后6周,hUC-MSCs移植组与hHGF基因修饰的hUC-MSCs移植组经静息核素心肌灌注显像检测的灌注质量缺损百分率变化和经胸超声心动图观察到的局部梗死区室壁舒张末期厚度与收缩期增厚率之间的差别均无统计学意义(P>0.05)。但是与hUC-MSCs移植组相比,hHGF基因修饰的hUC-MSCs移植组在局部缺血心肌中HGF的mRNA的表达明显上调(P<0.05),vWF免疫组化染色结果显示新生血管密度显著增加(P=0.011), Masson染色结果显示存活心肌明显增多(P=0.007)。
结论：
(1) hUC-MSCs与hHGF基因修饰的hUC-MSCs,经心外膜直接注射植入后可在小型猪急性心肌梗死模型的梗死区域内部分存活并分化为心肌和血管组织,同时也促进了固有心脏干细胞的募集和分化；可能通过外源性和内源性再生以及旁分泌三个方面的机制参与心梗后心肌与血管的新生,同时减少细胞凋亡和心肌纤维化,提高心肌存活和抑制心室重塑,改善梗死后心肌灌注和心室功能。
(2)与单纯的hUC-MSCs移植疗法相比,hHGF基因修饰的hUC-MSCs移植疗法具有更强的促进血管新生和保护存活心肌的能力。以干细胞为基础的血管新生基因疗法将成为治疗严重缺血性心血管疾病的新策略。
Objective:In this study, transplantation of human UC-MSCs (hUC-MSCs) cultured in vitro into infarct area was applied surgically on the Guangxi Bama miniswine model of AMI. The reparative effects of this therapy on ischemic myocardial injury were observed. Furthermore, whether a new strategy that combines hUC-MSCs transplantation and ex vivo human hepatocyte growth factor (hHGF) gene transferring with recombinant adenoviral vectors was more therapeutically efficient than hUC-MSCs cell therapy alone in the same AMI model was investigated, too.
Methods:The hUC-MSCs isolated from human umbilical cord were cultured and expanded to passage5, and subsequently transfected by high titer adenoviral stocks expressing hHGF (Ad-HGF). The hUC-MSCs or hHGF genetically modified hUC-MSCs were labeled with CM-Dil before transplantation. The mid-third of LAD was ligated surgically to establish miniswine AMI model. The miniswines were randomly divided into four groups (n=6in each):(Group A) control group (without any treatment),(Group B) PBS group (PBS injection),(Group C) hUC-MSCs group (hUC-MSCs transplantation),(Group D) HGF-hUC-MSCs group (hHGF genetically modified hUC-MSCs transplantation). A total of2×107hUC-MSCs, HGF-hUC-MSCs or PBS of same volume were injected into the myocardial infarct area at9-10different points in the latter three groups. Six weeks later, cardiac perfusion and function were evaluated by SPECT and echocardiography in each group. The animals were euthanized and the tissues in infarct area were analyzed for the engraftment, proliferation and differentiation of stem cells, capillary density, viable myocardium, apoptosis and the expression of cytokines and growth factors to explore the underlying mechanisms.
Results:(1) Six weeks later, the changes in MDP were significantly improved (P<0.001), EDWT and△WT%were increased significantly (P<0.001) in the hUC-MSCs and HGF-hUC-MSCs group compared with the control and PBS groups. Immunofluorescence results confirmed that the transplanted hUC-MSCs or HGF-hUC-MSCs were still alive and part of them appeared to have differentiated into cardiomyocytes and vascular endotheliums six weeks after transplantation. Meantime, it was also observed that resident cardiac stem cells (CSCs) differentiated into neonatal cardiomyocytes and vascular endotheliums, too. Angiogenesis was significantly enhanced by both hUC-MSCs group and HGF-hUC-MSCs group, which capillary density was higher than the control and PBS groups (P<0.001).The hUC-MSCs and HGF-hUC-MSCs groups showed more viable myocardial tissue in Masson's trichrome staining (P<0.001), less cell number of apoptosis in the TUNEL analysis (P<0.001) than the control and PBS groups. The mRNA expression of cytokines and growth factors like VEGF、HGF、TGF-β3、vWF、SDF-1and CXCR4in local ischemic myocardium undergoing intramuscular cell transplantation was more abundant in hUC-MSCs and HGF-hUC-MSCs groups than the other two groups (P<0.001).(2) Six weeks after transplantion, there is no statistically difference in△MDP、EDWT and△WT%(P>0.05). However, the mRNA expression of HGF in local ischemic myocardium was up-regulated in HGF-hUC-MSCs group compared with hUC-MSCs group (P<0.05). It was also demonstrated that vWF staining analysis showed an enhanced angiogenesis (P=0.011) and Masson's trichrome staining analysis showed an improvement in viable myocardium (P=0.007) in HGF-hUC-MSCs group relative to hUC-MSCs group.
Conclusions:(1) hUC-MSCs and HGF-hUC-MSCs transplanted by direct injection into the infarct area could not only survived and differentiated, but also promoted CSCs recruitment and differentiation. The mechanisms may be involved exogenous and endogenous regeneration as well as paracrine action. In addition, hUC-MSCs and HGF-hUC-MSCs transplantation reduced apoptosis and fibrosis. enhanced viable myocardium and suppressed the ventricular remodeling, and thus improved myocardial perfusion and ventricular function.(2) The study shows that hHGF genetically modified hUC-MSCs transplantation therapy induced more potent angiogenesis and more viable myocardium than hUC-MSCs therapy alone. Stem cell-based angiogenic gene therapy may be a new therapeutic strategy for the treatment of severe ischemic cardiovascular disease.
本实验选用广西巴马小型猪,通过外科手术建立急性心肌梗死模型,将体外培养的人脐带间充质干细胞(Human umbilical cord mesenchymal stem cells, hUC-MSCs)经心外膜植入心肌梗死区,观察hUC-MSCs移植对缺血性心肌损伤的修复作用并探讨其机制。同时比较人肝细胞生长因子(Human hepatocyte growth factor, hHGF)基因修饰的hUC-MSCs移植与单纯的hUC-MSCs移植在同一急性心肌梗死模型中的心肌损伤修复作用有无差别并探讨其可能的机制。
方法：
无菌条件下采集足月儿的脐带后,hUC-MSCs经体外分离、培养、扩增至第五代。用携带hHGF基因的重组腺病毒基因表达载体以150的感染强度转染hUC-MSCs,获得hHGF基因修饰的hUC-MSCs。两种干细胞均在术前以CM-Dil标记备用。采用外科手术方法于中、远端1/3交界处结扎冠状动脉前降支制成小型猪急性心肌梗死模型。随机将实验动物分为4组,每组6只。A组空白对照组(只造模而不做任何干预)；B组PBS组；C组hUC-MSCs移植组；D组hHGF基因修饰的hUC-MSCs移植组。C组与D组中每只动物分别接受总计2×107的hUC-MSCs或(?)hHGF基因修饰的hUC-MSCs,分成9-10个点经心外膜注入梗死后缺血的心肌；PBS组则注入同等体积的无菌PBS。6周后,采用静息核素心肌灌注显像与经胸超声心动图评价梗死区血流灌注与局部收缩功能的变化。实验动物处死后采集梗死区域的心肌标本,采用RT-PCR、免疫荧光与免疫组化、Masson和TUNEL染色的方法观察干细胞的植入、增殖及分化,血管新生,存活心肌、细胞凋亡的情况,以揭示可能的作用机制。
结果：
(1)术后6周与空白对照组和PBS组相比,hUC-MSCs移植组与hHGF基因修饰的hUC-MSCs移植组经静息核素心肌灌注显像检测的灌注质量缺损百分率变化显著改善(P<0.001)；经胸超声心动图观察到的局部梗死区室壁舒张末期厚度与收缩期增厚率显著改善(P<0.001)。免疫荧光检查发现hUC-MSCs与hHGF基因修饰的hUC-MSC这两种干细胞移植后6周,原梗死区域仍可见所移植的干细胞存活,其中部分向心肌和血管内皮细胞分化。同时亦可见固有心脏干细胞的募集与分化。与空白对照组和PBS组相比,hUC-MSCs移植组与hHGF基因修饰的hUC-MSCs移植组的vWF免疫组化染色结果显示新生血管密度显著增加(P<0.001), Masson染色结果显示存活心肌明显增多而纤维组织明显减少(P<0.001), TUNEL染色结果显示细胞凋亡明显减少(P<0.001),血管内皮生长因子(Vascular endothelial growth factor, VEGF)、肝细胞生长因子(Hepatocyte growth factor, HGF)、转化生长因子β3(Transforming growth factor-β3, TGF-β3)、血管性血友病因子(Von Willebrand Factor, vWF)、基质细胞衍生因子(Stromal cell-derived factor-1, SDF-1)和CXC族细胞因子受体4(CXC chemokine receptor4, CXCR4) mRNA的表达明显上调(P<0.001)。
(2)干细胞移植后6周,hUC-MSCs移植组与hHGF基因修饰的hUC-MSCs移植组经静息核素心肌灌注显像检测的灌注质量缺损百分率变化和经胸超声心动图观察到的局部梗死区室壁舒张末期厚度与收缩期增厚率之间的差别均无统计学意义(P>0.05)。但是与hUC-MSCs移植组相比,hHGF基因修饰的hUC-MSCs移植组在局部缺血心肌中HGF的mRNA的表达明显上调(P<0.05),vWF免疫组化染色结果显示新生血管密度显著增加(P=0.011), Masson染色结果显示存活心肌明显增多(P=0.007)。
结论：
(1) hUC-MSCs与hHGF基因修饰的hUC-MSCs,经心外膜直接注射植入后可在小型猪急性心肌梗死模型的梗死区域内部分存活并分化为心肌和血管组织,同时也促进了固有心脏干细胞的募集和分化；可能通过外源性和内源性再生以及旁分泌三个方面的机制参与心梗后心肌与血管的新生,同时减少细胞凋亡和心肌纤维化,提高心肌存活和抑制心室重塑,改善梗死后心肌灌注和心室功能。
(2)与单纯的hUC-MSCs移植疗法相比,hHGF基因修饰的hUC-MSCs移植疗法具有更强的促进血管新生和保护存活心肌的能力。以干细胞为基础的血管新生基因疗法将成为治疗严重缺血性心血管疾病的新策略。
Objective:In this study, transplantation of human UC-MSCs (hUC-MSCs) cultured in vitro into infarct area was applied surgically on the Guangxi Bama miniswine model of AMI. The reparative effects of this therapy on ischemic myocardial injury were observed. Furthermore, whether a new strategy that combines hUC-MSCs transplantation and ex vivo human hepatocyte growth factor (hHGF) gene transferring with recombinant adenoviral vectors was more therapeutically efficient than hUC-MSCs cell therapy alone in the same AMI model was investigated, too.
Methods:The hUC-MSCs isolated from human umbilical cord were cultured and expanded to passage5, and subsequently transfected by high titer adenoviral stocks expressing hHGF (Ad-HGF). The hUC-MSCs or hHGF genetically modified hUC-MSCs were labeled with CM-Dil before transplantation. The mid-third of LAD was ligated surgically to establish miniswine AMI model. The miniswines were randomly divided into four groups (n=6in each):(Group A) control group (without any treatment),(Group B) PBS group (PBS injection),(Group C) hUC-MSCs group (hUC-MSCs transplantation),(Group D) HGF-hUC-MSCs group (hHGF genetically modified hUC-MSCs transplantation). A total of2×107hUC-MSCs, HGF-hUC-MSCs or PBS of same volume were injected into the myocardial infarct area at9-10different points in the latter three groups. Six weeks later, cardiac perfusion and function were evaluated by SPECT and echocardiography in each group. The animals were euthanized and the tissues in infarct area were analyzed for the engraftment, proliferation and differentiation of stem cells, capillary density, viable myocardium, apoptosis and the expression of cytokines and growth factors to explore the underlying mechanisms.
Results:(1) Six weeks later, the changes in MDP were significantly improved (P<0.001), EDWT and△WT%were increased significantly (P<0.001) in the hUC-MSCs and HGF-hUC-MSCs group compared with the control and PBS groups. Immunofluorescence results confirmed that the transplanted hUC-MSCs or HGF-hUC-MSCs were still alive and part of them appeared to have differentiated into cardiomyocytes and vascular endotheliums six weeks after transplantation. Meantime, it was also observed that resident cardiac stem cells (CSCs) differentiated into neonatal cardiomyocytes and vascular endotheliums, too. Angiogenesis was significantly enhanced by both hUC-MSCs group and HGF-hUC-MSCs group, which capillary density was higher than the control and PBS groups (P<0.001).The hUC-MSCs and HGF-hUC-MSCs groups showed more viable myocardial tissue in Masson's trichrome staining (P<0.001), less cell number of apoptosis in the TUNEL analysis (P<0.001) than the control and PBS groups. The mRNA expression of cytokines and growth factors like VEGF、HGF、TGF-β3、vWF、SDF-1and CXCR4in local ischemic myocardium undergoing intramuscular cell transplantation was more abundant in hUC-MSCs and HGF-hUC-MSCs groups than the other two groups (P<0.001).(2) Six weeks after transplantion, there is no statistically difference in△MDP、EDWT and△WT%(P>0.05). However, the mRNA expression of HGF in local ischemic myocardium was up-regulated in HGF-hUC-MSCs group compared with hUC-MSCs group (P<0.05). It was also demonstrated that vWF staining analysis showed an enhanced angiogenesis (P=0.011) and Masson's trichrome staining analysis showed an improvement in viable myocardium (P=0.007) in HGF-hUC-MSCs group relative to hUC-MSCs group.
Conclusions:(1) hUC-MSCs and HGF-hUC-MSCs transplanted by direct injection into the infarct area could not only survived and differentiated, but also promoted CSCs recruitment and differentiation. The mechanisms may be involved exogenous and endogenous regeneration as well as paracrine action. In addition, hUC-MSCs and HGF-hUC-MSCs transplantation reduced apoptosis and fibrosis. enhanced viable myocardium and suppressed the ventricular remodeling, and thus improved myocardial perfusion and ventricular function.(2) The study shows that hHGF genetically modified hUC-MSCs transplantation therapy induced more potent angiogenesis and more viable myocardium than hUC-MSCs therapy alone. Stem cell-based angiogenic gene therapy may be a new therapeutic strategy for the treatment of severe ischemic cardiovascular disease.
引文
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