自体骨髓干细胞移植治疗下肢慢性缺血性疾病的临床研究
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摘要
目的:探讨自体骨髓干细胞移植在治疗下肢慢性缺血性疾病的临床应用以及对其安全性和疗效的评价;探讨下肢肌内注射法移植与动脉血管腔内注射法移植之间的疗效差别。
方法:分析2008年1月至2009年6月血管外科收治的下肢慢性缺血性疾病患者40例共计肢体40条(双下肢患者计病重侧),男32例,女8例,男女比例4∶1,年龄31~87岁,平均(68.2±7.1)岁。其中单纯下肢动脉硬化闭塞症(ASO)21例,糖尿病合并下肢动脉硬化(DF)15例,血栓闭塞性脉管炎(TAO)4例。临床症状包括疼痛37例,冷感39例,麻木29例,溃疡坏疽23例,跛行40例。按Fontaine分级:Ⅱ级6例,Ⅲ级11例,Ⅳ级23例。患者均经正规的非手术方法治疗半年以上无效。40例患者按移植方法的不同随机均分为下肢肌内局部注射组(第1组)和动脉血管腔内注射组(第2组)。糖尿病患者空腹血糖控制在7.0mmol/L以下,非空腹血糖控制在10.0mmol/L以下,糖化血红蛋白(HbAlc)控制在6.5%以下。患者在抽取骨髓前均使用人粒细胞集落刺激因子(G-CSF)刺激动员骨髓细胞2~3d,300μg/d ,动员末日抽取骨髓血200ml,经密度梯度离心法分离提纯后获得骨髓单个核细胞悬浊液,按上述两种方法移植入患肢(双下肢患者选取病重侧)。术后仍辅于抗血小板、扩血管等常规治疗。密切随访6个月,每月定期随访主观症状变化情况,6个月后复查皮温、经皮氧分压(TcPO2)、踝肱指数(ABI)、血管数字减影造影(DSA),记录疼痛、冷感、麻木、跛行距离,观察溃疡情况。采用SPSS16.0统计软件进行数据处理,治疗前后对比采用配对数据均数t检验,两组间疗效对比采用方差检验,检验水准ɑ=0.05。
结果:移植治疗后6个月,所有患者获得随访,各观察指标均进入统计学分析。两组辅助检查指标(皮温、侧支循环、TcPO2)及临床症状指标(疼痛、冷感、麻木、溃疡、跛行)移植治疗前后差异均有统计学意义(P<0.01)(表1、表2、图表2)。其中4例患者移植治疗后6个月侧支循环明显丰富(附图2.1.1~2.1.4),3例患者移植治疗后6个月溃疡创面愈合良好(附图2.2.1~2.2.3)。两组临床症状各指标评分及侧支循环再生程度评分示移植治疗总有效率均≥60%(表3、图表1)。两组ABI变化均不明显,移植治疗前后差异无统计学意义(P>0.05)(表1)。两组移植治疗后所有观察指标差异均无统计学意义(P>0.05)(表4),两组间疗效无明显差别。
结论:自体骨髓干细胞无论是采取下肢肌内局部注射法移植还是采取动脉血管腔内注射法移植治疗下肢慢性缺血性疾病均是一种简单、安全、有效的方法,两种移植方法疗效无明显差别。经动员刺激后的自体骨髓干细胞移植有抽取骨髓少,细胞含量多及安全性高等优点。
Objective: To probe into the application of autologous bone marrow stem cells transplantation in the treatment of chronically ischemic disease of lower extremity and evaluate the security and curative effect.Secondly, to probe into the difference of curative effect between Intramuscular transplantation and Endovascular transplantation.
Methods: 40 patients with chronically ischemic lower limb had been treated since January 2008 to June 2009. Among them, 32 males, 8 females; aged 31~87 years, averaged (68.2±7.1) years. Of the 40 patients, 21 diagnose atherosclerosis obliterans, 15 diagnose diabetic foot and 4 diagnose thromboangiitis obliterans. 37 had pain symptom, 39 had cold symptom, 29 had numbness symptom , 23 had ulcer symptom, 40 had intermittent claudication symptom. 6 patients were in FontaineⅡ, 11 patients were in FontaineⅢ, 23 patients were in FontaineⅣ. All patients had been defeated from standard medicamentous cure. By difference of transplantation means, divided equally 40 patients into Intramuscular transplantation group (the first group) and Endovascular transplantation group (the second group). The fasting blood glucose of diabetic must be controlled below 7.0mmol/L, and the non-fasting blood glucose must be controlled below 10.0mmol/L, and the HbAlc must be controlled below 6.5%. The bone marrow of each patient was stimulated by an injection of the recombinant human granulocyte macrophage colony-stimulatory factor(G-CSF), 300μg/d, for 2～3days. Upon completion of stimulation, the bone marrow 200ml was drawn from the iliac spine and the stem cells were obtained, after disassociated and depuated, transplanting into the more severely ischemic limb. Antiplatelet therapy and Vasodilator therapy must be continued, and they were followed once a month after the transplantation. The skin temperature, transcutaneous oxygen pressure(TcPO2), digital subtraction angiography(DSA)and ankle/brachia index (ABI) were rechecked at 6 months later, and the symptoms of pain, cold, numbness, intermittent claudication and physical signs of ulcer and gangrene were evaluated. SPSS16.0 statistical software were used for datum processing. The curative effect before and after treatment were compared using paired t-test. The curative effect between two groups were compared using Variance-test. Test level as :ɑ=0.05.
Results: Six months later, all of 40 patients were involved in the analysis of result. The indexes of the two groups of auxiliary examination and clinical symptoms before and after treatment had statistical significance((P<0.01) (table 1, table 2, chart 2). Among them, 4 patients had rich Collateral Circulation (image2.1.1~2.1.4), and 3 patients had ulcer healing well after transplantation (image2.2.1~2.2.3 ). The total effective rate of clinical symptoms and Collateral Circulation of two groups are larger than 60%(table 3, chart 1). ABI before and after treatment are all no statistical significance (P>0.05)(table 1). All of the indexes are no significant difference between the two groups((P>0.05))(table 4).
Conclusion: transplantation of autologous bone marrow stem cells is effective in the treatment of chronically ischemic disease of lower limb. which is a simple, safe and effective treatment for chronically ischemic disease of lower limb. There is no significant difference of curative effect between Intramuscular transplantation and Endovascular transplantation. The mobilization stimulated bone marrow stem cells transplantation has advantages of taken a less bone marrow, obtained a larger amount cells and had a high security.
方法:分析2008年1月至2009年6月血管外科收治的下肢慢性缺血性疾病患者40例共计肢体40条(双下肢患者计病重侧),男32例,女8例,男女比例4∶1,年龄31~87岁,平均(68.2±7.1)岁。其中单纯下肢动脉硬化闭塞症(ASO)21例,糖尿病合并下肢动脉硬化(DF)15例,血栓闭塞性脉管炎(TAO)4例。临床症状包括疼痛37例,冷感39例,麻木29例,溃疡坏疽23例,跛行40例。按Fontaine分级:Ⅱ级6例,Ⅲ级11例,Ⅳ级23例。患者均经正规的非手术方法治疗半年以上无效。40例患者按移植方法的不同随机均分为下肢肌内局部注射组(第1组)和动脉血管腔内注射组(第2组)。糖尿病患者空腹血糖控制在7.0mmol/L以下,非空腹血糖控制在10.0mmol/L以下,糖化血红蛋白(HbAlc)控制在6.5%以下。患者在抽取骨髓前均使用人粒细胞集落刺激因子(G-CSF)刺激动员骨髓细胞2~3d,300μg/d ,动员末日抽取骨髓血200ml,经密度梯度离心法分离提纯后获得骨髓单个核细胞悬浊液,按上述两种方法移植入患肢(双下肢患者选取病重侧)。术后仍辅于抗血小板、扩血管等常规治疗。密切随访6个月,每月定期随访主观症状变化情况,6个月后复查皮温、经皮氧分压(TcPO2)、踝肱指数(ABI)、血管数字减影造影(DSA),记录疼痛、冷感、麻木、跛行距离,观察溃疡情况。采用SPSS16.0统计软件进行数据处理,治疗前后对比采用配对数据均数t检验,两组间疗效对比采用方差检验,检验水准ɑ=0.05。
结果:移植治疗后6个月,所有患者获得随访,各观察指标均进入统计学分析。两组辅助检查指标(皮温、侧支循环、TcPO2)及临床症状指标(疼痛、冷感、麻木、溃疡、跛行)移植治疗前后差异均有统计学意义(P<0.01)(表1、表2、图表2)。其中4例患者移植治疗后6个月侧支循环明显丰富(附图2.1.1~2.1.4),3例患者移植治疗后6个月溃疡创面愈合良好(附图2.2.1~2.2.3)。两组临床症状各指标评分及侧支循环再生程度评分示移植治疗总有效率均≥60%(表3、图表1)。两组ABI变化均不明显,移植治疗前后差异无统计学意义(P>0.05)(表1)。两组移植治疗后所有观察指标差异均无统计学意义(P>0.05)(表4),两组间疗效无明显差别。
结论:自体骨髓干细胞无论是采取下肢肌内局部注射法移植还是采取动脉血管腔内注射法移植治疗下肢慢性缺血性疾病均是一种简单、安全、有效的方法,两种移植方法疗效无明显差别。经动员刺激后的自体骨髓干细胞移植有抽取骨髓少,细胞含量多及安全性高等优点。
Objective: To probe into the application of autologous bone marrow stem cells transplantation in the treatment of chronically ischemic disease of lower extremity and evaluate the security and curative effect.Secondly, to probe into the difference of curative effect between Intramuscular transplantation and Endovascular transplantation.
Methods: 40 patients with chronically ischemic lower limb had been treated since January 2008 to June 2009. Among them, 32 males, 8 females; aged 31~87 years, averaged (68.2±7.1) years. Of the 40 patients, 21 diagnose atherosclerosis obliterans, 15 diagnose diabetic foot and 4 diagnose thromboangiitis obliterans. 37 had pain symptom, 39 had cold symptom, 29 had numbness symptom , 23 had ulcer symptom, 40 had intermittent claudication symptom. 6 patients were in FontaineⅡ, 11 patients were in FontaineⅢ, 23 patients were in FontaineⅣ. All patients had been defeated from standard medicamentous cure. By difference of transplantation means, divided equally 40 patients into Intramuscular transplantation group (the first group) and Endovascular transplantation group (the second group). The fasting blood glucose of diabetic must be controlled below 7.0mmol/L, and the non-fasting blood glucose must be controlled below 10.0mmol/L, and the HbAlc must be controlled below 6.5%. The bone marrow of each patient was stimulated by an injection of the recombinant human granulocyte macrophage colony-stimulatory factor(G-CSF), 300μg/d, for 2～3days. Upon completion of stimulation, the bone marrow 200ml was drawn from the iliac spine and the stem cells were obtained, after disassociated and depuated, transplanting into the more severely ischemic limb. Antiplatelet therapy and Vasodilator therapy must be continued, and they were followed once a month after the transplantation. The skin temperature, transcutaneous oxygen pressure(TcPO2), digital subtraction angiography(DSA)and ankle/brachia index (ABI) were rechecked at 6 months later, and the symptoms of pain, cold, numbness, intermittent claudication and physical signs of ulcer and gangrene were evaluated. SPSS16.0 statistical software were used for datum processing. The curative effect before and after treatment were compared using paired t-test. The curative effect between two groups were compared using Variance-test. Test level as :ɑ=0.05.
Results: Six months later, all of 40 patients were involved in the analysis of result. The indexes of the two groups of auxiliary examination and clinical symptoms before and after treatment had statistical significance((P<0.01) (table 1, table 2, chart 2). Among them, 4 patients had rich Collateral Circulation (image2.1.1~2.1.4), and 3 patients had ulcer healing well after transplantation (image2.2.1~2.2.3 ). The total effective rate of clinical symptoms and Collateral Circulation of two groups are larger than 60%(table 3, chart 1). ABI before and after treatment are all no statistical significance (P>0.05)(table 1). All of the indexes are no significant difference between the two groups((P>0.05))(table 4).
Conclusion: transplantation of autologous bone marrow stem cells is effective in the treatment of chronically ischemic disease of lower limb. which is a simple, safe and effective treatment for chronically ischemic disease of lower limb. There is no significant difference of curative effect between Intramuscular transplantation and Endovascular transplantation. The mobilization stimulated bone marrow stem cells transplantation has advantages of taken a less bone marrow, obtained a larger amount cells and had a high security.
引文
[1] AI-Omran M,Tu JV,Johnston KW,et al. Outcome ofrevascularization procedures for peripheral arterial occlusive disease in Ontario between 1991 and 1998:a population-based study[J].Vase Surg,2003,38(2):279-288.
[2]孙文郁,涂巍,梁健.自体骨髓干细胞移植治疗下肢动脉硬化闭塞症11例报告[J].中国医师进修杂志,2006,29(11):62-62.
[3] Oufiel K.Peripheral arterial disease[J].Lancet,2001,358(9289):1257-1264.
[4]郭连瑞,谷涌泉,张建,等.不同途径移植骨髓单个核细胞治疗大鼠后肢缺血.中国临床康复[J],2005,9(10):57-59.
[5] Yamamoto K,Kondo T ,Suzuki S,et a1. Moleeular evaluation of endothelial progenitor cells in patients with ischemic limbs : therapeutic effect by stem cell transplantation[J].Arterioscler Thromb Vasc Biol,2004,24(12):e192-e196.
[6] Silvestre JS,Levhy BI,Angiogenesis therapy in ischemic disease[J]. Arch Mal Coeur Vaiss ,2002,95:189-196.
[7] AI-Khaldi A,AI-Sabti H,Galipeau J,et al. Therapeutic angiogenesis using autologus bone marrow stromal cells: improved blood flow in a chronic limb ischema model[J]. Ann Thorac Surg,2003,75:204-209.
[8] Makinen K. Angiogenesis-a new goal in peripheral artery occlusive disease therapy[J]. Acta Chir Belg. 2003,103(5):470-474.
[9] Tateishi-Yuyama E,Matsubara H,Murohara T,et a1.Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells:B pilot study and H randnmiscd controlled tria1.1ancet,2002,360(9331):427-435.
[10] Nizankowski R,Petriczek T,Skotnicki A,et al. The treatment of advanced chronic lower limb ischaemia with marrow stem cell autotransplantation[J].Kardiol Pol, 2005,63(4):351-60.
[11]谷涌泉.糖尿病下肢缺血的外科治疗进展.临床外科杂志[J],2008,16(5):306-306.
[12]谷涌泉,张建,齐立行,等.骨髓动员刺激后自体骨髓源单个核细胞移治疗下肢缺血的初步临床研究[J].中国修复重建外科杂志,2006,20(10):1019-1020.
[13]谷涌泉,张建,齐立行,等.自体骨髓干细胞和外周血干细胞移植治疗下肢缺血的对比研究[J].中国修复重建外科杂志,2007,21(7):675-678.
[14]张建,谷涌泉,李建新,等.干细胞移植治疗糖尿病足.中国实用内科杂志,2007,27(7):500-501.
[15]孙元,金毕,赵玉国,等.自体骨髓干细胞移植治疗下肢动脉缺血性疾病[J].华中医学杂志,2005,29(6):459-460.
[16]谷涌泉,张建,郭连瑞,等.自体骨髓干细胞移植治疗下肢严重缺血32例报告[J].中国临床康复,2004,8(35):7970-7972.
[17] Tateishi-Yuyama E,M atsubara H,M urohara T,et a1.Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells:a pilot study and a random ized controlled tria1[J].Lancet,2002,360(9331):427-435.
[18] sner J,Asahara T.Angiogenesis and vasculaogenesis as therapeutic strategies for postnatal neovascularization[J].Clin Invest,1999,103:1231-1236.
[19]曾昭凡,唐新华,谷涌泉.自体骨髓单个核细胞移植治疗慢性下肢缺血的研究进展[J].江西医学院学报,2009,49(5):126-126.
[20] Kohlman-Trigoboff D,Lawson JH,Murphy MP.Stem cell use in a patient with an ischemic foot ulcer: a case study[J].Vasc Nurs,2006 ,24(2):56-61.
[21] Uribch C,Dimmeler S. Endothelial progenitor cells:Characterization and role in vascular biology[J].Cire Res,2004,95(8):343-353.
[22] Tse HF,Kwong YL,Chan JK,et al. angiogenesis in ischaemic myocardium by intramyocardial autolgous bone marrow mononuclear cell implantation[J]. Lancet,2003,361(9531):47-49.
[23] Ziegelhoeffer T,Femandez B,Kostin S,et al. Bone marrow-derived cells do not incorporate into adult growing vasculature[J]. Circ Res,2004,94(2):230-238.
[24] Kinnaird T,Stabile E,Bumett MS,et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanism[J]. Circ Res,2004,94(5):678-685.
[25] Peichev M,Naiyer AJ,Pereira D,et a1.Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors[J].Blood,2000,95(3):952-958.
[26] Pesce M,Orlandi A,lachinoto MG. Myoendothelial differentiation of human umhilical cord blood-derived sterna cells in ischemic limb tissues[J].Circ Res,2003,93(5):e51-e62.
[27] Murohara T.Therapeutic vasculogenesis using human cord blood-derived endothelial progenitors[J].Trends Cardiovasc Med,2001,11(8):303-307.
[28] Takakura N,Watanabe T,Suenobu S,et a1.A role for hematopoietic stem cells in promoting angiogenesis[J].Cell,2000,102(2):199-209.
[29] Janowska-Wieczorek A,Marquez LA,Nabholtz JM,et a1.Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34+ cells and their transmigration through reconstituted basement membrane[J].Blood,1999,93(10):3379-3390.
[30] Woodbury D,Schwarz E J,Prockop D J,et al. Adult rat and human bone marrow stromal cells differentiate into neurons[J]. Neurosci Res, 2000, 61:364-370.
[31] Jain M,Pfister 0,Roger J,et al. Mesenchymal stem cells in the infracted heart[J]. Coronary Artery Disease,2005,16(2):93-97.
[32] Orlic D,Kajstura J,Chimenti S,et al. Bone marrow cells regenerate infracted myocardium[J]. Nature,2001, 410:710-715.
[33] Jiang Y,Jahagirdar BN,Reinhardt RL,et al. Pluripotency of mesenchymal stem cells derived from adult marrow[J]. Nature,2002, 418:41-49.
[34] Asahara T,Masuda H,Tukuhashi T,et a1. Isolation of putative progenitor endothelial cells for angiogenesis[J] . Science,1997,275(5302):964-967.
[35] Asahara T,Masuda H,Takahashi T,et a1.Bone marrow origin of endotlaelial cell responsible for postnatal vasculogenesis in physiological and pathological neovascularizatuion[J].Cir Res,1999,85(11):221-232.
[36] Hattori K,Dias S,Heissing B,et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopiesis by recruitment of vasculogenic and hematopoietic stem cells[J]. Exp Med,2001,193:1005~1014.
[37] Cross ML,Claesson-Welsh L.FGF and VEGF function in angiogenesis:signaling pathways,biological response and therapeutic inhibition[J].Trends Pharma Sci,2001,22:201-207.
[38] Tilton RG , Chang KC,Leieune WS,et al. Role of nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGE [J]. Invest Ophthalmol Vis Sci,1999,40:689-696.
[39] 28 Rehman J,Li J,Orschell C,et a1.Peripheral blood endothelial progenitor cells are derived from monocyte/macrophages and secrete angiogenic growth factors[J].Circulation,2003,107:1164-1169.
[40] Annabi B,Lee Y,Turcotte S,at a1.Hypoxia promotes murine bone marrow derived stromal cell migration and tube formation[J].Stem Cells,2003,21(3):337-347.
[41] Hu J,Takatoku M,Sellers SE,et al. Analysis of origin and optipmization of expansin and transduction of circulating peripheral blood endothelial progenitor cells in the rhsus macaque model[J]. Hum Gene Ther,2002,13:2041-2050.
[42] eda Y,Fujita J,Ieda M,et al. G-CSF and HGF:combination of vasculogenesis and angiogenesis synergistically improves recovery in murine hind limb ischemia[J]. Mol Cell Cardiol,2007,42(3):540-548.
[43]赵春华主编.干细胞原理、技术与临床[M].北京:化学工业出版社,2006:417-419.
[44]谷涌泉,张建,郭连瑞,等.自体骨髓干细胞移植治疗下肢严重缺血:32例报告中国临床康复[J].2004,8(35):7971-7972.
[45] Das H,George JC,Joseph M,et al. Stem cell therapy with overexpressed VEGF and PDGF genes improves cardiac function in a rat infarct model[J]. PLoS One, 2009,4(10):e7325-e7326.
[46] waguro H,Yamaguchi J,Kalka C,et al. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration[J]. Circulation,2002,105:732~738.
[1]谷涌泉,张建,齐立行,等.自体骨髓干细胞移植治疗慢性下肢缺血94例不同病变分期患者的效果比较.中国临床康复,2005,9(38):7-10.
[2]谷涌泉.糖尿病下肢缺血的外科治疗进展.临床外科杂志,2008,16(5):306-306.
[3] Weissman IL.Translating stem cell and progenitor cell biology to the clinic: Barriers and opportunities[J].Science,2000,287(5457):1442-1446
[4]方伟综述,郭曙光审校.血管内皮生长因子治疗下缺血性疾病的研究进展.中华普通外科杂志,2006,15(12):953-953.
[5]赵春华主编.干细胞原理、技术与临床[M].第1版.化学工业出版社,2006:222-284.
[6]谷涌泉,张建,齐立行,等.自体骨髓干细胞和外周血干细胞移植治疗下肢缺血的对比研究.中国修复重建外科杂志,2007,21(7):675-678.
[7]谷涌泉,张建,齐立行,等.骨髓动员刺激后自体骨髓源单个核细胞移治疗下肢缺血的初步临床研究.中国修复重建外科杂志,2006,20(10):1019-1020.
[8]谷涌泉,张建,郭连瑞,等.自体骨髓干细胞移植治疗下肢严重缺血:32例报告.中国临床康复,2004,8(35):7970-7971.
[9]董国祥.造血干细胞移植在慢性下肢缺血治疗中意义和发展前景.中国实用外科杂志,2005,2(54):242-242.
[10]张建,谷涌泉,李建新,等.干细胞移植治疗糖尿病足.中国实用内科杂志,2007,27(7):500-501.
[2]孙文郁,涂巍,梁健.自体骨髓干细胞移植治疗下肢动脉硬化闭塞症11例报告[J].中国医师进修杂志,2006,29(11):62-62.
[3] Oufiel K.Peripheral arterial disease[J].Lancet,2001,358(9289):1257-1264.
[4]郭连瑞,谷涌泉,张建,等.不同途径移植骨髓单个核细胞治疗大鼠后肢缺血.中国临床康复[J],2005,9(10):57-59.
[5] Yamamoto K,Kondo T ,Suzuki S,et a1. Moleeular evaluation of endothelial progenitor cells in patients with ischemic limbs : therapeutic effect by stem cell transplantation[J].Arterioscler Thromb Vasc Biol,2004,24(12):e192-e196.
[6] Silvestre JS,Levhy BI,Angiogenesis therapy in ischemic disease[J]. Arch Mal Coeur Vaiss ,2002,95:189-196.
[7] AI-Khaldi A,AI-Sabti H,Galipeau J,et al. Therapeutic angiogenesis using autologus bone marrow stromal cells: improved blood flow in a chronic limb ischema model[J]. Ann Thorac Surg,2003,75:204-209.
[8] Makinen K. Angiogenesis-a new goal in peripheral artery occlusive disease therapy[J]. Acta Chir Belg. 2003,103(5):470-474.
[9] Tateishi-Yuyama E,Matsubara H,Murohara T,et a1.Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells:B pilot study and H randnmiscd controlled tria1.1ancet,2002,360(9331):427-435.
[10] Nizankowski R,Petriczek T,Skotnicki A,et al. The treatment of advanced chronic lower limb ischaemia with marrow stem cell autotransplantation[J].Kardiol Pol, 2005,63(4):351-60.
[11]谷涌泉.糖尿病下肢缺血的外科治疗进展.临床外科杂志[J],2008,16(5):306-306.
[12]谷涌泉,张建,齐立行,等.骨髓动员刺激后自体骨髓源单个核细胞移治疗下肢缺血的初步临床研究[J].中国修复重建外科杂志,2006,20(10):1019-1020.
[13]谷涌泉,张建,齐立行,等.自体骨髓干细胞和外周血干细胞移植治疗下肢缺血的对比研究[J].中国修复重建外科杂志,2007,21(7):675-678.
[14]张建,谷涌泉,李建新,等.干细胞移植治疗糖尿病足.中国实用内科杂志,2007,27(7):500-501.
[15]孙元,金毕,赵玉国,等.自体骨髓干细胞移植治疗下肢动脉缺血性疾病[J].华中医学杂志,2005,29(6):459-460.
[16]谷涌泉,张建,郭连瑞,等.自体骨髓干细胞移植治疗下肢严重缺血32例报告[J].中国临床康复,2004,8(35):7970-7972.
[17] Tateishi-Yuyama E,M atsubara H,M urohara T,et a1.Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells:a pilot study and a random ized controlled tria1[J].Lancet,2002,360(9331):427-435.
[18] sner J,Asahara T.Angiogenesis and vasculaogenesis as therapeutic strategies for postnatal neovascularization[J].Clin Invest,1999,103:1231-1236.
[19]曾昭凡,唐新华,谷涌泉.自体骨髓单个核细胞移植治疗慢性下肢缺血的研究进展[J].江西医学院学报,2009,49(5):126-126.
[20] Kohlman-Trigoboff D,Lawson JH,Murphy MP.Stem cell use in a patient with an ischemic foot ulcer: a case study[J].Vasc Nurs,2006 ,24(2):56-61.
[21] Uribch C,Dimmeler S. Endothelial progenitor cells:Characterization and role in vascular biology[J].Cire Res,2004,95(8):343-353.
[22] Tse HF,Kwong YL,Chan JK,et al. angiogenesis in ischaemic myocardium by intramyocardial autolgous bone marrow mononuclear cell implantation[J]. Lancet,2003,361(9531):47-49.
[23] Ziegelhoeffer T,Femandez B,Kostin S,et al. Bone marrow-derived cells do not incorporate into adult growing vasculature[J]. Circ Res,2004,94(2):230-238.
[24] Kinnaird T,Stabile E,Bumett MS,et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanism[J]. Circ Res,2004,94(5):678-685.
[25] Peichev M,Naiyer AJ,Pereira D,et a1.Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors[J].Blood,2000,95(3):952-958.
[26] Pesce M,Orlandi A,lachinoto MG. Myoendothelial differentiation of human umhilical cord blood-derived sterna cells in ischemic limb tissues[J].Circ Res,2003,93(5):e51-e62.
[27] Murohara T.Therapeutic vasculogenesis using human cord blood-derived endothelial progenitors[J].Trends Cardiovasc Med,2001,11(8):303-307.
[28] Takakura N,Watanabe T,Suenobu S,et a1.A role for hematopoietic stem cells in promoting angiogenesis[J].Cell,2000,102(2):199-209.
[29] Janowska-Wieczorek A,Marquez LA,Nabholtz JM,et a1.Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34+ cells and their transmigration through reconstituted basement membrane[J].Blood,1999,93(10):3379-3390.
[30] Woodbury D,Schwarz E J,Prockop D J,et al. Adult rat and human bone marrow stromal cells differentiate into neurons[J]. Neurosci Res, 2000, 61:364-370.
[31] Jain M,Pfister 0,Roger J,et al. Mesenchymal stem cells in the infracted heart[J]. Coronary Artery Disease,2005,16(2):93-97.
[32] Orlic D,Kajstura J,Chimenti S,et al. Bone marrow cells regenerate infracted myocardium[J]. Nature,2001, 410:710-715.
[33] Jiang Y,Jahagirdar BN,Reinhardt RL,et al. Pluripotency of mesenchymal stem cells derived from adult marrow[J]. Nature,2002, 418:41-49.
[34] Asahara T,Masuda H,Tukuhashi T,et a1. Isolation of putative progenitor endothelial cells for angiogenesis[J] . Science,1997,275(5302):964-967.
[35] Asahara T,Masuda H,Takahashi T,et a1.Bone marrow origin of endotlaelial cell responsible for postnatal vasculogenesis in physiological and pathological neovascularizatuion[J].Cir Res,1999,85(11):221-232.
[36] Hattori K,Dias S,Heissing B,et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopiesis by recruitment of vasculogenic and hematopoietic stem cells[J]. Exp Med,2001,193:1005~1014.
[37] Cross ML,Claesson-Welsh L.FGF and VEGF function in angiogenesis:signaling pathways,biological response and therapeutic inhibition[J].Trends Pharma Sci,2001,22:201-207.
[38] Tilton RG , Chang KC,Leieune WS,et al. Role of nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGE [J]. Invest Ophthalmol Vis Sci,1999,40:689-696.
[39] 28 Rehman J,Li J,Orschell C,et a1.Peripheral blood endothelial progenitor cells are derived from monocyte/macrophages and secrete angiogenic growth factors[J].Circulation,2003,107:1164-1169.
[40] Annabi B,Lee Y,Turcotte S,at a1.Hypoxia promotes murine bone marrow derived stromal cell migration and tube formation[J].Stem Cells,2003,21(3):337-347.
[41] Hu J,Takatoku M,Sellers SE,et al. Analysis of origin and optipmization of expansin and transduction of circulating peripheral blood endothelial progenitor cells in the rhsus macaque model[J]. Hum Gene Ther,2002,13:2041-2050.
[42] eda Y,Fujita J,Ieda M,et al. G-CSF and HGF:combination of vasculogenesis and angiogenesis synergistically improves recovery in murine hind limb ischemia[J]. Mol Cell Cardiol,2007,42(3):540-548.
[43]赵春华主编.干细胞原理、技术与临床[M].北京:化学工业出版社,2006:417-419.
[44]谷涌泉,张建,郭连瑞,等.自体骨髓干细胞移植治疗下肢严重缺血:32例报告中国临床康复[J].2004,8(35):7971-7972.
[45] Das H,George JC,Joseph M,et al. Stem cell therapy with overexpressed VEGF and PDGF genes improves cardiac function in a rat infarct model[J]. PLoS One, 2009,4(10):e7325-e7326.
[46] waguro H,Yamaguchi J,Kalka C,et al. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration[J]. Circulation,2002,105:732~738.
[1]谷涌泉,张建,齐立行,等.自体骨髓干细胞移植治疗慢性下肢缺血94例不同病变分期患者的效果比较.中国临床康复,2005,9(38):7-10.
[2]谷涌泉.糖尿病下肢缺血的外科治疗进展.临床外科杂志,2008,16(5):306-306.
[3] Weissman IL.Translating stem cell and progenitor cell biology to the clinic: Barriers and opportunities[J].Science,2000,287(5457):1442-1446
[4]方伟综述,郭曙光审校.血管内皮生长因子治疗下缺血性疾病的研究进展.中华普通外科杂志,2006,15(12):953-953.
[5]赵春华主编.干细胞原理、技术与临床[M].第1版.化学工业出版社,2006:222-284.
[6]谷涌泉,张建,齐立行,等.自体骨髓干细胞和外周血干细胞移植治疗下肢缺血的对比研究.中国修复重建外科杂志,2007,21(7):675-678.
[7]谷涌泉,张建,齐立行,等.骨髓动员刺激后自体骨髓源单个核细胞移治疗下肢缺血的初步临床研究.中国修复重建外科杂志,2006,20(10):1019-1020.
[8]谷涌泉,张建,郭连瑞,等.自体骨髓干细胞移植治疗下肢严重缺血:32例报告.中国临床康复,2004,8(35):7970-7971.
[9]董国祥.造血干细胞移植在慢性下肢缺血治疗中意义和发展前景.中国实用外科杂志,2005,2(54):242-242.
[10]张建,谷涌泉,李建新,等.干细胞移植治疗糖尿病足.中国实用内科杂志,2007,27(7):500-501.