丹参酮ⅡA对骨髓间充质干细胞在心梗大鼠体内定向募集的影响及机制研究
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摘要
心肌梗死会严重影响心功能并导致有害的心室重构,最终导致循环的不稳定甚至休克、死亡。由于心肌细胞和神经元细胞一样是处于分化末端的细胞,心肌梗死所致的心脏衰竭是不可逆的,因此逆转心脏衰竭必须替换损伤的心肌细胞,并且恢复血供。研究证实,干细胞在体外能分化成心肌细胞、内皮细胞和周细胞；对心梗动物模型进行细胞移植治疗也发现,其具有改善心功能、减小梗死面积、促进血管新生的能力。因此,干细胞治疗作为一种有效、快速的治疗手段,被赋予了很多期待。但是研究发现,只有很小部分的移植细胞会植入受损心脏并存活下来,而干细胞发挥治疗作用的前提是其必须首先募集到心脏的受损部位。因此,增加干细胞在受损部位的植入数量对于干细胞移植疗效有重要意义。研究发现,间质细胞因子-1(SDF-1)及其特异性受体CXCR4组成的SDF-1-CXCR4轴在干细胞的募集过程中起到了关键作用。它们通过选择性的募集循环中或者定居的干细胞,参与组织的修复和新生。实验表明,用转基因等方法提高心脏的SDF-1表达能够促进干细胞向受损心脏的募集,激活细胞生存信号通路,增加心梗部位的血管新生,最终促进心梗后心功能的恢复。因此,上调SDF-1/CXCR4通路不失为一个增加干细胞在受损组织内植入、促进心功能恢复的好方法。
丹参是中医临床上治疗心脑血管疾病的一种常用药,具有活血化瘀、养血宁神、调经止痛、凉血消痈的功效。作为丹参主要活性成分之一,丹参酮ⅡA(TanⅡA)被证明具有抗氧化、抗凋亡的药理学作用。此外,TanⅡA对内皮细胞有直接的保护作用,同时能增加EPCs数量并改善其功能。我们前期的实验也表明,与丹参其他主要活性成分(丹参素、丹酚酸B、丹参酮Ⅰ)相比,TanⅡA能显著增加BMSCs的迁移能力,提高BMSCs向受损心脏募集的数量。但对TanⅡA是如何干预骨髓干细胞的募集过程,尚有待进一步研究。本实验拟以SDF-1/CXCR4轴为切入点,研究TanⅡA对BMSCs向梗死心肌募集的影响及机制,为中药干预干细胞的研究提供一些新的思路。
实验一骨髓间充质干细胞在心肌梗死大鼠体内定向募集的研究
实验目的：观察静脉移植BMSCs在心梗大鼠体内的定向募集及分化情况。
实验方法：采用结扎雌性大鼠冠状动脉左前降支(LAD)的方法建立急性心肌梗死模型(MI). MI 3小时后静脉移植5×106/0.5ml Dil标记的BMSCs,1周或4周后取心脏等脏器进行冰冻切片。荧光显微镜观察BMSCs移植1周后在各脏器中的分布情况；免疫荧光染色观察BMSCs移植4周后在心脏受损部位的分化情况。
实验结果：心梗大鼠静脉移植BMSCs后1周,可在心梗大鼠的心脏受损部位及其他特定器官如(肺、肝脏、脾脏、骨髓)中观察到BMSCs;心梗大鼠静脉移植BMSCs后4周,可在心梗部位发现少量BMSCs表达心肌特异性标记(Connexin43和TroponinⅠ),但BMSCs仍保留干细胞形态。
实验二丹参酮ⅡA对BMSCs在心梗大鼠体内定向募集的影响及机制研究
实验目的：以SDF-1/CXCR4轴为切入点,研究TanⅡA对BMSCs向梗死心肌募集的影响及机制。
实验方法：整体实验分为5组：①假手术组；②模型组；③TanⅡA台疗组；④BMSCs移植治疗组；⑤TanⅡA合并BMSCs移植治疗组。治疗1周或4周后,记录大鼠血流动力学指标；以Real-time PCR相对定量募集至心梗部位BMSCs数量；ELISA测定心梗大鼠血清及左心室壁SDF-1α蛋白的含量；Masson三色染色检测心肌梗死程度及血管新生情况；免疫组化检测VEGF的表达；体外迁移实验考察TanⅡA对于BMSCs体外迁移能力的影响；细胞免疫荧光法检测BMSCs表面CXCR4表达情况。
实验结果：TanⅡA能够显著增加BMSCs向心梗心脏的募集,并相应的提高心功能,减小梗死面积,提高VEGF的表达,促进血管新生。TanⅡA能够适当促进心梗组织分泌SDF-1α,增强SDF-1α及HIF-1αmRNA的表达,提高血循环中SDF-1a的浓度。同时,它能够增强体外培养BMSCs的CXCR4表达。体外迁移实验同样证明,TanⅡA能够显著提高BMSCs的迁移能力,并且这种促迁移能力可被CXCR4的拮抗剂AMD3100消除。结果说明,TanⅡA是通过调控SDF1/CXCR4轴以促进BMSCs向心梗部位的募集。
实验结论
1、静脉移植的BMSCs可募集至心梗大鼠的心脏受损部位；
2、TanⅡA能够显著增加BMSCs向心梗心脏的募集,提高BMSCs的治疗效果；
3、TanⅡA是通过调控SDF1/CXCR4轴以促进BMSCs向心梗部位的募集。
Effect of TanshinoneⅡA on Bone Marrow Mesenchymal Stem Cells Recruitment to Infarct Heart
Millions of people suffer heart attacks each year, most experience irreversible myocardial damage, which due to lack of oxygen. Although current treatments could improve the quality and duration of life, they do not restore cardiac function, nor do they increase the number of functional myocardial cells. On the other hand, shortage of donor heart limits the heart transplantation. For these reasons, there has been a growing interest in using cellular therapy to restore lost heart function. Until now, a great many of preclinical studies of cellular therapeutics as well as clinical trials are being carried worldwide.
Mesenchymal stem cells (MSCs) found in bone marrow (BM) are multipotent progenitors of mesenchymal tissues and have novel regenerative and immune properties. Systemic delivery of BMSCs were shown to facilitate myocardial repair following myocardial infarction (MI). However, many experiments and clinical studies find that only a small fraction of the transplanted cells engraft and survive in the injured hearts during the first week after transplantation, which undoubtedly limits the efficacy of cell transplar tation. No matter whether the transplanted cells transdifferentiate or not, they need to be recruited and retained in the injured myocardium in order to exert effects.
SDF-la and its receptor CXCR4 are crucial for bone marrow retention, mobilization, and homing of hematopoietic stem cells, they are highly related to tissue repair ar d regeneration, which involves the selective recruitment of circulating or resident progenitor cells. Both ex vivo SDF-1αtransgene and protease-resistant SDF-1 nanofiber-mediated delivery or forced overexpression of SDF-1 can promote stem and progenitor cell migration to the heart, activates cell survival signaling, enhances angiomyogenesis in the infarcted area, and improved cardiac function after myocardial infarction eventually. So upregulation SDF-1/CXCR4 pathway may good way to enhance cell engraftment in target tissue, therefore improve the heart recovery.
In China, Salvia miltiorrhiza has been widely used for treating the cardiovascular diseases in clinical practice for many years. As one of the main active compounds of Salvia miltiorrhiza, TanshinoneⅡA(TanⅡA) exhibits antioxidative and anti-apoptosis properties. Our previous experiment showed that TanⅡA can enhance the BMSCs Migration significantly. In this study, we aim to test the effect of TanⅡA on BMSC Migration in vitro and vivo, and the mechanism of it. We hypothesized that TanⅡA treatment promotes BMSCs migration into the infarct area by augmenting SDF1/CXCR4 axis.
Experiment I:Study on BMSCs Recruitment in MI Rat
Aim:To investigate the recruitment and differentiation of BMSCs in vivo.
Methods:Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in rat. BMSCs(stained with Dil-dye) were injected by tail vein,3 hours after MI. lweek later, The survival of the transplanted BMSCs was demonstrated by the presence of DiI-labeled cells; 4 weeks later, differentiation of BMSCs wes detected by immunofluorescence.
Result:BMSCs can be detected in ischemia area of heart and some other important organs, such as lung, liver, spleen and marrow,1 week after systemic transplantation.4 weeks later, a few of BMSCs which recruitmented to ischemia area, started to express cardiac specific marker(Connexin 43 and Troponin I), but they still maintained BMSCs morphous.
ExperimentⅡ:Effect of TanshinoneⅡA on BMSCs Recruitment to Infarct Heart
Aim:To test whether TanⅡA treatment promotes BMSC migration into the infarct area by augmenting SDF1/CXCR4 axis.
Methods:Rats were randomly divided into 5 groups:(1) Sham group; (2) MI group; (3) MI+TanⅡA group; (4) MI+BMSCs group; (5) MI+BMSCs+TanⅡA group. Hemodynamic studies were performed 1week or 4weeks after MI. Real-time PCR was performed for the quantification of sry gene. The secretion of SDF-1αwas determined by rat SDF-1αELISA kit. Transwell system was used to test whether TanⅡA regulates BMSC migration. Immunofluorescent staining was performed to detect the expression of CXCR4 on BMSCs.
Result:In this study, we demonstrated that TanⅡA could significantly increase BMSCs recruitment to infraction area after MI which correlates with cardiac function recovery, IS improvement and VEGF expression enhancement. TanⅡA can promote SDF-1 a expression in infarct area, and the concentration of SDF-1αin PB as well. Meanwhile it significantly enhances the CXCR4 expression in cultured BMSCs. Addtionally, in vitro study proved that TanⅡA can enhance BMSCs migration signfincantly, and this effect can be blocked by AMD3100 (a CXCR4 blocker).
Conclusion
1. BMSCs were preferentially attracted to the ischemic area in MI rats.
2. TanⅡA could significantly increase BMSCs recruitment to infraction area after MI which correlates with cardiac function recovery.
3. TanⅡA can increase BMSCs migration via SDF1/CXCR4 axis.
丹参是中医临床上治疗心脑血管疾病的一种常用药,具有活血化瘀、养血宁神、调经止痛、凉血消痈的功效。作为丹参主要活性成分之一,丹参酮ⅡA(TanⅡA)被证明具有抗氧化、抗凋亡的药理学作用。此外,TanⅡA对内皮细胞有直接的保护作用,同时能增加EPCs数量并改善其功能。我们前期的实验也表明,与丹参其他主要活性成分(丹参素、丹酚酸B、丹参酮Ⅰ)相比,TanⅡA能显著增加BMSCs的迁移能力,提高BMSCs向受损心脏募集的数量。但对TanⅡA是如何干预骨髓干细胞的募集过程,尚有待进一步研究。本实验拟以SDF-1/CXCR4轴为切入点,研究TanⅡA对BMSCs向梗死心肌募集的影响及机制,为中药干预干细胞的研究提供一些新的思路。
实验一骨髓间充质干细胞在心肌梗死大鼠体内定向募集的研究
实验目的：观察静脉移植BMSCs在心梗大鼠体内的定向募集及分化情况。
实验方法：采用结扎雌性大鼠冠状动脉左前降支(LAD)的方法建立急性心肌梗死模型(MI). MI 3小时后静脉移植5×106/0.5ml Dil标记的BMSCs,1周或4周后取心脏等脏器进行冰冻切片。荧光显微镜观察BMSCs移植1周后在各脏器中的分布情况；免疫荧光染色观察BMSCs移植4周后在心脏受损部位的分化情况。
实验结果：心梗大鼠静脉移植BMSCs后1周,可在心梗大鼠的心脏受损部位及其他特定器官如(肺、肝脏、脾脏、骨髓)中观察到BMSCs;心梗大鼠静脉移植BMSCs后4周,可在心梗部位发现少量BMSCs表达心肌特异性标记(Connexin43和TroponinⅠ),但BMSCs仍保留干细胞形态。
实验二丹参酮ⅡA对BMSCs在心梗大鼠体内定向募集的影响及机制研究
实验目的：以SDF-1/CXCR4轴为切入点,研究TanⅡA对BMSCs向梗死心肌募集的影响及机制。
实验方法：整体实验分为5组：①假手术组；②模型组；③TanⅡA台疗组；④BMSCs移植治疗组；⑤TanⅡA合并BMSCs移植治疗组。治疗1周或4周后,记录大鼠血流动力学指标；以Real-time PCR相对定量募集至心梗部位BMSCs数量；ELISA测定心梗大鼠血清及左心室壁SDF-1α蛋白的含量；Masson三色染色检测心肌梗死程度及血管新生情况；免疫组化检测VEGF的表达；体外迁移实验考察TanⅡA对于BMSCs体外迁移能力的影响；细胞免疫荧光法检测BMSCs表面CXCR4表达情况。
实验结果：TanⅡA能够显著增加BMSCs向心梗心脏的募集,并相应的提高心功能,减小梗死面积,提高VEGF的表达,促进血管新生。TanⅡA能够适当促进心梗组织分泌SDF-1α,增强SDF-1α及HIF-1αmRNA的表达,提高血循环中SDF-1a的浓度。同时,它能够增强体外培养BMSCs的CXCR4表达。体外迁移实验同样证明,TanⅡA能够显著提高BMSCs的迁移能力,并且这种促迁移能力可被CXCR4的拮抗剂AMD3100消除。结果说明,TanⅡA是通过调控SDF1/CXCR4轴以促进BMSCs向心梗部位的募集。
实验结论
1、静脉移植的BMSCs可募集至心梗大鼠的心脏受损部位；
2、TanⅡA能够显著增加BMSCs向心梗心脏的募集,提高BMSCs的治疗效果；
3、TanⅡA是通过调控SDF1/CXCR4轴以促进BMSCs向心梗部位的募集。
Effect of TanshinoneⅡA on Bone Marrow Mesenchymal Stem Cells Recruitment to Infarct Heart
Millions of people suffer heart attacks each year, most experience irreversible myocardial damage, which due to lack of oxygen. Although current treatments could improve the quality and duration of life, they do not restore cardiac function, nor do they increase the number of functional myocardial cells. On the other hand, shortage of donor heart limits the heart transplantation. For these reasons, there has been a growing interest in using cellular therapy to restore lost heart function. Until now, a great many of preclinical studies of cellular therapeutics as well as clinical trials are being carried worldwide.
Mesenchymal stem cells (MSCs) found in bone marrow (BM) are multipotent progenitors of mesenchymal tissues and have novel regenerative and immune properties. Systemic delivery of BMSCs were shown to facilitate myocardial repair following myocardial infarction (MI). However, many experiments and clinical studies find that only a small fraction of the transplanted cells engraft and survive in the injured hearts during the first week after transplantation, which undoubtedly limits the efficacy of cell transplar tation. No matter whether the transplanted cells transdifferentiate or not, they need to be recruited and retained in the injured myocardium in order to exert effects.
SDF-la and its receptor CXCR4 are crucial for bone marrow retention, mobilization, and homing of hematopoietic stem cells, they are highly related to tissue repair ar d regeneration, which involves the selective recruitment of circulating or resident progenitor cells. Both ex vivo SDF-1αtransgene and protease-resistant SDF-1 nanofiber-mediated delivery or forced overexpression of SDF-1 can promote stem and progenitor cell migration to the heart, activates cell survival signaling, enhances angiomyogenesis in the infarcted area, and improved cardiac function after myocardial infarction eventually. So upregulation SDF-1/CXCR4 pathway may good way to enhance cell engraftment in target tissue, therefore improve the heart recovery.
In China, Salvia miltiorrhiza has been widely used for treating the cardiovascular diseases in clinical practice for many years. As one of the main active compounds of Salvia miltiorrhiza, TanshinoneⅡA(TanⅡA) exhibits antioxidative and anti-apoptosis properties. Our previous experiment showed that TanⅡA can enhance the BMSCs Migration significantly. In this study, we aim to test the effect of TanⅡA on BMSC Migration in vitro and vivo, and the mechanism of it. We hypothesized that TanⅡA treatment promotes BMSCs migration into the infarct area by augmenting SDF1/CXCR4 axis.
Experiment I:Study on BMSCs Recruitment in MI Rat
Aim:To investigate the recruitment and differentiation of BMSCs in vivo.
Methods:Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in rat. BMSCs(stained with Dil-dye) were injected by tail vein,3 hours after MI. lweek later, The survival of the transplanted BMSCs was demonstrated by the presence of DiI-labeled cells; 4 weeks later, differentiation of BMSCs wes detected by immunofluorescence.
Result:BMSCs can be detected in ischemia area of heart and some other important organs, such as lung, liver, spleen and marrow,1 week after systemic transplantation.4 weeks later, a few of BMSCs which recruitmented to ischemia area, started to express cardiac specific marker(Connexin 43 and Troponin I), but they still maintained BMSCs morphous.
ExperimentⅡ:Effect of TanshinoneⅡA on BMSCs Recruitment to Infarct Heart
Aim:To test whether TanⅡA treatment promotes BMSC migration into the infarct area by augmenting SDF1/CXCR4 axis.
Methods:Rats were randomly divided into 5 groups:(1) Sham group; (2) MI group; (3) MI+TanⅡA group; (4) MI+BMSCs group; (5) MI+BMSCs+TanⅡA group. Hemodynamic studies were performed 1week or 4weeks after MI. Real-time PCR was performed for the quantification of sry gene. The secretion of SDF-1αwas determined by rat SDF-1αELISA kit. Transwell system was used to test whether TanⅡA regulates BMSC migration. Immunofluorescent staining was performed to detect the expression of CXCR4 on BMSCs.
Result:In this study, we demonstrated that TanⅡA could significantly increase BMSCs recruitment to infraction area after MI which correlates with cardiac function recovery, IS improvement and VEGF expression enhancement. TanⅡA can promote SDF-1 a expression in infarct area, and the concentration of SDF-1αin PB as well. Meanwhile it significantly enhances the CXCR4 expression in cultured BMSCs. Addtionally, in vitro study proved that TanⅡA can enhance BMSCs migration signfincantly, and this effect can be blocked by AMD3100 (a CXCR4 blocker).
Conclusion
1. BMSCs were preferentially attracted to the ischemic area in MI rats.
2. TanⅡA could significantly increase BMSCs recruitment to infraction area after MI which correlates with cardiac function recovery.
3. TanⅡA can increase BMSCs migration via SDF1/CXCR4 axis.
引文
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