丹参联合骨髓间充质干细胞移植对心肌梗死区血管新生的影响
摘要
目的:探讨骨髓间充质干细胞移植、丹参干预骨髓间充质干细胞零天、七天静脉注射对急性心肌梗死后梗死区血管新生的影响。
材料与方法:将70只兔随机分为正常组10只、造模组60只(根据预实验的最低造模成功率70%计算)。造模组心肌梗死模型复制成功后随机分为模型组、零天注射干细胞组、零天静脉注射丹参+MSCs组和第七天静脉注射丹参+MSCs组。每组10只,各组间体重差异无显著性(P>0.05)。(1)正常组:不予干预。(2)模型对照组:单纯造模。
(3)静脉零天注射干细胞组:造模后即刻予干细胞混悬液2×10~6细胞一次性注射。(4)零天静脉注射MSCs+丹参组:急性心肌梗死形成后,马上予干细胞混悬液2×10~6细胞一次性静脉注射,同时按15.4mg/kg予配制的丹参注射液,日一次静脉滴注,连续10天。
(5)七天静脉注射MSCs+丹参组:造模后予15.4mg/kg配制的丹参注射液,日一次静脉滴注,连续10天,第七天静脉注射MSCs组2×10~6细胞一次性静脉注射。结果:免疫组化CD31积分光密度值分析显示:与正常组比较,其他各组均降低,除零天干细胞+丹参组,其余组差别均有统计学意义(P<0.05)。与模型组比较,干细胞组、零天干细胞+丹参组、七天干细胞+丹参组的免疫组化CD31均有升高(P<0.05),但干细胞组、零天干细胞+丹参组、七天干细胞+丹参组组间免疫组化CD31数值差别不大,无统计学差异(P>0.05)。血管内皮生长因子(bFGF)、碱性成纤维细胞生长因子(VEGF)各组间无统计学差异(P>0.05)。
结论:
1.骨髓间充质干细胞静脉注射可以迁移至心肌梗死区及周围区。
2.骨髓间充质干细胞移植可促进心肌梗死区及梗死周围区血管新生。
3.丹参可增强骨髓间充质干细胞移植的促进血管新生的作用,但统计学没有差异。
4.在零天和七天两个时间点,联合丹参进行干细胞移植注射组间无差异。
An experimental study of Danshen intervention to Bone marrow-derived mesenchymal stem cells transplantation in the treatment of acute miocardial infarction about Angiogenesis.
Purpose:To evaluate the SM intervention mesenchymal stem cells in zero-day, seven days of intravenous injection on rabbits with acute myocardial infarction infarction angiogenesis.
Material and method:70 randomly divided into normal group, 10 rats in model 60(according to pre-experimental modeling minimum 70% success rate). MI model successfully reproduced in the model were randomly divided into model, zero-day injection of stem cell group, zero-day intravenous Danshen injection(SM) + marrow MSCs group and the seventh day intravenous SM + marrow MSCs group. N = 10 in each group no significant difference in body weight(P> 0.05).(1)normal group: no intervention,(2)model group: simple modeling,(3)intravenous injection of zero-day stem cells Group: After the suspension immediately to the stem cells injected with 2×10~6 cells,(4)Zero-day intravenous SM + MSCs group: after the formation of acute myocardial infarction, immediately to the stem cell suspension 2×10~6 cells single intravenous injection, while I prepared by 15.4mg/kg Danshen injection, on an intravenous drip for 10 days,(5)seven days intravenous injection of MSCs + SM group: After the preparation of Salvia to 15.4mg/kg injection on an intravenous drip for 10 days, the seventh day of intravenous injection of Danshen and bone marrow MSCs groups: acute formed 1 week after myocardial infarction, to the stem cell suspension 2×10~6 cells single intravenous injection.
Results:CD31 immunohistochemical analysis of integrated optical density values:Compared with normal group were lower in other groups, in addition to zero Heavenly Stems Cells + SM group the other group were statistically significant(P <0.05), compared with model group, stem cell group, zero Heavenly Stems cells + SM group, seven days a stem cell + SM group had higher(P <0.05), stem cell group, zero Heavenly Stems cells + SM group, seven days a stem cell + SM group was no significant difference between groups. bFGF, VEGF was no significant difference among the groups.
Conclusion:
1.Point transplantation of bone marrow mesenchymal stem cells, can be moved totheinfarctzone.
2.Bone marrow mesenchymal stem cell transplantation for myocardial infarction and surrounding area infarction angiogenesis.
3.Danshen can enhance bone marrow mesenchymal stem cells promote angiogenesis, but there was no difference.
4.In the zero-day and seven days of two time points stem cell transplantation combined with Danshen injection were no different.
材料与方法:将70只兔随机分为正常组10只、造模组60只(根据预实验的最低造模成功率70%计算)。造模组心肌梗死模型复制成功后随机分为模型组、零天注射干细胞组、零天静脉注射丹参+MSCs组和第七天静脉注射丹参+MSCs组。每组10只,各组间体重差异无显著性(P>0.05)。(1)正常组:不予干预。(2)模型对照组:单纯造模。
(3)静脉零天注射干细胞组:造模后即刻予干细胞混悬液2×10~6细胞一次性注射。(4)零天静脉注射MSCs+丹参组:急性心肌梗死形成后,马上予干细胞混悬液2×10~6细胞一次性静脉注射,同时按15.4mg/kg予配制的丹参注射液,日一次静脉滴注,连续10天。
(5)七天静脉注射MSCs+丹参组:造模后予15.4mg/kg配制的丹参注射液,日一次静脉滴注,连续10天,第七天静脉注射MSCs组2×10~6细胞一次性静脉注射。结果:免疫组化CD31积分光密度值分析显示:与正常组比较,其他各组均降低,除零天干细胞+丹参组,其余组差别均有统计学意义(P<0.05)。与模型组比较,干细胞组、零天干细胞+丹参组、七天干细胞+丹参组的免疫组化CD31均有升高(P<0.05),但干细胞组、零天干细胞+丹参组、七天干细胞+丹参组组间免疫组化CD31数值差别不大,无统计学差异(P>0.05)。血管内皮生长因子(bFGF)、碱性成纤维细胞生长因子(VEGF)各组间无统计学差异(P>0.05)。
结论:
1.骨髓间充质干细胞静脉注射可以迁移至心肌梗死区及周围区。
2.骨髓间充质干细胞移植可促进心肌梗死区及梗死周围区血管新生。
3.丹参可增强骨髓间充质干细胞移植的促进血管新生的作用,但统计学没有差异。
4.在零天和七天两个时间点,联合丹参进行干细胞移植注射组间无差异。
An experimental study of Danshen intervention to Bone marrow-derived mesenchymal stem cells transplantation in the treatment of acute miocardial infarction about Angiogenesis.
Purpose:To evaluate the SM intervention mesenchymal stem cells in zero-day, seven days of intravenous injection on rabbits with acute myocardial infarction infarction angiogenesis.
Material and method:70 randomly divided into normal group, 10 rats in model 60(according to pre-experimental modeling minimum 70% success rate). MI model successfully reproduced in the model were randomly divided into model, zero-day injection of stem cell group, zero-day intravenous Danshen injection(SM) + marrow MSCs group and the seventh day intravenous SM + marrow MSCs group. N = 10 in each group no significant difference in body weight(P> 0.05).(1)normal group: no intervention,(2)model group: simple modeling,(3)intravenous injection of zero-day stem cells Group: After the suspension immediately to the stem cells injected with 2×10~6 cells,(4)Zero-day intravenous SM + MSCs group: after the formation of acute myocardial infarction, immediately to the stem cell suspension 2×10~6 cells single intravenous injection, while I prepared by 15.4mg/kg Danshen injection, on an intravenous drip for 10 days,(5)seven days intravenous injection of MSCs + SM group: After the preparation of Salvia to 15.4mg/kg injection on an intravenous drip for 10 days, the seventh day of intravenous injection of Danshen and bone marrow MSCs groups: acute formed 1 week after myocardial infarction, to the stem cell suspension 2×10~6 cells single intravenous injection.
Results:CD31 immunohistochemical analysis of integrated optical density values:Compared with normal group were lower in other groups, in addition to zero Heavenly Stems Cells + SM group the other group were statistically significant(P <0.05), compared with model group, stem cell group, zero Heavenly Stems cells + SM group, seven days a stem cell + SM group had higher(P <0.05), stem cell group, zero Heavenly Stems cells + SM group, seven days a stem cell + SM group was no significant difference between groups. bFGF, VEGF was no significant difference among the groups.
Conclusion:
1.Point transplantation of bone marrow mesenchymal stem cells, can be moved totheinfarctzone.
2.Bone marrow mesenchymal stem cell transplantation for myocardial infarction and surrounding area infarction angiogenesis.
3.Danshen can enhance bone marrow mesenchymal stem cells promote angiogenesis, but there was no difference.
4.In the zero-day and seven days of two time points stem cell transplantation combined with Danshen injection were no different.
引文
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[2]Bianco P,Riminucci M,Gronthos S,et al.Bone marrow stromal cell: nature, biology and potential application. J Stem cells, 2001,19:180-192.
[3]Pittingey M,Mackay A,Beck S,et al.Multilinage potential of adult human mesenchymal stem cells.J Science,1999,284(54Ⅱ):143-147.
[4]Prockop DJ.Marrow stromal cell as stem cells for nonhematopoietic tissues. J Science,1997,276:71-74.
[5]周忠江,刘伊丽.心肌血管新生和心肌再生化研究进展.临床心血管杂志,2001,17(7):331-337.
[6]Weissman I L,Baltimore D.Disappearing stem cells,disappearing science. Science 2001,292:601-601.
[7]Mckay R.Stem cells-hype and hope.Nature.2000,406:361-364.
[8]Soonpae MH,Koh GY,Klug MG,et al.Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. Science, 1994, 246:98-101.
[9]Beltrami AP,Urbanek K,Kajstura J,et al.Evidencde that human cardi- acmyocytes divide after myocardial infarction.N Engl J Med, 2001,344: 1750-1757.
[10]Gill M,Dias S,Hattori K,et al.Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+)endothelial precursor cells.Cir Res, 2001,88:167-174.
[11]Fukuda K. Development of regenerative cardiomyocytes from mesench- ymal stem cells for cardiovascular tissue engineering. Aritif Organs,2001;25 (3):187-193.
[12]Kadiyala S,Young R G,Thide M A. Culture expanded canine mesenchymal stem cells possess osteochondrogenic potenial in vivo and in vitro.Cell Transplant.1997,6:125-134.
[13]Pittenger M F,Mackay A M, Beck S C,et al.Multilineage potential of adulthuman mesenchymal stem cells.Science.1999,284:143-147.
[14]Deng W, Obrocka M,Fischer I,et al.In vitro differentiation of human stromal cells into early progenitors of neural cells by conditions that marrow increase intracellular cyclic AMP. Biochem. Biophys. Res. Commun. 2001,282:148-152.
[15]Zhao L R, Duan W M,Reyes M,et al.Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp. Neurol.2002,174:11-20
[16]Tomita S, Li RK, Weisel RD,et al.Autologous transplantation of bone marrow cells improves damaged heart function.Circulation,1999,100(Suppl II):II 247-256.
[17]Strauer B E,Brehm M, Zeus T,et al.Intracoronary human autologous stem cell transplantation for myocardial regeneration following myocardial infarction[J].Dtsch Med Wochenschr,2001,126(34235):932-938.
[18]Rifkin DB,Moscatelli D.Recent developments in the cell biology of basic fibroblast grwth factor.J Ccll Biol,1989,109(1):1-6
[19]Goncalves LM.Angiogenic growth factor:potential new treatment for acute myocardial infarction? Cardiovasc Res,2000 Jan 14,45(2):294-302
[20]Leung DW,Cachianes G,Kuang WJ.Vascular endothelial growth factor is a secreted angiogenic mitogen [J].Science,1989,246:1306-1309
[21]于晓辉,刘玲,万小平.酪氨酸激酶受体B介导的信号传导通路与肿瘤的失巢凋亡抑制.中华妇产科杂志。2007,42(4):280-282
[22]陈维洲.丹参的药理[J].药学学报,1984,19(11):876-878.
[23]杜冠华,张均田.丹参现代研究概况与进展.医药导报2004;23(7):435-439.Du GH,Zhang JT.The general situation and progress of themodern research of Rad Sage Root.Her Med 2004;23(7):435-439.
[24]李连达,李映欧,刘志云,等.冠心II号方及其有效成分对体外培养心肌细胞缺糖缺氧损伤的保护作用.陈可冀.活血化瘀研究与临术,北京:北京医科大学中国协和医科大学联合出版社,1999:272-274.
[25]徐理纳.关于活血化瘀药研究途径的概况.中医杂志,1995,7(2):74-79.
[26]杨天德,刘桥义,陶军,等.丹参酮?纳络酮对缺血再灌注心肌局部血流量的影响[J]中国药理学通报,1997,13(1):45-47.
[27]孙学刚,贾玉华,张丽华.丹参酮ⅡA对大鼠缺氧及正常心肌细胞内钙?膜电位和线粒体膜电位的影响[J].中国中医药信息杂志,2002,9(9):21-23.
[28]Li RK,Mickle DA,Weisel RD,et al.Optimal time for cardiomyocyte transplantation to maximize myocardial function after left ventricular injury. Ann Thorac Surg,2001,72(6): 1957-1963.
[29]Lu L,Zhang JQ, Ramires FJ, et al. Molecular and cellular events at the site of myocardial infarction: from the perspective of rebuilding myocardial tissue. Biochem Biophys Res Commun,2004,320(3): 907 - 913.
[30]Ren G, Michael LH, Entman ML,et al.Morphological characteristics of the microvasculature in healing myocardial infarcts. J Histochem Cytochem,2002,50(1):71-79.
[31]Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans.Circulation,2002,106(15):1913-1918.
[32]刘建华,陈运贤,钟雪云.骨髓间质干细胞横向分化为心肌细胞的机制和诱导因素[J].国外医学内科学分册,2005,32(5):189-227.
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[2]Bianco P,Riminucci M,Gronthos S,et al.Bone marrow stromal cell: nature, biology and potential application. J Stem cells, 2001,19:180-192.
[3]Pittingey M,Mackay A,Beck S,et al.Multilinage potential of adult human mesenchymal stem cells.J Science,1999,284(54Ⅱ):143-147.
[4]Prockop DJ.Marrow stromal cell as stem cells for nonhematopoietic tissues. J Science,1997,276:71-74.
[5]周忠江,刘伊丽.心肌血管新生和心肌再生化研究进展.临床心血管杂志,2001,17(7):331-337.
[6]Weissman I L,Baltimore D.Disappearing stem cells,disappearing science. Science 2001,292:601-601.
[7]Mckay R.Stem cells-hype and hope.Nature.2000,406:361-364.
[8]Soonpae MH,Koh GY,Klug MG,et al.Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. Science, 1994, 246:98-101.
[9]Beltrami AP,Urbanek K,Kajstura J,et al.Evidencde that human cardi- acmyocytes divide after myocardial infarction.N Engl J Med, 2001,344: 1750-1757.
[10]Gill M,Dias S,Hattori K,et al.Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+)endothelial precursor cells.Cir Res, 2001,88:167-174.
[11]Fukuda K. Development of regenerative cardiomyocytes from mesench- ymal stem cells for cardiovascular tissue engineering. Aritif Organs,2001;25 (3):187-193.
[12]Kadiyala S,Young R G,Thide M A. Culture expanded canine mesenchymal stem cells possess osteochondrogenic potenial in vivo and in vitro.Cell Transplant.1997,6:125-134.
[13]Pittenger M F,Mackay A M, Beck S C,et al.Multilineage potential of adulthuman mesenchymal stem cells.Science.1999,284:143-147.
[14]Deng W, Obrocka M,Fischer I,et al.In vitro differentiation of human stromal cells into early progenitors of neural cells by conditions that marrow increase intracellular cyclic AMP. Biochem. Biophys. Res. Commun. 2001,282:148-152.
[15]Zhao L R, Duan W M,Reyes M,et al.Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp. Neurol.2002,174:11-20
[16]Tomita S, Li RK, Weisel RD,et al.Autologous transplantation of bone marrow cells improves damaged heart function.Circulation,1999,100(Suppl II):II 247-256.
[17]Strauer B E,Brehm M, Zeus T,et al.Intracoronary human autologous stem cell transplantation for myocardial regeneration following myocardial infarction[J].Dtsch Med Wochenschr,2001,126(34235):932-938.
[18]Rifkin DB,Moscatelli D.Recent developments in the cell biology of basic fibroblast grwth factor.J Ccll Biol,1989,109(1):1-6
[19]Goncalves LM.Angiogenic growth factor:potential new treatment for acute myocardial infarction? Cardiovasc Res,2000 Jan 14,45(2):294-302
[20]Leung DW,Cachianes G,Kuang WJ.Vascular endothelial growth factor is a secreted angiogenic mitogen [J].Science,1989,246:1306-1309
[21]于晓辉,刘玲,万小平.酪氨酸激酶受体B介导的信号传导通路与肿瘤的失巢凋亡抑制.中华妇产科杂志。2007,42(4):280-282
[22]陈维洲.丹参的药理[J].药学学报,1984,19(11):876-878.
[23]杜冠华,张均田.丹参现代研究概况与进展.医药导报2004;23(7):435-439.Du GH,Zhang JT.The general situation and progress of themodern research of Rad Sage Root.Her Med 2004;23(7):435-439.
[24]李连达,李映欧,刘志云,等.冠心II号方及其有效成分对体外培养心肌细胞缺糖缺氧损伤的保护作用.陈可冀.活血化瘀研究与临术,北京:北京医科大学中国协和医科大学联合出版社,1999:272-274.
[25]徐理纳.关于活血化瘀药研究途径的概况.中医杂志,1995,7(2):74-79.
[26]杨天德,刘桥义,陶军,等.丹参酮?纳络酮对缺血再灌注心肌局部血流量的影响[J]中国药理学通报,1997,13(1):45-47.
[27]孙学刚,贾玉华,张丽华.丹参酮ⅡA对大鼠缺氧及正常心肌细胞内钙?膜电位和线粒体膜电位的影响[J].中国中医药信息杂志,2002,9(9):21-23.
[28]Li RK,Mickle DA,Weisel RD,et al.Optimal time for cardiomyocyte transplantation to maximize myocardial function after left ventricular injury. Ann Thorac Surg,2001,72(6): 1957-1963.
[29]Lu L,Zhang JQ, Ramires FJ, et al. Molecular and cellular events at the site of myocardial infarction: from the perspective of rebuilding myocardial tissue. Biochem Biophys Res Commun,2004,320(3): 907 - 913.
[30]Ren G, Michael LH, Entman ML,et al.Morphological characteristics of the microvasculature in healing myocardial infarcts. J Histochem Cytochem,2002,50(1):71-79.
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