自体骨髓干细胞移植治疗兔糖尿病下肢缺血性疾病的实验研究
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摘要
研究背景:随着人类生活水平的提高和老龄社会的到来,糖尿病的发病率逐年增高,其并发症糖尿病足和截肢所带来的医疗耗费巨大,给社会带来沉重的经济负担。传统治疗主要是内科的药物治疗、外科的手术治疗及介入治疗进行血流重建,疗效均不够理想。干细胞移植这项新技术在此领域的临床应用得到越来越多的关注,给糖尿病足的治愈提供了新方法。
第一部分
糖尿病动物模型的制作
目的:本实验选用四氧嘧啶(ALX)诱导糖尿病动物模型,探索一种安全、稳定、动物低死亡率的糖尿病模型建立方法。
方法:健康新西兰兔20只,随机分为A、B两组,每组10只。两组给药前均禁食12小时,A组为一次给药法组,即按150mg/ kg经耳缘静脉快速注射新鲜配置的5%ALX;B组为两次给药法组,第1次给药,按80mg/ kg经耳缘静脉快速注射新鲜配置的5%ALX,24小时后第2次给药,按120mg/ kg再次经耳缘静脉快速注射新鲜配置的5%ALX。14天后测空腹血糖值,以空腹血糖>16mmol/L作为造模成功的标准。
结果:A组48小时内死亡4只,第3天死亡2只,第5天死亡1只,死亡率70%,1只血糖短暂升高,两周后恢复正常,2只达到糖尿病模型标准,成模率20%;B组48小时内死亡1只,死亡率10%,1只血糖短暂升高,两周后恢复正常,8只达到糖尿病模型标准,成模率80%。
结论:
1.ALX连续2次小剂量给药法优于1次性高剂量给药,降低了死亡率,提高了成模率。
2.应用ALX制备糖尿病模型,是一种经济、安全、可靠的方法。
第二部分
糖尿病兔骨髓干细胞动员及影响
目的:通过监测健康兔、糖尿病兔及未成模兔三组应用相同剂量粒细胞集落刺激因子(G-CSF)动员后的外周血单个核细胞数、骨髓单个核细胞数及骨髓粒-单核细胞集落形成单位(CFU-GM)培养计数,对比三组的动员效果有无差别,以探讨糖尿病对骨髓干细胞动员有无影响。通过比较糖尿病动物模型在动员前后血红蛋白、血小板、空腹血糖、血液流变学等各项指标的变化情况,探讨骨髓干细胞动员对糖尿病的影响。
方法:健康新西兰兔,随机分为A、B、C三组。A组为健康兔10只,B组为糖尿病兔10只,C组为未成模兔5只(ALX剂量同B组)。A、B、C三组在动员前分别测外周血单个核细胞数,然后三组分别皮下注射10ug/kg G-CSF进行动员,每天1次,连续5天。在应用G-CSF动员期间,每天检测三组外周血单个核细胞数,观察各组动员效果,动员第6天检测三组外周血单个核细胞数,同时三组均抽取骨髓液3ml,分离骨髓单个核细胞,检测骨髓单个核细胞数,并进行CFU-GM培养。B组(糖尿病组)中的10只糖尿病兔在动员前及动员第6天分别监测血红蛋白、血小板、空腹血糖、血液流变学变化情况。
结果:
1.动员前三组外周血单个核细胞数无差别。动员后三组外周血单个核细胞均较前明显升高,计数比较无统计学差异。动员后三组骨髓单个核细胞数计数比较无差别。
2.CFU-GM培养发现,三组均在培养的5～6天开始有集落形成,以后数目逐渐增多,大约12天达高峰,此后集落不断增大,总的集落数不再增加,三组集落培养计数无差别。
3.动员前后10只糖尿病兔的晨空腹血糖值有一定的下降趋势,血红蛋白、血小板均有所升高,但变化均无统计学差异。10只糖尿病兔的晨空腹血流变中的血浆粘度及红细胞聚集性动员前后无明显变化;全血粘度动员后较动员前均明显升高。
结论:
1.糖尿病对骨髓干细胞动员效果无影响。
2.应用G-CSF骨髓干细胞动员对糖尿病兔的血糖、血红蛋白、血小板无影响,对血流变有影响,提示临床应予重视并干预。
第三部分
自体骨髓干细胞移植治疗兔糖尿病下肢缺血性疾病
目的:对比骨髓干细胞移植、皮下注射G-CSF、骨髓干细胞移植联合G-CSF皮下注射三种方法对缺血组织血管新生的作用效果。
方法:健康新西兰兔40只,以第一部分中介绍的二次给药法,用ALX诱导成为糖尿病兔后,均结扎右后肢股动脉,建立糖尿病下肢缺血动物模型,随机分成A、B、C、D四组,每组10只。A组:模型建立后,开始皮下注射10ug/kg G-CSF进行动员,每天1次,连续5天。B组:如A组方法动员,并于动员第6天采髓5ml,分离骨髓单个核细胞。以右侧股内侧正中部位为中心等距离分10个位点,用1ml注射器依次等量肌肉注射0.1ml骨髓单个核细胞悬液(其中5×106个骨髓单个核细胞/位点),每一实验动物局部移植的骨髓单个核细胞总数量为5×107个。C组:模型建立后,不进行动员直接采髓10ml,右侧股内侧肌肉注射骨髓单个核细胞,注射方法同B组。D组:模型建立后,不进行动员,右侧股内侧肌肉注射PBS,注射方法同B组。术后第28天全麻,4组均以右侧股内侧正中部位为中心等距离取局部肌肉组织,4%多聚甲醛固定,石蜡包埋,制作切片,免疫组化染色,检测各组骨骼肌微血管密度及血管内皮细胞生长因子(VEGF)表达水平。
结果:
1.单纯用G-CSF治疗或单纯骨髓干细胞移植治疗,均能使局部缺血组织微血管数量增加。G-CSF动员后再配合骨髓干细胞移植治疗对血管新生的作用更加显著,局部缺血组织微血管数量增加更明显。
2.单纯用G-CSF治疗或单纯骨髓干细胞移植治疗,均能使局部缺血组织VEGF的表达量增加。G-CSF动员后再配合骨髓干细胞移植治疗对血管新生的作用更加有效,VEGF的表达量增加更明显。
结论:
1.单纯G-CSF动员骨髓干细胞能取得单纯自体骨髓干细胞移植相似的促血管新生作用。
2.G-CSF动员后再配合骨髓干细胞移植治疗糖尿病下肢缺血性疾病,其效果明显优于单纯用G-CSF治疗和单纯的骨髓干细胞移植治疗。
Background:With the development of living standard and the advent of ageing society, disease incidence of diabetes was increasing year by year, and the enormous medical expenditure on the complication diabetic foot and amputated extremity brought about heavy economic burden. The traditional therapy includes medication, operation and interventional therapy, but the therapeutic effect is not inadequate. The technique of autologous bone marrow stem cell transplantation provides new method for curing diabetic foot.
Part 1 Diabetes Animal Models
Objective: We selects ALX to set up diabetes animal model, in order to explore a kind of safe, stable, low mortality method. Method:
20 healthy rabbits were divided into 2 groups by random, and were abrosia 12 hours' before dosage. Rabbits in group A were directly given ALX 5% at 150mg/kg, and rabbits in group B were given ALX at twice, 80mg/kg of ALX 5% was intravenously injected firstly, 24 hours later, 120mg/kg of ALX 5% was given again. 14 days later, fasting blood glucose >16mmol/L means that the diabetes animal models were achievement.
Results:
In group A, 7 rabbits deceased within 5 days and the mortality was 70%, and 2 weeks later the fasting blood glucose of 1 rabbit recovered to the normal, then 2 rabbits were achievement and the achievement ratio was 20%;In group B, 1 rabbits deceased and the mortality was 10%, and 2 weeks later the fasting blood glucose of 1 rabbit recovered to the normal, then 8 rabbits were achievement and the achievement ratio was 80%.
Conclusion:
1. The twice administration method was better than the once with a higher model achievement ratio and lower mortality. 2. Selection of ALX to set up diabetes animal model was a kind of safe, economic, reliable method.
Part 2 Mobilization and Effect of Bone Marrow Stem Cell Transplantation to Diabetes Rabbits
Objective: According to counting the peripheral blood mononuclear cells and the bone marrow mononuclear cells and the bone marrow CFU-GM of the three groups(I.e. the group of healthy rabbits, the group of diabetes rabbits and the group of the non-diabetes rabbits)followed by mobilization with identical dose G-CSF, we observed the effect of diabetes for stem cell mobilization.
According to the comparison of hemoglobin, platelet, fasting blood glucose and haemorheology before and after mobilization, we observed the effect of bone marrow stem cell mobilization for diabetes.
Method:
Healthy rabbits were divided into 3 groups by random. Group A were healthy rabbits, Group B were diabetes rabbits, Group C were non-diabetes rabbits (the dosage of ALX was same to group B). We counted peripheral blood mononuclear cells of the 3 groups before and after G-CSF mobilization, once a day and continued 5 days, and then the next day we draw-off bone marrow 3ml, counted bone marrow mononuclear cells, cultivated CFU-GM. We tested the counts of hemoglobin, platelet, fasting blood glucose and haemorheology of the diabetes rabbits of group B before and after mobilization, compared the diversity.
Results:
1. Peripheral blood mononuclear cells of 3 groups were indiscrimination before and after mobilization. Mononuclear bone marrow cells of 3 groups were indiscrimination after mobilization.
2. The counts of CFU-GM of 3 groups were indiscrimination after mobilization.
3. Before and after mobilization, the fasting blood glucose general average of the 10 diabetes rabbits showed downtrend, and the hemoglobin and the platelet general average showed rise tendency. The plasma viscosity and the erythrocyte aggregation were indiscrimination before and after mobilization. The whole blood viscosities were heightened after mobilization than before.
Conclusion:
1. The diabetes was no effect on bone marrow stem cell mobilization.
2. G-CSF mobilization was no effect on hemoglobin, platelet, fasting blood glucose, but mobilization was effect on haemorheology, which remind us to think highly of it and interfere in it.
Part 3 Transplantation of Autologous Bone Marrow Stem Cell for the Treatment of Rabbits Diabetic Lowe Limb Ischemia
Objective: The objective was contrast the effect on neovascularization of the three methods, which were bone marrow stem cell transplantation, hypodermic injection G-CSF and the association of above both.
Method:
We took 40 diabetes rabbits and ligatured arteria femoralis of the right side posterior limb to found diabetes lower limb ischemia animal models. Then the 40 diabetes rabbits were divided into 4 groups by random. Group A:We mobilized by hypodermic injection G-CSF,once a day and continue 5 days. Group B:We mobilized 5 days, On the 6 day of mobilization, we draw-off bone marrow 5ml and injected bone marrow mononuclearcell in ischemia tissue. Group C: We draw-off bone marrow 10ml without mobilization and injected like group B. Group D:We only injected PBS in ischemia tissue. 28 days latter, rabbits of 4 groups were executed. Partial musculatures were stained by the method of immunohistochemistry to detect the expression of vWF and VEGF.
Results:
Bone marrow stem cell transplantation and hypodermic injection G-CSF can strengthen the expression of vWF and VEGF. But when association of the both, the expression of vWF and VEGF were more strengthen.
Conclusion:
1. The G-CSF treatment can also be beneficial to regenerate vascular structure as the autologous BM-MNCS transplantation.
2. Associating bone marrow stem cell transplantation with hypodermic injection G-CSF was better than the any single one.
第一部分
糖尿病动物模型的制作
目的:本实验选用四氧嘧啶(ALX)诱导糖尿病动物模型,探索一种安全、稳定、动物低死亡率的糖尿病模型建立方法。
方法:健康新西兰兔20只,随机分为A、B两组,每组10只。两组给药前均禁食12小时,A组为一次给药法组,即按150mg/ kg经耳缘静脉快速注射新鲜配置的5%ALX;B组为两次给药法组,第1次给药,按80mg/ kg经耳缘静脉快速注射新鲜配置的5%ALX,24小时后第2次给药,按120mg/ kg再次经耳缘静脉快速注射新鲜配置的5%ALX。14天后测空腹血糖值,以空腹血糖>16mmol/L作为造模成功的标准。
结果:A组48小时内死亡4只,第3天死亡2只,第5天死亡1只,死亡率70%,1只血糖短暂升高,两周后恢复正常,2只达到糖尿病模型标准,成模率20%;B组48小时内死亡1只,死亡率10%,1只血糖短暂升高,两周后恢复正常,8只达到糖尿病模型标准,成模率80%。
结论:
1.ALX连续2次小剂量给药法优于1次性高剂量给药,降低了死亡率,提高了成模率。
2.应用ALX制备糖尿病模型,是一种经济、安全、可靠的方法。
第二部分
糖尿病兔骨髓干细胞动员及影响
目的:通过监测健康兔、糖尿病兔及未成模兔三组应用相同剂量粒细胞集落刺激因子(G-CSF)动员后的外周血单个核细胞数、骨髓单个核细胞数及骨髓粒-单核细胞集落形成单位(CFU-GM)培养计数,对比三组的动员效果有无差别,以探讨糖尿病对骨髓干细胞动员有无影响。通过比较糖尿病动物模型在动员前后血红蛋白、血小板、空腹血糖、血液流变学等各项指标的变化情况,探讨骨髓干细胞动员对糖尿病的影响。
方法:健康新西兰兔,随机分为A、B、C三组。A组为健康兔10只,B组为糖尿病兔10只,C组为未成模兔5只(ALX剂量同B组)。A、B、C三组在动员前分别测外周血单个核细胞数,然后三组分别皮下注射10ug/kg G-CSF进行动员,每天1次,连续5天。在应用G-CSF动员期间,每天检测三组外周血单个核细胞数,观察各组动员效果,动员第6天检测三组外周血单个核细胞数,同时三组均抽取骨髓液3ml,分离骨髓单个核细胞,检测骨髓单个核细胞数,并进行CFU-GM培养。B组(糖尿病组)中的10只糖尿病兔在动员前及动员第6天分别监测血红蛋白、血小板、空腹血糖、血液流变学变化情况。
结果:
1.动员前三组外周血单个核细胞数无差别。动员后三组外周血单个核细胞均较前明显升高,计数比较无统计学差异。动员后三组骨髓单个核细胞数计数比较无差别。
2.CFU-GM培养发现,三组均在培养的5～6天开始有集落形成,以后数目逐渐增多,大约12天达高峰,此后集落不断增大,总的集落数不再增加,三组集落培养计数无差别。
3.动员前后10只糖尿病兔的晨空腹血糖值有一定的下降趋势,血红蛋白、血小板均有所升高,但变化均无统计学差异。10只糖尿病兔的晨空腹血流变中的血浆粘度及红细胞聚集性动员前后无明显变化;全血粘度动员后较动员前均明显升高。
结论:
1.糖尿病对骨髓干细胞动员效果无影响。
2.应用G-CSF骨髓干细胞动员对糖尿病兔的血糖、血红蛋白、血小板无影响,对血流变有影响,提示临床应予重视并干预。
第三部分
自体骨髓干细胞移植治疗兔糖尿病下肢缺血性疾病
目的:对比骨髓干细胞移植、皮下注射G-CSF、骨髓干细胞移植联合G-CSF皮下注射三种方法对缺血组织血管新生的作用效果。
方法:健康新西兰兔40只,以第一部分中介绍的二次给药法,用ALX诱导成为糖尿病兔后,均结扎右后肢股动脉,建立糖尿病下肢缺血动物模型,随机分成A、B、C、D四组,每组10只。A组:模型建立后,开始皮下注射10ug/kg G-CSF进行动员,每天1次,连续5天。B组:如A组方法动员,并于动员第6天采髓5ml,分离骨髓单个核细胞。以右侧股内侧正中部位为中心等距离分10个位点,用1ml注射器依次等量肌肉注射0.1ml骨髓单个核细胞悬液(其中5×106个骨髓单个核细胞/位点),每一实验动物局部移植的骨髓单个核细胞总数量为5×107个。C组:模型建立后,不进行动员直接采髓10ml,右侧股内侧肌肉注射骨髓单个核细胞,注射方法同B组。D组:模型建立后,不进行动员,右侧股内侧肌肉注射PBS,注射方法同B组。术后第28天全麻,4组均以右侧股内侧正中部位为中心等距离取局部肌肉组织,4%多聚甲醛固定,石蜡包埋,制作切片,免疫组化染色,检测各组骨骼肌微血管密度及血管内皮细胞生长因子(VEGF)表达水平。
结果:
1.单纯用G-CSF治疗或单纯骨髓干细胞移植治疗,均能使局部缺血组织微血管数量增加。G-CSF动员后再配合骨髓干细胞移植治疗对血管新生的作用更加显著,局部缺血组织微血管数量增加更明显。
2.单纯用G-CSF治疗或单纯骨髓干细胞移植治疗,均能使局部缺血组织VEGF的表达量增加。G-CSF动员后再配合骨髓干细胞移植治疗对血管新生的作用更加有效,VEGF的表达量增加更明显。
结论:
1.单纯G-CSF动员骨髓干细胞能取得单纯自体骨髓干细胞移植相似的促血管新生作用。
2.G-CSF动员后再配合骨髓干细胞移植治疗糖尿病下肢缺血性疾病,其效果明显优于单纯用G-CSF治疗和单纯的骨髓干细胞移植治疗。
Background:With the development of living standard and the advent of ageing society, disease incidence of diabetes was increasing year by year, and the enormous medical expenditure on the complication diabetic foot and amputated extremity brought about heavy economic burden. The traditional therapy includes medication, operation and interventional therapy, but the therapeutic effect is not inadequate. The technique of autologous bone marrow stem cell transplantation provides new method for curing diabetic foot.
Part 1 Diabetes Animal Models
Objective: We selects ALX to set up diabetes animal model, in order to explore a kind of safe, stable, low mortality method. Method:
20 healthy rabbits were divided into 2 groups by random, and were abrosia 12 hours' before dosage. Rabbits in group A were directly given ALX 5% at 150mg/kg, and rabbits in group B were given ALX at twice, 80mg/kg of ALX 5% was intravenously injected firstly, 24 hours later, 120mg/kg of ALX 5% was given again. 14 days later, fasting blood glucose >16mmol/L means that the diabetes animal models were achievement.
Results:
In group A, 7 rabbits deceased within 5 days and the mortality was 70%, and 2 weeks later the fasting blood glucose of 1 rabbit recovered to the normal, then 2 rabbits were achievement and the achievement ratio was 20%;In group B, 1 rabbits deceased and the mortality was 10%, and 2 weeks later the fasting blood glucose of 1 rabbit recovered to the normal, then 8 rabbits were achievement and the achievement ratio was 80%.
Conclusion:
1. The twice administration method was better than the once with a higher model achievement ratio and lower mortality. 2. Selection of ALX to set up diabetes animal model was a kind of safe, economic, reliable method.
Part 2 Mobilization and Effect of Bone Marrow Stem Cell Transplantation to Diabetes Rabbits
Objective: According to counting the peripheral blood mononuclear cells and the bone marrow mononuclear cells and the bone marrow CFU-GM of the three groups(I.e. the group of healthy rabbits, the group of diabetes rabbits and the group of the non-diabetes rabbits)followed by mobilization with identical dose G-CSF, we observed the effect of diabetes for stem cell mobilization.
According to the comparison of hemoglobin, platelet, fasting blood glucose and haemorheology before and after mobilization, we observed the effect of bone marrow stem cell mobilization for diabetes.
Method:
Healthy rabbits were divided into 3 groups by random. Group A were healthy rabbits, Group B were diabetes rabbits, Group C were non-diabetes rabbits (the dosage of ALX was same to group B). We counted peripheral blood mononuclear cells of the 3 groups before and after G-CSF mobilization, once a day and continued 5 days, and then the next day we draw-off bone marrow 3ml, counted bone marrow mononuclear cells, cultivated CFU-GM. We tested the counts of hemoglobin, platelet, fasting blood glucose and haemorheology of the diabetes rabbits of group B before and after mobilization, compared the diversity.
Results:
1. Peripheral blood mononuclear cells of 3 groups were indiscrimination before and after mobilization. Mononuclear bone marrow cells of 3 groups were indiscrimination after mobilization.
2. The counts of CFU-GM of 3 groups were indiscrimination after mobilization.
3. Before and after mobilization, the fasting blood glucose general average of the 10 diabetes rabbits showed downtrend, and the hemoglobin and the platelet general average showed rise tendency. The plasma viscosity and the erythrocyte aggregation were indiscrimination before and after mobilization. The whole blood viscosities were heightened after mobilization than before.
Conclusion:
1. The diabetes was no effect on bone marrow stem cell mobilization.
2. G-CSF mobilization was no effect on hemoglobin, platelet, fasting blood glucose, but mobilization was effect on haemorheology, which remind us to think highly of it and interfere in it.
Part 3 Transplantation of Autologous Bone Marrow Stem Cell for the Treatment of Rabbits Diabetic Lowe Limb Ischemia
Objective: The objective was contrast the effect on neovascularization of the three methods, which were bone marrow stem cell transplantation, hypodermic injection G-CSF and the association of above both.
Method:
We took 40 diabetes rabbits and ligatured arteria femoralis of the right side posterior limb to found diabetes lower limb ischemia animal models. Then the 40 diabetes rabbits were divided into 4 groups by random. Group A:We mobilized by hypodermic injection G-CSF,once a day and continue 5 days. Group B:We mobilized 5 days, On the 6 day of mobilization, we draw-off bone marrow 5ml and injected bone marrow mononuclearcell in ischemia tissue. Group C: We draw-off bone marrow 10ml without mobilization and injected like group B. Group D:We only injected PBS in ischemia tissue. 28 days latter, rabbits of 4 groups were executed. Partial musculatures were stained by the method of immunohistochemistry to detect the expression of vWF and VEGF.
Results:
Bone marrow stem cell transplantation and hypodermic injection G-CSF can strengthen the expression of vWF and VEGF. But when association of the both, the expression of vWF and VEGF were more strengthen.
Conclusion:
1. The G-CSF treatment can also be beneficial to regenerate vascular structure as the autologous BM-MNCS transplantation.
2. Associating bone marrow stem cell transplantation with hypodermic injection G-CSF was better than the any single one.
引文
1 方厚华 医学实验模型动物[M] 北京:军事医学科学出版社 2002:57-58
2 王晓颖,段有金。四氧嘧啶实验性糖尿病大鼠模型的复制 及 其 发 病 机 制 的 探 讨 [J] 。 中 国 医 学 理 论 与 实践,2002(7):802-803
3 徐淑云,卞如濂,陈修,等。药理实验方法学[M]3 版。北京:人民卫生出版社,2002: 1006-1007
4 艾 静,王 宁,杜 杰,等。Wistar 大鼠 2 型糖尿病动物模型的建立。中国药理学通报 2004,20(11):1309~1312
5 Hajizadeh S, Shiran K, Fathollahi Y. Responsiveness of vascular alphal-adrernoceptors of diabetic rat knee joint to phernylephrine in acute inflammation.J Basic Clin Physiol Pharmacol. 2005, 16 (4): 301-309
6 Xu BY,Morrison CM,Yang H,et al .Ti lapia islet grafts are highly a11oxan-resistant.Gen Comp Endocrinol.2004, 137 (2):132-140
7 Noishiki Y, Tomizawa Y, Yamane Y ,et al.Autocrine angiogenic vascular prosthesis with bone marrow transplantation[J].Nat Med,1996,2(1):90-93
8 杨志明,李占海,边云飞,等。自体骨髓细胞局部移植与粒细胞集落刺激因子皮下注射对缺血区血管生成作用的对比研究.生物医学工程与临床, 2006;10(3) :173-176
9 陈莉罗,绍凯彭,爱华,等。急性白血病细胞体外自主生长与自分泌 GM-CSF 水平测定及其临床意义。癌症,1998,17(6):444~446
10 Canneliet P. Mechanisms of angiogenesis and arteriogenesis. NatMed, 2000,6(10): 389-395
11 Oikc Y. Hoanatopoicsis and angiogenesis [J]. Int J Hematol, 2000,71:99- 107
12 Loomans CJ, Koning EJ, Staal FJ, et al. Endothelial progenitor cell dys-function: a novel concept in the pathogenesis of vascular complications of type 1 diabetes [J]. Diabetes, 2004,53(1):195-199
13 Schmidt-Lucke C, Rossig L, Fichtlscherer S, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair [J].Circulation,2005,111(22): 2981-2987
14 Adams V, Lenk K, Linke A, et al. Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise induced ischemia [J]. Arterioscler Thromb Vasc Biol,2004,24:684-690
15 Urbich C, Dmimeler S. Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors [J].Kidney Int, 2005, S67(5): 1672-1676
16 Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors.Blood,2000, 95(3):952-958
17 Pesce M, Orlandi A,lachinoto MG. Myoendothelial differentiation of human umhilical cord blood-derived sterm cells in ischemic limb tissues. Circ Res, 2003, 93(5):e51-e62
18 Murohara T, Therapeutic vasculogenesis using human cord blood-derived endothelial progenitors. Trends Cardiovasc Med,2001,11(8):303-307
19 Stadtfeld M,Graf T. Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by non-invasive lineage tracing. Development, 2005,132, 203-213
20 Asahara T, Masuda H,Tukuhashi T, et al. Isolation of putative progenitor endothelial cells for angiogenesis [J]. Science,1997,275(5302):964-967
21 Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cell responsible for postnatal vasculogenesis in physiological and pathological neovascularizatuion. Cir Res. 1999,85: (11):221-232
22 Powell TM, Paul JD, Hill JM, et al. Granulocyte colony-stimulating factor mobilizes functional endothelial progenitor cells in patients with coronary artery disease [J]. Arterioscler Thromb Vasc Biol, 2005, 25(2):296-301
23 Cross ML,C1aesson-Welsh L.FGF and VEGF function in angiogenesis: signaling pathways, biological response and therapeutic inhibition[J].Trends Pharma Sci, 2001,22: 201-207
24 Tilton RG, Chang KC, Leieune WS, et al Role of nitric
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26 Vasa M, Fichtlscherer S, Adler K , et al. Increase in cir-culating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circula-lion, 2001;103 (24):2885～2890
27 Sbaa E, Dewever J, Martinive P, et al. Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1 driven postischemic vasculogenesis [J]. Circ Res,2006, [Epub ahead of print]
28 Rehman J, Li J, Orschell C, et al. Peripheral blood endothelial progenitor cells are derived from monocyte/macrophages and secrete angiogenic growth factors [J]. Circulation,2003,107:1164-1169
29 Annabi B, Lee Y, Turcotte S, at al. Hypoxia promotes murine bone marrow derived stromal cell migration and tube formation [J].Stem Cells, 2003;21(3):337-347
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2 王晓颖,段有金。四氧嘧啶实验性糖尿病大鼠模型的复制 及 其 发 病 机 制 的 探 讨 [J] 。 中 国 医 学 理 论 与 实践,2002(7):802-803
3 徐淑云,卞如濂,陈修,等。药理实验方法学[M]3 版。北京:人民卫生出版社,2002: 1006-1007
4 艾 静,王 宁,杜 杰,等。Wistar 大鼠 2 型糖尿病动物模型的建立。中国药理学通报 2004,20(11):1309~1312
5 Hajizadeh S, Shiran K, Fathollahi Y. Responsiveness of vascular alphal-adrernoceptors of diabetic rat knee joint to phernylephrine in acute inflammation.J Basic Clin Physiol Pharmacol. 2005, 16 (4): 301-309
6 Xu BY,Morrison CM,Yang H,et al .Ti lapia islet grafts are highly a11oxan-resistant.Gen Comp Endocrinol.2004, 137 (2):132-140
7 Noishiki Y, Tomizawa Y, Yamane Y ,et al.Autocrine angiogenic vascular prosthesis with bone marrow transplantation[J].Nat Med,1996,2(1):90-93
8 杨志明,李占海,边云飞,等。自体骨髓细胞局部移植与粒细胞集落刺激因子皮下注射对缺血区血管生成作用的对比研究.生物医学工程与临床, 2006;10(3) :173-176
9 陈莉罗,绍凯彭,爱华,等。急性白血病细胞体外自主生长与自分泌 GM-CSF 水平测定及其临床意义。癌症,1998,17(6):444~446
10 Canneliet P. Mechanisms of angiogenesis and arteriogenesis. NatMed, 2000,6(10): 389-395
11 Oikc Y. Hoanatopoicsis and angiogenesis [J]. Int J Hematol, 2000,71:99- 107
12 Loomans CJ, Koning EJ, Staal FJ, et al. Endothelial progenitor cell dys-function: a novel concept in the pathogenesis of vascular complications of type 1 diabetes [J]. Diabetes, 2004,53(1):195-199
13 Schmidt-Lucke C, Rossig L, Fichtlscherer S, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair [J].Circulation,2005,111(22): 2981-2987
14 Adams V, Lenk K, Linke A, et al. Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise induced ischemia [J]. Arterioscler Thromb Vasc Biol,2004,24:684-690
15 Urbich C, Dmimeler S. Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors [J].Kidney Int, 2005, S67(5): 1672-1676
16 Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors.Blood,2000, 95(3):952-958
17 Pesce M, Orlandi A,lachinoto MG. Myoendothelial differentiation of human umhilical cord blood-derived sterm cells in ischemic limb tissues. Circ Res, 2003, 93(5):e51-e62
18 Murohara T, Therapeutic vasculogenesis using human cord blood-derived endothelial progenitors. Trends Cardiovasc Med,2001,11(8):303-307
19 Stadtfeld M,Graf T. Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by non-invasive lineage tracing. Development, 2005,132, 203-213
20 Asahara T, Masuda H,Tukuhashi T, et al. Isolation of putative progenitor endothelial cells for angiogenesis [J]. Science,1997,275(5302):964-967
21 Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cell responsible for postnatal vasculogenesis in physiological and pathological neovascularizatuion. Cir Res. 1999,85: (11):221-232
22 Powell TM, Paul JD, Hill JM, et al. Granulocyte colony-stimulating factor mobilizes functional endothelial progenitor cells in patients with coronary artery disease [J]. Arterioscler Thromb Vasc Biol, 2005, 25(2):296-301
23 Cross ML,C1aesson-Welsh L.FGF and VEGF function in angiogenesis: signaling pathways, biological response and therapeutic inhibition[J].Trends Pharma Sci, 2001,22: 201-207
24 Tilton RG, Chang KC, Leieune WS, et al Role of nitric
25 Teppero M,Capla J M,Gallano R D, et al. Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells [J]. Blood, 2005, 105:1068-1077
26 Vasa M, Fichtlscherer S, Adler K , et al. Increase in cir-culating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circula-lion, 2001;103 (24):2885～2890
27 Sbaa E, Dewever J, Martinive P, et al. Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1 driven postischemic vasculogenesis [J]. Circ Res,2006, [Epub ahead of print]
28 Rehman J, Li J, Orschell C, et al. Peripheral blood endothelial progenitor cells are derived from monocyte/macrophages and secrete angiogenic growth factors [J]. Circulation,2003,107:1164-1169
29 Annabi B, Lee Y, Turcotte S, at al. Hypoxia promotes murine bone marrow derived stromal cell migration and tube formation [J].Stem Cells, 2003;21(3):337-347
30 Iwaguro H, Yamaguchi J. Kalka C. et al. Endothelial progenitor cell vascular endothelia growth factor gene transfer for vascular regeneration. Circulation. 2002; 105(6):732-738
1 Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived fromhuman blastocysts J. Science, 1998,282(5391):1145-1147
2 Schwartz RE, Reyes M, Koodie L, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest,2002,109: 1291-1302
3 Tateish iYuyama E, M atsubara H, M urohara T, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone marrow cells: a pilot study and a randomized controlled trial. Lancet, 2002, 360 (9331):427-435
4 谷涌泉,郭连瑞.自体干细胞移植在治疗下肢缺血性疾病中的应用.中华医学杂志,2005,85(36):2536-2537
5 Kerr DA, Llado J, Shmablott MJ, et al. Human embryonic germ cell derivatives facilitate motor recovery of rats with diffuse motor neuron injury. J Neurosci. 2003, 23(12):5131-5140
6 Kim D, Gu Y, Ishii M, et al. In vivo functioning and transplantable mature pancreatic islet-like cell clusters differentiated from embryonic stem cell. Pancreas. 2003, 27(2): E34-E41
7 Johkura K, Cui L, Suzuki A, et al. Survival and function of mouse embryonic stem cell-derived cardiomyocytes inectopic transplants. Cardiovasc Res.2003,58(2): 435-443
8 王爱红,李强,等。中国部分省市糖尿病足调查及医学经济学分析,中华内分泌代谢杂志,2005,21(6):496-449
9 王嘉桔。糖尿病肢体动脉闭塞症的发病概况和治疗现状,糖尿病足诊疗新进展,第一版,2006:22-38
10 Canneliet P. Mechanisms of angiogenesis and arteriogenesis. NatMed, 2000,6(10): 389-395
11 Oikc Y. Hoanatopoicsis and angiogenesis [J]. Int J Hematol, 2000,71:99-107
12 Carmen Urbich, Stefanie Dimmeler. Endothelial Progenitor Cells Characterization and Role in Vascular Biology. Circulation Research. 2004;95:343-353
13 Joachim R. G?thert, Sonja E. Gustin, J. Anke M. van Eekelen, Uli Schmidt, Mark A. Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not contribute to tumor endothelium.Blood,2004, 104:1769-1777
14 Asahara T, Masuda H,Tukuhashi T, et al. Isolation of putative progenitor endothelial cells for angiogenesis [J]. Science,1997,275(5302):964-967
15 Isner JM, Asahara T. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clinical Investigation[J],1999,103(9):1231-1236
16 Edelberg JM Tang L, Hatton k, et al.Young adult bone marrow-derived endothelial precursor cells restore aging-impaired cardiac angiongenic function. Cir res,2002,90(10):E89-93
17 Loomans CJ, Koning EJ, Staal FJ, et al. Endothelial progenitor cell dys-function: a novel concept in the pathogenesis of vascular complications of type 1 diabetes [J]. Diabetes, 2004,53(1):195-199
18 Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infracted myocardium. Nature.2001;410:701-705
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