淫羊藿苷对骨髓间充质干细胞增殖及向心肌细胞分化的影响
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摘要
目的:研究温阳补肾中药淫羊藿的活性成分淫羊藿苷(ICA)对体外培养的骨髓间充质干细胞(MSCs)增殖及向心肌细胞分化的影响,为中药联合干细胞移植治疗心力衰竭奠定基础。
方法:体外培养人MSCs,取第三代MSCs,用MTT法检测淫羊藿苷(分20ug/l、40ug/l、80ug/l、160ug/l四个浓度组)对MSCs增殖的影响。以淫羊藿苷(ICA)、5-氮杂胞苷(5-aza)及两者联合作用,作为分化诱导剂,连续观察四周,相差显微镜下观察其形态变化,免疫荧光方法检测心肌特异性肌钙蛋白I(TroponinI,cTnI)、连接蛋白43(C0nnexin43,CX43),流式细胞技术检测心肌样细胞分化率(即cTnI、CX43表达阳性的细胞百分比),应用半定量RT-PCR技术分析GATA-4、Nkx2-5相关调空基因在分化过程中的表达,应用Western-blotting方法从蛋白水平分析GATA-4、Nkx2-5在分化过程中的表达。
结果:淫羊藿苷组吸光度(OD值)较对照组高(P＜0.01),且淫羊藿苷浓度为80ug/l最合适。免疫荧光结果:5-aza诱导剂组和淫羊藿苷+5-aza诱导剂组均有cTnI和CX43表达,淫羊藿苷组有微弱的cTnI和CX43表达,而对照组无表达。流式细胞技术检测结果:淫羊藿苷+5-aza组表达cTnI、CX43分别为47.22%、44.43%,5-aza组表达cTnI、CX43分别为29.10%、27.15%,两组比较有统计学差异(P＜0.01),单纯淫羊藿苷组弱表达cTnI、CX43分别为7.02%、7.69%,对照组基本不表达cTnI、CX43。半定量RT-PCR结果显示:5-aza组和淫羊藿苷+5-aza组在诱导28天后,有较强表达GATA-4、Nkx2-5,且淫羊藿苷+5-aza组表达GATA-4、Nkx2-5较5-aza组增强,淫羊藿组弱表达GATA-4、Nkx2-5,对照组均无GATA-4、Nkx2-5表达。Western-blotting结果显示5-aza组和淫羊藿苷+5-aza组在诱导28天后,有较强表达GATA-4、Nkx2-5,且淫羊藿苷+5-aza组表达GATA-4、Nkx2-5较5-aZa组增强,淫羊藿组弱表达GATA-4,无表达Nkx2-5,对照组无GATA-4、Nkx2-5表达。
结论:淫羊藿苷能促进MSCs增殖。淫羊藿苷能协同5-aza诱导MSCs向心肌细胞分化,可以作为更好的促进MSCs向心肌细胞分化的条件。淫羊藿苷可能有诱导MSCs向心肌细胞分化的趋势,有待进一步研究。
Objective:To study the influnce on proliferation and differentiation of cardiomyocytes from marrow mesenchymal stem cells (MSCs) in vitro by icarilin (ICA) which is the active component of epimedium. Epimedium has the function of warming yang and nourishing kidney.
Methods: MSCs were isolated and cultured from human bone marrow. MSCs derived from the third or the forth were cultured in vitro for experiment. The effect of icarilin (four concentration groups :20ug/l, 40ug/l,80ug/l,160ug/l)on proliferation of MSCs was tested by MTT method. During the inducing process,ICA, 5-azacytidine and ICA+5-aza were used as inducing factors. The MSCs differentiation was observed for four weeks under phase-contrast microscope. The Immunofluorescence technique was used for the expression of TroponinI (cTnI), Connexin43 (CX43), and using flow cytometry to test the cardiomyocytes different-tiation rate(percentage of the cells with expression of cTnI, CX43). The expression of GATA-4 and Nkx2-5 was tested by semi-quanti- tative PCR and Western-blotting.
Results: The OD of ICA group was higher than the control group(P< 0.01), and the ICA concentration of 80ug/l was best. Fluorescence result showed that, both 5-aza group and ICA+5-aza group had expression of cTnI and CX43. The expression of cTnI and CX43 was weak for ICA group, and it was no expression for control group. Flow cytometry showed that the percentage of cTnI, CX43 expression was 47.22% and 44.43% for ICA+5-aza group, 29. 10% and 27. 15% for 5-aza group. The rate of positive cells with ICA+5-aza induction was higher than the induction of 5-aza(P< 0. 01). The ICA group had lower expression(7. 02%、7. 69%) and the control group had almost no expression. Semi-quantitative PCR and Western-blotting showed that the expression levels of GATA-4 and Nkx2-5 with ICA+5-aza and 5-aza induction were significantly higher than the induction of simplex ICA and no induction. The expression levels of GATA-4 and Nkx2-5 with induction of ICA+5-aza were higher than that of 5-aza.
Conclusion: ICA can accelerate the proliferation of MSCs. ICA can accelerate the differentiation of cardiomyocytes from MSCs combining with 5-aza.The effect of 5-aza plus ICA is the better factor in inducing MSCs to differentiate into cardiomyocytes. ICA might has the trend of inducing MSCs to differentiate into cardiomyocytes, which needs further study.
方法:体外培养人MSCs,取第三代MSCs,用MTT法检测淫羊藿苷(分20ug/l、40ug/l、80ug/l、160ug/l四个浓度组)对MSCs增殖的影响。以淫羊藿苷(ICA)、5-氮杂胞苷(5-aza)及两者联合作用,作为分化诱导剂,连续观察四周,相差显微镜下观察其形态变化,免疫荧光方法检测心肌特异性肌钙蛋白I(TroponinI,cTnI)、连接蛋白43(C0nnexin43,CX43),流式细胞技术检测心肌样细胞分化率(即cTnI、CX43表达阳性的细胞百分比),应用半定量RT-PCR技术分析GATA-4、Nkx2-5相关调空基因在分化过程中的表达,应用Western-blotting方法从蛋白水平分析GATA-4、Nkx2-5在分化过程中的表达。
结果:淫羊藿苷组吸光度(OD值)较对照组高(P＜0.01),且淫羊藿苷浓度为80ug/l最合适。免疫荧光结果:5-aza诱导剂组和淫羊藿苷+5-aza诱导剂组均有cTnI和CX43表达,淫羊藿苷组有微弱的cTnI和CX43表达,而对照组无表达。流式细胞技术检测结果:淫羊藿苷+5-aza组表达cTnI、CX43分别为47.22%、44.43%,5-aza组表达cTnI、CX43分别为29.10%、27.15%,两组比较有统计学差异(P＜0.01),单纯淫羊藿苷组弱表达cTnI、CX43分别为7.02%、7.69%,对照组基本不表达cTnI、CX43。半定量RT-PCR结果显示:5-aza组和淫羊藿苷+5-aza组在诱导28天后,有较强表达GATA-4、Nkx2-5,且淫羊藿苷+5-aza组表达GATA-4、Nkx2-5较5-aza组增强,淫羊藿组弱表达GATA-4、Nkx2-5,对照组均无GATA-4、Nkx2-5表达。Western-blotting结果显示5-aza组和淫羊藿苷+5-aza组在诱导28天后,有较强表达GATA-4、Nkx2-5,且淫羊藿苷+5-aza组表达GATA-4、Nkx2-5较5-aZa组增强,淫羊藿组弱表达GATA-4,无表达Nkx2-5,对照组无GATA-4、Nkx2-5表达。
结论:淫羊藿苷能促进MSCs增殖。淫羊藿苷能协同5-aza诱导MSCs向心肌细胞分化,可以作为更好的促进MSCs向心肌细胞分化的条件。淫羊藿苷可能有诱导MSCs向心肌细胞分化的趋势,有待进一步研究。
Objective:To study the influnce on proliferation and differentiation of cardiomyocytes from marrow mesenchymal stem cells (MSCs) in vitro by icarilin (ICA) which is the active component of epimedium. Epimedium has the function of warming yang and nourishing kidney.
Methods: MSCs were isolated and cultured from human bone marrow. MSCs derived from the third or the forth were cultured in vitro for experiment. The effect of icarilin (four concentration groups :20ug/l, 40ug/l,80ug/l,160ug/l)on proliferation of MSCs was tested by MTT method. During the inducing process,ICA, 5-azacytidine and ICA+5-aza were used as inducing factors. The MSCs differentiation was observed for four weeks under phase-contrast microscope. The Immunofluorescence technique was used for the expression of TroponinI (cTnI), Connexin43 (CX43), and using flow cytometry to test the cardiomyocytes different-tiation rate(percentage of the cells with expression of cTnI, CX43). The expression of GATA-4 and Nkx2-5 was tested by semi-quanti- tative PCR and Western-blotting.
Results: The OD of ICA group was higher than the control group(P< 0.01), and the ICA concentration of 80ug/l was best. Fluorescence result showed that, both 5-aza group and ICA+5-aza group had expression of cTnI and CX43. The expression of cTnI and CX43 was weak for ICA group, and it was no expression for control group. Flow cytometry showed that the percentage of cTnI, CX43 expression was 47.22% and 44.43% for ICA+5-aza group, 29. 10% and 27. 15% for 5-aza group. The rate of positive cells with ICA+5-aza induction was higher than the induction of 5-aza(P< 0. 01). The ICA group had lower expression(7. 02%、7. 69%) and the control group had almost no expression. Semi-quantitative PCR and Western-blotting showed that the expression levels of GATA-4 and Nkx2-5 with ICA+5-aza and 5-aza induction were significantly higher than the induction of simplex ICA and no induction. The expression levels of GATA-4 and Nkx2-5 with induction of ICA+5-aza were higher than that of 5-aza.
Conclusion: ICA can accelerate the proliferation of MSCs. ICA can accelerate the differentiation of cardiomyocytes from MSCs combining with 5-aza.The effect of 5-aza plus ICA is the better factor in inducing MSCs to differentiate into cardiomyocytes. ICA might has the trend of inducing MSCs to differentiate into cardiomyocytes, which needs further study.
引文
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