Chinese Journal of Tissue Engineering Research ›› 2013, Vol. 17 ›› Issue (18): 3389-3396.doi: 10.3969/j.issn.2095-4344.2013.18.022
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Wang Hong1, Li Jin-cheng2, Li Zheng3, Sun Hai-feng4, Yin Hui1
Received:
2012-12-25
Revised:
2013-03-01
Online:
2013-04-30
Published:
2013-04-30
Contact:
Li Jin-cheng, Associate researcher, School of Basic Medical Science, Jilin University, Changchun 130031, Jilin Province, China
wanghong199135@126.com
About author:
Wang Hong★, Master,Nurse- in-charge, Department of Endocrinology, the First Hospital of Jilin University, Changchun 130031, Jilin Province, China
wanghong199135@126.com
CLC Number:
Wang Hong, Li Jin-cheng, Li Zheng, Sun Hai-feng, Yin Hui. From islet cell transplantation to pancreatic stem cell transplantation in the treatment of diabetes[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(18): 3389-3396.
2 胰岛细胞核胰腺干细胞移植治疗糖尿病的相关研究以及影响因素 资料来源:①胰岛细胞移植和胰腺干细胞移植治疗糖尿病研究的相关文献[27-28],研究文献范围1990至2011年,检索词为“细胞移植(Cell transplantation);胰岛细胞移植(Islet cell transplantation);胰腺干细胞移植(Pancreatic stem cell transplantation);糖尿病(Diabetes);诱导分化(Induced differentiation);免疫耐受(Immune tolerance);免疫排斥反应(Immune rejection)”,选取文献32篇[31-62]。 纳入标准:①胰岛细胞移植治疗糖尿病的相关研究。②胰腺干细胞在糖尿病治疗中的应用相关研究。③胰岛细胞移植的临床免疫问题相关研究。④胰岛细胞移植中的非特异性炎症反应的相关研究。⑤胰腺干细胞移植标记物的相关研究。 排除标准:①排除综述及循证医学类型的文章。②重复性研究类型文献。 分析指标:①胰岛细胞移植治疗糖尿病的的实验与临床研究。②胰腺干细胞移植治疗糖尿病的实验研究。③移植部位对胰岛细胞移植治疗糖尿病的影响。④移植数量对胰岛细胞移植治疗糖尿病的影响。⑤胰腺干细胞标志物对干细胞移植治疗糖尿病的影响。⑥胰岛细胞移植与胰腺干细胞移植治疗糖尿病面临的问题及对策。 2.1 国内外关于胰岛细胞移植治疗糖尿病的实验与临床研究 胰岛细胞移植治疗糖尿病已有近百年的历史[29]。加拿大科学家报道的新型胰岛细胞分离纯化技术和无激素免疫抑制方案,使成人胰岛细胞移植的临床应用成为可能[30]。是作为1型糖尿病治疗最有前景的方法之一,已经取得重要进展。国外关于胰岛细胞移植治疗糖尿病已有很多研究。 国外部分关于胰岛细胞移植治疗糖尿病的实验与临床研究:"
在中国,从2000年开始解放军南京军区福州总医院与上海市第一人民医院联合攻关,进行成人胰岛细胞分离与临床移植的研究。据统计到2007年为止[37],中国开展成人胰岛细胞移植报道的有:解放军南京军区福州总医院和上海市第一人民医院开展成人胰岛细胞移植共7例,哈尔滨医科大学第一临床医学院卫生部细胞移植重点实验室开展了1例成人胰岛与胚胎胰组织混合移植,无锡市第一人民医院开展了1例肝脏移植与未纯化成人胰岛组织联合移植,中南大学附属湘雅三医院开展了1例猪胰岛细胞移植等。然而无论是异种来源的胰岛细胞还是手工分离的同种异体胰岛细胞移植,其临床应用效果均不理想。究其原因有很多,胰岛细胞移植活性、良好胰岛细胞数量及其存活是影响胰岛细胞移植成功的关键,另外一个主要原因是供体不足,远远不能达到胰岛细胞移植所需胰岛的来源,供体来源的不足严重影响了胰岛细胞移植的发展,寻找胰岛细胞新来源成为全球糖尿病研究的热点之一[38-39]。 2.2 胰腺干细胞移植治疗糖尿病的实验研究进展 胰腺干细胞移植主要是针对胰岛细胞移植数量不足而进行的一种体外诱导扩增的方法,即将胰腺干细胞进行分离培养并传代,在体外多种细胞因子的诱导和抑制的作用下,快速增殖并具有多向分化潜能,同时能分化形成胰岛α和β细胞,再进行体内移植。具有多分化潜能、在合适的外源性刺激条件下可分化形成胰腺内外分泌组织的细胞称为胰腺干细胞,应用不同来源胰腺干细胞移植治疗糖尿病也已有很多相关研究。 以胚胎干细胞进行的研究,Soria等[40]研究发现在小鼠胚胎干细胞中诱导分化出胰岛β样细胞,并在糖尿病小鼠体内移植这种细胞,“治愈”小鼠糖尿病达1年以上。以胰腺导管干细胞进行的研究,宋振顺等[41]研究发现成人胰腺的导管上皮具有干细胞潜能,并可在体外转分化为大量具有内分泌功能的胰岛。用此方法获胰腺导管干细胞,将其转化分为胰岛细胞获得成功。以巢素蛋白阳性的胰岛前体细胞进行的研究,Zulewski等[42]发现在人及大鼠胰腺中确实有这种前体细胞存在,并且这种前体细胞还表达巢素蛋白,并可由巢素蛋白阳性的胰岛前体细胞诱导分化得到胰腺干细胞。以人体可增殖性胰岛细胞进行的研究,Macfarlane等[43]从来源于婴儿期持续高胰岛素低血糖患儿的新生期胰岛中分离到可增殖的胰岛素分泌细胞,这些细胞的胰岛素分泌可受葡萄糖诱导。以通过转分化得到胰岛素分泌细胞进行的研究,Ferber等[44]将含有胰十二指肠同源异型盒基因和巨细胞病毒启动子的重组腺病毒注入鼠尾静脉后,检测到胰十二指肠同源异型盒基因主要在肝脏表达,这表明一部分肝细胞在外源性基因的作用下可能发生转分化而表达胰岛素。 2.3 影响胰岛细胞移植治疗糖尿病的相关因素分析 2.3.1 移植部位 制约胰岛细胞移植治疗糖尿病广泛应用的因素,除胰岛细胞供体不足和难以解决的排斥反应外,缺乏理想的移植部位也是影响胰岛细胞移植的重要因素。理想的胰岛细胞移植部位应安全、方便、血供丰富、植入细胞易于成活并发挥功能、可逃逸免疫反应[45]。目前除了常用部位外,脑室或蛛网膜下腔及睾丸组织中缺乏免疫活性细胞,免疫反应微弱,通常认为是“免疫特惠部位”[46],是胰岛细胞移植的重要部位。国外也有将胰岛经背俞穴穴位注射进行胰岛移植的报道[47]。王奋明[48]进行了糖尿病大鼠不同部位胰岛细胞移植的实验研究,将糖尿病大鼠模型随机分为门静脉内移植组、胸腺内移植组、肾包膜下移植组,胰岛细胞移植后每日观察各组大鼠尿量及饮食活动情况,并从尾静脉采血测血糖。胰岛细胞移植前后血糖动态观察结果,见表1。"
[1] 唐雅望,尔秀江,张玉海.胰岛细胞及肾联合移植治疗胰岛素依赖型糖尿病合并尿毒症四例[J].中华器官移植杂志,2000,21 (3): 180-182.[2] 陈思娇,李铁民,雷阳峰,等.大鼠胰岛细胞的分离提纯及移植效果观察[J].中国组织工程研究与临床康复,2007,11(12): 2385- 2388.[3] 庞新路,薛武军,冯新顺,等.大鼠胰岛细胞分离纯化的实验研究[J].陕西医学杂志,2006,35(10):1238-1240.[4] 谢永红,潘晓燕,林霞,等.大鼠胰岛移植后血管重建和排斥反应的实验研究[J].浙江预防医学,2009,21(1):6-8.[5] 袁超,于立新,杜传福,等.免疫抑制剂对糖尿病小鼠胰岛细胞移植长期存活效果的研究[J].中国现代医药杂志,2006,8(8):1-4.[6] 刘全达,何振平,蔡志民.异种胰岛移植的免疫耐受诱导[J].免疫学杂志,2001,17(1):91-94.[7] 信照亮,贾延杰,胡海涛,等.犬脑内移植大鼠胰岛细胞的凋亡状况[J].第四军医大学学报,2002,23(24):2279-2281.[8] Robertson RP.Insights into alloislets from successful autoislet transplantation in patients with chronic pancreatitis.J Investig Med.2001;49(6):563-565.[9] 刘伟峰,章乐虹,胡以则.成人胰岛细胞同种移植进展[J].华夏医学,2003,16(3):429-431.[10] 赵国华,刘永锋,许国岩,等.小鼠同种异体胰岛移植排斥反应中可诱导共刺激分子的表达及阻断其对排斥反应的影响[J].中华实验外科杂志,2007,24(4):505. [11] 杨梅芳,李振甲,朱守荣,等.骨钙素RIA试剂盒研制及其临床应用[J].中华核医学杂志,1994,14(3):167-169.[12] 赵雪倩.B7-H4基因修饰的胰岛细胞对小鼠同种异体胰岛移植排斥反应的影响[D].上海:第二军医大学,2007:1-71. [13] Kenmochi T,Asano T,Jingu K,et al.IEffectiveness of hydroxyethyl starch (HES) on purification of pancreatic islets.J Surg Res.2003;111(1):16-22. [14] Zwillich T.Diabetes research. Islet transplants not yet ready for prime time.Science.2000;289(5479):531-533.[15] 叶斌,廖坚,聂唯,等.经肝动脉及经门静脉异种胰岛移植治疗1型糖尿病恒河猴[J].中国组织工程研究,2012,16(18):3285-3289.[16] 许世清,门秀丽,张文健,等.诱导干细胞分化的胰岛细胞形成胰岛样结构的实验研究[J].中国医药生物技术,2009,4(6):417-423.[17] 陈向锋,谭建明,董维平,等.免疫抑制药物对成人胰岛移植物毒性作用的体外研究[J].中华医学杂志,2005,5(18):1276-1279.[18] 岑妍慧,谢小薰,陈维平,等.体外诱导胰腺干细胞向胰岛样细胞团的分化[J].中国组织工程研究,2012,16(10):1799-1802.[19] 蔡寒青,葛焕琦,门秀丽,等.胰腺干细胞体外诱导分化为胰岛素分泌细胞及对1型糖尿病模型鼠的治疗作用[J].中国组织工程研究与临床康复,2008,12(29):5768-5772.[20] 葛焕琦,蔡寒青,门秀丽,等.胰腺干细胞诱导分化为胰岛素分泌细胞的实验研究[J].中国糖尿病杂志,2007,15(3):171-175.[21] 史光军,张磊,许评,等.胰腺干细胞诱导分化后同种移植治疗糖尿病的实验研究[J].中华胰腺病杂志,2011,11(1):48-51.[22] May R,Sureban SM,Lightfoot SA,et al.Identification of a novel putative pancreatic stem/progenitor cell marker DCAMKL-1 in normal mouse pancreas.Am J Physiol Gastrointest Liver Physiol.2010;299(2):303-310.[23] 张玲,洪天配,胡江,等.胎儿胰腺组织中巢蛋白阳性细胞的分离和体外增殖以及诱导分化[J].中国糖尿病杂志,2003,11(6): 416-420.[24] Declercq J,Kumar A,Van Diepen JA,et al.Increased beta-cell mass by islet transplantation and PLAG1 overexpression causes hyperinsulinemic normoglycemia and hepatic insulin resistance in mice.Diabetes.2010;59(8):1957-1965.[25] Chen TS,Tan SS,Yeo RW,et al.Delineating biological pathways unique to embryonic stem cell-derived insulin-producing cell lines from their noninsulin-producing progenitor cell lines.Endocrinology.2010;151(8):3600-3610.[26] Longoni B,Szilagyi E,Quaranta P,et al.Mesenchymal stem cells prevent acute rejection and prolong graft function in pancreatic islet transplantation.Diabetes Technol Ther.2010;12(6):435-446.[27] 中国知网.中国学术期刊总库[DB/OL].2012-08-10. [28] SCI数据库.Web of Sciencevia ISI Web of Knowledge [DB/OL]. 2012-08-10.[29] Merani S,Shapiro AM.Current status of pancreatic islet transplantation.Clin Sci (Lond).2006;110(6):611-625.[30] Shapiro AM,Lakey JR,Ryan EA,et al.Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.N Engl J Med.2000;343(4):230-238.[31] Ballinger WF,Lacy PE.Transplantation of intact pancreatic islets in rats.Surgery.1972;72(2):175-186.[32] Kemp CB,Knight MJ,Scharp DW,et al.Effect of transplantation site on the results of pancreatic islet isografts in diabetic rats.Diabetologia.1973;9(6):486-491.[33] Sutherland DE,Gores PF,Farney AC,et al.Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota.Am J Surg.1993;166(5): 456-491.[34] Largiadèr F,Kolb E,Binswanger U.A long-term functioning human pancreatic islet allotransplant.Transplantation. 1980; 29(1):76-77.[35] Scharp DW,Lacy PE,Santiago JV, et al.Insulin independence after islet transplantation into type I diabetic patient.Diabetes. 1990;39(4):515-518.[36] Shapiro AM,Lakey JR,Ryan EA,et al.Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.N Engl J Med.2000;343(4):230-238.[37] 谭建明.成人胰岛细胞移植治疗糖尿病的现状与发展[J].中国实用内科杂志,2007,27(7):537-541.[38] 宋涛,黄彬红.影响胰岛移植治疗糖尿病远期效果的因素[J].中国组织工程研究与临床康复,2008,12(31):6097-6100.[39] 崔岱,刘超.糖尿病胰岛移植及细胞治疗的细胞来源[J].国外医学(内分泌学分册),2004,24(1):36-38.[40] Soria B,Roche E,Berná G,et al.Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice.Diabetes. 2000;49(2): 157-162.[41] 宋振顺,顾克菊.成人胰腺干细胞转分化为胰岛细胞过程中的形态学观察[J].外科理论与实践,2002,7(3):196-200.[42] Zulewski H,Abraham EJ,Gerlach MJ,et al.Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes.Diabetes.2001;50(3):521-533.[43] Macfarlane WM,Cragg H,Docherty HM,et al.Impaired expression of transcription factor IUF1 in a pancreatic beta-cell line derived from a patient with persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis).FEBS Lett.1997;413(2):304-308.[44] Ferber S,Halkin A,Cohen H,et al.Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia.Nat Med.2000;6(5):568-572.[45] 李富荣,龙爱梅,齐晖,等.胰岛干细胞转分化胰岛样细胞与天然胰岛功能的比较[J].中国组织工程研究与临床康复,2008, 12(25): 4833-4836.[46] Bonner-Weir S,Taneja M,Weir GC,et al.In vitro cultivation of human islets from expanded ductal tissue.Proc Natl Acad Sci U S A.2000;97(14):7999-8004.[47] 谌剑飞,何兴伟.Ⅱ型重度糖尿病穴位内胰岛移植临床疗效观察[J].中国针灸,1999,19(11):647-650.[48] 王奋明.糖尿病大鼠不同部位胰岛细胞同种移植的实验研究[D].内蒙古:内蒙古医学院,2009:1-27.[49] Yolcu ES,Askenasy N,Singh NP,et al.Cell membrane modification for rapid display of proteins as a novel means of immunomodulation: FasL-decorated cells prevent islet graft rejection.Immunity.2002;17(6):795-808.[50] Kessler L,Passemard R,Oberholzer J,et al.Reduction of blood glucose variability in type 1 diabetic patients treated by pancreatic islet transplantation: interest of continuous glucose monitoring.Diabetes Care.2002;25(12):2256-2262.[51] Cerf ME.Transcription factors regulating beta-cell function.Eur J Endocrinol.2006;155(5):671-679.[52] Hunziker E,Stein M.Nestin-expressing cells in the pancreatic islets of Langerhans.Biochem Biophys Res Commun.2000; 271(1):116-119.[53] Gmyr V,Kerr-Conte J,Belaich S,et al.Adult human cytokeratin 19-positive cells reexpress insulin promoter factor 1 in vitro: further evidence for pluripotent pancreatic stem cells in humans. Diabetes.2000;49(10):1671-1680.[54] 金世龙,顾红光,王亚旭,等.CTLA4Ig基因对大鼠胰岛移植后排斥反应的治疗作用[J].中华器官移植杂志,2000,21(4):204-206.[55] 刘涛,范骥,王春友.转录因子PDX-1在猪胰干细胞体外诱导分化过程中的表达及意义[J].胰腺病学,2003,3(1):11-13.[56] 赵国华,张佳林,许国岩,等.阻断ICOS对小鼠移植胰岛功能影响的实验研究[J].中国医科大学学报,2006,35(6):591-593.[57] Dutta S,Gannon M,Peers B,PDX:PBX complexes are required for normal proliferation of pancreatic cells during development.Proc Natl Acad Sci U S A.2001;98(3): 1065-1070.[58] 伍丽,刘建,马蓉,等.妊娠期糖尿病患者肌肉组织中胰岛素信号转导和GLUT-4表达的变化[J].第三军医大学学报,2011,33(12): 1269-1272.[59] 高静.EGF与Gastrin联合应用对糖尿病大鼠胰岛β细胞再生作用[D].吉林:吉林大学,2008:1-56.[60] 杨芬,杨乃龙.胰岛干细胞来源及诱导分化与分子标记物[J].中国组织工程研究与临床康复,2007,11(7):1333-1336.[61] Zhao M,Amiel SA,Christie MR,et al.Evidence for the presence of stem cell-like progenitor cells in human adult pancreas.J Endocrinol.2007;195(3):407-417.[62] 勾善淼.胰腺导管干细胞与骨髓间充质干细胞融合参与胰腺癌起源的实验研究[D].湖北:华中科技大学,2009:1-89.[63] Benhamou PY,Oberholzer J,Toso C,et al.Human islet transplantation network for the treatment of Type I diabetes: first data from the Swiss-French GRAGIL consortium (1999-2000). Groupe de Recherche Rhin Rh?ne Alpes Genève pour la transplantation d'Ilots de Langerhans. Diabetologia.2001;44(7):859-864.[64] Contreras JL,Bilbao G,Smyth C,et al.Gene transfer of the Bcl-2 gene confers cytoprotection to isolated adult porcine pancreatic islets exposed to xenoreactive antibodies and complement.Surgery.2001;130(2):166-174.[65] Jörns A,Klempnauer J,Tiedge M,et al.Recovery of pancreatic beta cells in response to long-term normoglycemia after pancreas or islet transplantation in severely streptozotocin diabetic adult rats.Pancreas.2001;23(2):186-196.[66] Bennet W,Björkland A,Sundberg B,et al.Expression of complement regulatory proteins on islets of Langerhans: a comparison between human islets and islets isolated from normal and hDAF transgenic pigs.Transplantation. 2001; 72(2):312-319. |
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