转染HO-1基因的骨髓间充质干细胞（MSCs）移植治疗慢性心衰的实验研究
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摘要
扩张型心肌病(dilated cardiomyopathy，DCM)是原发性心肌疾病最常见的类型，原因至今未完全明了。此心肌病发病率逐年上升，到目前为止已经成为继冠心病、风心病、先心病之后的发病率较高的心脏疾病，并且是慢性心力衰竭（Chronic heartfailure，CHF）的重要原发病之一。DCM到目前为止缺乏有效的治疗，预后较差，病死率高，其治疗方法一直是心血管疾病的研究热点。
研究结果发现，移植干细胞进入受者的心脏内部可以存活，干细胞能够分化成为心肌细胞、血管内皮细胞等。干细胞移植治疗心血管疾病的主要机制在病损心区部位的微环境可对干细胞的分化增殖产生一定的影响，使之向心肌细胞和或血管内皮细胞方向分化，代偿受损的心肌和血管组织，从而起到改善心功能的作用，减少心脏损伤程度，一些基础实验和临床试验也证明了此种推断。
血红素氧合酶HO-1是血红素代谢过程中的限速酶，在体内有多种生物学功能，包括血管舒张作用、抗氧化作用、抗凋亡作用、抗炎作用，被认为是一种保护性因子。本研究利用阿霉素构建大鼠扩张型心脏病慢性心衰模型，分离得到骨髓间充质干细胞并利用5-aza进行诱导分化成心肌样细胞，利用脂质体载体将HO-1基因转染至诱导细胞内并表达，将转染HO-1基因的干细胞移植入心衰大鼠模型内，观察其治疗大鼠慢性心衰的效果，并对其机制进行初步探讨。
Objective
Bone marrow mesenchymal stem cell transplantation in the treatment of cardiovasculardisease mainly in acute myocardial lesions and myocardial local lesion, and on the diffusedilated heart disease research is very little. This study use of adriamycin construction of ratmodel of chronic heart failure with dilated heart disease, isolated from bone marrowmesenchymal stem cells and the use of5-aza were induced to differentiate intocardiomyocyte-like cells, using a recombinant adenoviral vector HO-1gene transfection toinduce cell and expression of transfected HO-1gene, stem cell transplantation into heartfailure rat model, to observe the treatment of rats with chronic heart failure effect, and themechanism was discussed.
Method
1.The adriamycin rat dilated cardiomyopathy heart failure model preparation
Experimental rats tail vein injection of doxorubicin hydrochloride solution,1mg/kg,weekly one time injection1times, for a total of6weeks; the normal control group tail veininjection of equal volumes of saline, the same time weekly injections of1, a total of6weeks.In the last2weeks after drug withdrawal after the injection, the rats' general physiologicalstatus and circumstances of death. The use of ultrasound in detecting left ventricular endsystolic diameter (LVDs), left ventricular end diastolic diameter and ejection fraction(LVDd), fractional shortening of FS EF. The polygraph record left ventricular systolicpressure (LVSP), left ventricular end diastolic pressure (LVEDP) and left ventricularpressure rising and falling speed (DP/dtmax). In experiment and the day of injection drugsfor two weeks after the beginning of heavy weight, respectively, and end weight.Measurement of ventricular mass (VW), and VW/BW ratio calculation. Myocardialpathology.
2. Bone marrow mesenchymal stem cell separation, culture and induced to differentiate
Charge and mass of stem cells and subculture density gradient separation method ofbone marrow to draw the three generations of MSCs growth curve immunohistochemistyevaluation,5-aza induction of the third generation of bone marrow between the charge and quality of stem cell differentiation into cardiomyocyte-like cells, the differentiation ofcardiomyocyte-like cells identification and calculation of the cardiomyocyte-like cellsconversion rate.
3.Recombinant pcDNA3.1-of HO-1plasmid and its expression in MSCs
Digested fragment of the GFP and the plasmid pcDNA3.1-HO-1connection, and toconstruct the recombinant plasmid pcDNA3.1-GFP-HO-1HO-1eukaryotic cell expression,the use of a single enzyme digestion of BamH Ⅰ and Hind Ⅲrestriction endonuclease thesize and the direction of the transferred gene, and amplification and purification. Theminimum lethal dose of G418for bone marrow mesenchymal stem cells were measuredusing lipofectamine plasmids were transformed into the spinal cord-derived bone marrowmesenchymal stem cells, the use of fluorescent protein expression by RT-PCR, Westernblotting detection of HO-1expression.
4.Experimental study of transfer of HO-1gene, transplantation of MSCs in the treatment ofchronic heart failure
Rat model of heart failure were randomly divided into3groups of10. Will be inducedcardiomyocyte-like cells were labeled with BrdU, syringe-induced expression of MSCssuspension2:00injected into the left ventricular wall myocardium. Four weeks later, eachgroup were sacrificed5rats, ultrasound detection of left ventricular end systolic diameter,left ventricular end-diastolic diameter, left ventricular ejection fraction, and determination ofthe maximum pressure change rate and other hemodynamic parameters. Heart tissueembedded sections Brdu immunohistochemical staining.
Result
1. Adriamycin rat model of heart failure of dilated cardiomyopathy Preparation
Rat mortality rate was26.7%, while control animals did not kill. Compared with normalrats of CHF experimental rats at12days poisoning phenomenon. Significant increase in thenormal control group, body weight (BW), BW was significantly lower in the experimentalgroup, P <0.05, two significant differences in ventricular weight (VW) compared the twogroups was no significant difference, while the experimental group, VW/BW increasedsignificantly, and The normal control group, P <0.05, two significant differences. Andnormal control group compared to the experimental group of rat cardiac systolic functionand diastolic function was significantly impaired, were significantly lower heart rate, LVSPwas significantly lower LVEDP was significantly elevated±dp/dt max significantlydecreased (P <0.05), have different sex. Experimental myocardial tissue damage, myocardial fibers arranged in a wavy, myocardial cells showed a pathological kind of change. Electronmicroscope observation of the visible swelling of mitochondria in the rat model of heartfailure intracellular vacuoles, steep to reduce some of the myocardial fibers breakage,myocardial fibrosis.
2. Bone marrow mesenchymal stem cell separation, culture and induced to differentiate
Primary cultured cells adherent for12h, the first exchange of medium for24h,adherent cells increased significantly after48h, and stretch for long spindle shape, about7dclose covered,3~4d can be passaged. Generation of MSCs is similar to the growth curve.MSCs cell specific markers CD44, cell surface antigen CD34negative.5-aza added to theculture medium to about8d about MSCs by flat polygonal into long fusiform, arrangedbetween the colony after15days with a directional, to differentiate into cardiomyocyte-likecells. Immunocytochemical staining show part culture cell TroponinT positive expression.5-aza-induced MSCs conversion of27%conversion rate of myocardial cells.
3.Recombinant pcDNA3.1-of HO-1plasmid and its expression in MSCs
BamH Ⅰ digested plasmid pcDNA3.1-GFP-HO-1is linearized; digested with Hind Ⅲdigestion under2998bp,5256bp two fragments, demonstrate the direction of the plasmidsand the correct size. G418selection by preliminary experiments to determine the screeningconcentration of0.4μg/ml. The use of fluorescence microscopy to observe GFP expression inGFP expression started24h after lipofection gradually weakened, show that HO-1also has acertain level of expression. After RT-PCR, and transfected with plasmidpcDNA3.1-GFP-HO-1available to a length of about809bp of the bands and a length tomatch the target gene. Western blotting analysis of transfected cells HO-1protein expressionwas positive.
4.Experimental study of transfer of HO-1gene, transplantation of MSCs in the treatment ofchronic heart failure
MSCs in BrdU incorporation24h after immunohistochemical staining, the nucleistained for the tan to prove the incorporation of BrdU in the nucleus, the labeling efficiencyof more than80%. After four weeks, four weeks after surgery, compared with the controlgroup, MSCs transplantation group, left ventricular end-systolic pressure, left ventricularejection fraction and left ventricular pressure, maximum rate of change were significantlyhigher (P <0.05), left ventricular diastolic the end pressure was significantly lower (P <0.01)compared with MSCs group, transfection of HO-1MSCs group left ventricular end systolicpressure, left ventricular ejection fraction and left ventricular pressure, maximum rate of change were significantly higher (P <0.05), left ventricular end diastolic pressure wassignificantly lower (P <0.01). The remaining indicators were not statistically significant (P>0.05). Four weeks CHF after transplant team can detect Brdu labeling-positive cells, controlthe group brdu immunization combined test results were negative.
Conclusion:
HO-1gene transfected MSCs in the treatment of chronic heart failure can improvecardiac function and provides a new method for the treatment of chronic heart failure.
研究结果发现，移植干细胞进入受者的心脏内部可以存活，干细胞能够分化成为心肌细胞、血管内皮细胞等。干细胞移植治疗心血管疾病的主要机制在病损心区部位的微环境可对干细胞的分化增殖产生一定的影响，使之向心肌细胞和或血管内皮细胞方向分化，代偿受损的心肌和血管组织，从而起到改善心功能的作用，减少心脏损伤程度，一些基础实验和临床试验也证明了此种推断。
血红素氧合酶HO-1是血红素代谢过程中的限速酶，在体内有多种生物学功能，包括血管舒张作用、抗氧化作用、抗凋亡作用、抗炎作用，被认为是一种保护性因子。本研究利用阿霉素构建大鼠扩张型心脏病慢性心衰模型，分离得到骨髓间充质干细胞并利用5-aza进行诱导分化成心肌样细胞，利用脂质体载体将HO-1基因转染至诱导细胞内并表达，将转染HO-1基因的干细胞移植入心衰大鼠模型内，观察其治疗大鼠慢性心衰的效果，并对其机制进行初步探讨。
Objective
Bone marrow mesenchymal stem cell transplantation in the treatment of cardiovasculardisease mainly in acute myocardial lesions and myocardial local lesion, and on the diffusedilated heart disease research is very little. This study use of adriamycin construction of ratmodel of chronic heart failure with dilated heart disease, isolated from bone marrowmesenchymal stem cells and the use of5-aza were induced to differentiate intocardiomyocyte-like cells, using a recombinant adenoviral vector HO-1gene transfection toinduce cell and expression of transfected HO-1gene, stem cell transplantation into heartfailure rat model, to observe the treatment of rats with chronic heart failure effect, and themechanism was discussed.
Method
1.The adriamycin rat dilated cardiomyopathy heart failure model preparation
Experimental rats tail vein injection of doxorubicin hydrochloride solution,1mg/kg,weekly one time injection1times, for a total of6weeks; the normal control group tail veininjection of equal volumes of saline, the same time weekly injections of1, a total of6weeks.In the last2weeks after drug withdrawal after the injection, the rats' general physiologicalstatus and circumstances of death. The use of ultrasound in detecting left ventricular endsystolic diameter (LVDs), left ventricular end diastolic diameter and ejection fraction(LVDd), fractional shortening of FS EF. The polygraph record left ventricular systolicpressure (LVSP), left ventricular end diastolic pressure (LVEDP) and left ventricularpressure rising and falling speed (DP/dtmax). In experiment and the day of injection drugsfor two weeks after the beginning of heavy weight, respectively, and end weight.Measurement of ventricular mass (VW), and VW/BW ratio calculation. Myocardialpathology.
2. Bone marrow mesenchymal stem cell separation, culture and induced to differentiate
Charge and mass of stem cells and subculture density gradient separation method ofbone marrow to draw the three generations of MSCs growth curve immunohistochemistyevaluation,5-aza induction of the third generation of bone marrow between the charge and quality of stem cell differentiation into cardiomyocyte-like cells, the differentiation ofcardiomyocyte-like cells identification and calculation of the cardiomyocyte-like cellsconversion rate.
3.Recombinant pcDNA3.1-of HO-1plasmid and its expression in MSCs
Digested fragment of the GFP and the plasmid pcDNA3.1-HO-1connection, and toconstruct the recombinant plasmid pcDNA3.1-GFP-HO-1HO-1eukaryotic cell expression,the use of a single enzyme digestion of BamH Ⅰ and Hind Ⅲrestriction endonuclease thesize and the direction of the transferred gene, and amplification and purification. Theminimum lethal dose of G418for bone marrow mesenchymal stem cells were measuredusing lipofectamine plasmids were transformed into the spinal cord-derived bone marrowmesenchymal stem cells, the use of fluorescent protein expression by RT-PCR, Westernblotting detection of HO-1expression.
4.Experimental study of transfer of HO-1gene, transplantation of MSCs in the treatment ofchronic heart failure
Rat model of heart failure were randomly divided into3groups of10. Will be inducedcardiomyocyte-like cells were labeled with BrdU, syringe-induced expression of MSCssuspension2:00injected into the left ventricular wall myocardium. Four weeks later, eachgroup were sacrificed5rats, ultrasound detection of left ventricular end systolic diameter,left ventricular end-diastolic diameter, left ventricular ejection fraction, and determination ofthe maximum pressure change rate and other hemodynamic parameters. Heart tissueembedded sections Brdu immunohistochemical staining.
Result
1. Adriamycin rat model of heart failure of dilated cardiomyopathy Preparation
Rat mortality rate was26.7%, while control animals did not kill. Compared with normalrats of CHF experimental rats at12days poisoning phenomenon. Significant increase in thenormal control group, body weight (BW), BW was significantly lower in the experimentalgroup, P <0.05, two significant differences in ventricular weight (VW) compared the twogroups was no significant difference, while the experimental group, VW/BW increasedsignificantly, and The normal control group, P <0.05, two significant differences. Andnormal control group compared to the experimental group of rat cardiac systolic functionand diastolic function was significantly impaired, were significantly lower heart rate, LVSPwas significantly lower LVEDP was significantly elevated±dp/dt max significantlydecreased (P <0.05), have different sex. Experimental myocardial tissue damage, myocardial fibers arranged in a wavy, myocardial cells showed a pathological kind of change. Electronmicroscope observation of the visible swelling of mitochondria in the rat model of heartfailure intracellular vacuoles, steep to reduce some of the myocardial fibers breakage,myocardial fibrosis.
2. Bone marrow mesenchymal stem cell separation, culture and induced to differentiate
Primary cultured cells adherent for12h, the first exchange of medium for24h,adherent cells increased significantly after48h, and stretch for long spindle shape, about7dclose covered,3~4d can be passaged. Generation of MSCs is similar to the growth curve.MSCs cell specific markers CD44, cell surface antigen CD34negative.5-aza added to theculture medium to about8d about MSCs by flat polygonal into long fusiform, arrangedbetween the colony after15days with a directional, to differentiate into cardiomyocyte-likecells. Immunocytochemical staining show part culture cell TroponinT positive expression.5-aza-induced MSCs conversion of27%conversion rate of myocardial cells.
3.Recombinant pcDNA3.1-of HO-1plasmid and its expression in MSCs
BamH Ⅰ digested plasmid pcDNA3.1-GFP-HO-1is linearized; digested with Hind Ⅲdigestion under2998bp,5256bp two fragments, demonstrate the direction of the plasmidsand the correct size. G418selection by preliminary experiments to determine the screeningconcentration of0.4μg/ml. The use of fluorescence microscopy to observe GFP expression inGFP expression started24h after lipofection gradually weakened, show that HO-1also has acertain level of expression. After RT-PCR, and transfected with plasmidpcDNA3.1-GFP-HO-1available to a length of about809bp of the bands and a length tomatch the target gene. Western blotting analysis of transfected cells HO-1protein expressionwas positive.
4.Experimental study of transfer of HO-1gene, transplantation of MSCs in the treatment ofchronic heart failure
MSCs in BrdU incorporation24h after immunohistochemical staining, the nucleistained for the tan to prove the incorporation of BrdU in the nucleus, the labeling efficiencyof more than80%. After four weeks, four weeks after surgery, compared with the controlgroup, MSCs transplantation group, left ventricular end-systolic pressure, left ventricularejection fraction and left ventricular pressure, maximum rate of change were significantlyhigher (P <0.05), left ventricular diastolic the end pressure was significantly lower (P <0.01)compared with MSCs group, transfection of HO-1MSCs group left ventricular end systolicpressure, left ventricular ejection fraction and left ventricular pressure, maximum rate of change were significantly higher (P <0.05), left ventricular end diastolic pressure wassignificantly lower (P <0.01). The remaining indicators were not statistically significant (P>0.05). Four weeks CHF after transplant team can detect Brdu labeling-positive cells, controlthe group brdu immunization combined test results were negative.
Conclusion:
HO-1gene transfected MSCs in the treatment of chronic heart failure can improvecardiac function and provides a new method for the treatment of chronic heart failure.
引文
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