诱导脐带间充质干细胞分化为胰岛素分泌细胞的方法探讨
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摘要
β细胞功能受损会引发1型糖尿病和部分2型糖尿病,因此,向患者体内移植正常的β细胞是一种理想的治疗方法,但供体的严重紧缺限制了它的应用,研究者们试图用胰岛素分泌细胞(insulin producing cells,IPCs)来替代β细胞用于细胞移植治疗。脐带间充质干细胞(umbilical cord mesenchymal stem cells,UCMSCs)是一种多能干细胞,能够被诱导分化为IPCs,进而可以用于细胞移植治疗。该文综述了诱导UCMSCs分化为IPCs的主要方法(多步诱导法、基因工程法和共培养法),探讨了各方法存在的问题及改进方向,以期为这些方法的进一步完善提供有益信息。
Dysfunction of pancreatic β cell can cause type 1 diabetes and part of type 2 diabetes. Transplantation of functional pancreatic β cell is an ideal therapy for diabetics. However, the serious shortage of donors restricted the clinical application of this therapy. At present, insulin producing cells(IPCs) have been used in the transplantation treatment for years instead pancreatic β cell. Umbilical cord mesenchymal stem cells(UCMSCs) are a pluripotent stem cells which can be induced into IPCs. Here, we reviewed the major induction methods of differentiate UCMSCs into IPCs, including multi-step induction method, genetic engineering method and co-culture method, and then tried to provide more information for futher improvement by comparing these methods.
Dysfunction of pancreatic β cell can cause type 1 diabetes and part of type 2 diabetes. Transplantation of functional pancreatic β cell is an ideal therapy for diabetics. However, the serious shortage of donors restricted the clinical application of this therapy. At present, insulin producing cells(IPCs) have been used in the transplantation treatment for years instead pancreatic β cell. Umbilical cord mesenchymal stem cells(UCMSCs) are a pluripotent stem cells which can be induced into IPCs. Here, we reviewed the major induction methods of differentiate UCMSCs into IPCs, including multi-step induction method, genetic engineering method and co-culture method, and then tried to provide more information for futher improvement by comparing these methods.
引文
1康继宏,宁光,吴家睿,管又飞.中国糖尿病防治研究的现状和挑战.转化医学研究(电子版)[Kang Jihong,Ning Guang,Wu Jiarui,Guan Youfei.Diabetes research in China:Current status and future challenges.Translational Medicine Research(Electronic Edition)]2012;2(3):1-24.
2 Russ HA,Efrat S.Development of human insulin-producing cells for cell therapy of diabetes.Pediatr Endocrinol Rev 2011;9(2):590-7.
3 Calafiore R,Montanucci P,Basta G.Stem cells for pancreaticβ-cell replacement in diabetes mellitus:Actual perspectives.Curr Opin Organ Transplant 2014;19(2):162-8.
4 Gioviale MC,Bellavia M,Damiano G,Lo Monte AI.Beyond islet transplantation in diabetes cell therapy:From embryonic stem cells to transdifferentiation of adult cells.Transplant Proc2013;45(5):2019-24.
5 Gabr MM,Zakaria MM,Refaie AF,Ismail AM,Abou-ElMahasen MA,Ashamallah SA,et al.Insulin-producing cells from adult human bone marrow mesenchymal stem cells control streptozotocin-induced diabetes in nude mice.Cell Transplant2013;22(1):133-45.
6 Rezania A,Bruin JE,Arora P,Rubin A,Batushansky I,Asadi A,et al.Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells.Nat Biotechnol 2014;32(11):1121-33.
7 Fu YS,Cheng YC,Lin MYA,Cheng H,Chu PM,Chou SC,et al.Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro:Potential therapeutic application for Parkinsonism.Stem Cells 2006;24(1):115-24.
8 Weiss ML,Medicetty S,Bledsoe AR,Rachakatla RS,Choi M,Merchav S,et al.Human umbilical cord matrix stem cells:Preliminary characterization and effect of transplantation in a rodent model of Parkinson’s disease.Stem Cells 2006;24(3):781-92.
9 Smith JR,Pfeifer K,Petry F,Powell N,Delzeit J,Weiss ML.Standardizing umbilical cord mesenchymal stromal cells for translation to clinical use:Selection of GMP-compliant medium and a simplified isolation method.Stem Cells Int 2016;2016:1-14.
10 Wang L,Ott L,Seshareddy K,Weiss ML,Detamore MS.Musculoskeletal tissue engineering with human umbilical cord mesenchymal stromal cells.Regen Med 2011;6(1):95-109.
11 Kim DW,Staples M,Shinozuka K,Pantcheva P,Kang SD,Borlongan CV.Wharton’s jelly-derived mesenchymal stem cells:Phenotypic characterization and optimizing their therapeutic potential for clinical applications.Int J Mol Sci 2013;14(6):11692-712.
12 Cai H,Wu LL,Sun XC,Zhu W,Qian H,Hu JB,et al.Effects of puerarin on proliferation and differentiation of umbilical cord mesenchymal stem cells into osteoblasts in vitro.Acta Pharm Sin B 2011;46(6):738-41.
13 Li N,Pan S,Zhu H,Mu H,Liu W,Hua J.BMP4 promotes SSEA-1+h UC-MSC differentiation into male germ-like cells in vitro.Cell Prolif 2014;47(4):299-309.
14 Xue G,Han X,Ma X,Wu H,Qin Y,Liu J,et al.Effect of microenvironment on differentiation of human umbilical cord mesenchymal stem cells into hepatocytes in vitro and in vivo.Biomed Res Int 2016;2016(5):1-13.
15 Chen S,Zhang W,Wang JM,Duan HT,Kong JH,Wang YX,et al.Differentiation of isolated human umbilical cord mesenchymal stem cells into neural stem cells.Int J Ophthalmol 2016;9(1):41-7.
16 Jiang L,Wang Y,Pan F,Zhao X,Zhang H,Lei M,et al.Synergistic effect of bioactive lipid and condition medium on cardiac differentiation of human mesenchymal stem cells from different tissues.Cell Biochem Funct 2016;34(3):163-72.
17 Chen Y,Yu Y,Chen L,Ye L,Cui J,Sun Q,et al.Human umbilical cord mesenchymal stem cells:A new therapeutic option for tooth regeneration.Stem Cells Int 2015;2015:1-11.
18 Yuan H,Liu L,Zheng S,Liu Z,Yang L,Pu C,et al.Experimental study of differentiation of umbilical cord mesenchymal stem cells into smooth muscle cells induced by bladder smooth muscle cells conditioned medium.Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2013;27(12):1506-11.
19 Slack JM.Developmental biology of the pancreas.Development1995;121(6):1569-80.
20 Kaneto H,Miyatsuka T,Nakatani Y,Matsuoka TA.PDX-1 and Maf A:Key transcription factors in pancreas.Am J Biochem Biotechnol 2005;1(2):54-63.
21陈桃,王云帅,谷乐辉,周淑艳,叶剑,简优强,等.胰岛新生相关蛋白肽在促进脐带间充质干细胞分化为胰岛素分泌细胞中的作用.细胞与分子免疫学杂志(Chen Tao,Wang Yunshuai,Gu Lehui,Zhou Shuyan,Ye Jian,Jian Youqiang.Role of INGAP-pp in the differentiation of h UCMSCs into insulin producing cells.Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi)2013;29(2):141-5.
22 Kim SJ,Choi YS,Ko ES,Lim SM,Lee CW,Kim DI.Glucosestimulated insulin secretion of various mesenchymal stem cells after insulin-producing cell differentiation.J Biosci Bioeng 2012;113(6):771-7.
23 Limbert C,P?th G,Ebert R,Rothhammer V,Kassem M,Jakob F,et al.PDX1and NGN3mediated in vitro reprogramming of human bone marrow-derived mesenchymal stromal cells into pancreatic endocrine lineages.Cytotherapy 2011;13(7):802-13.
24 Chao KC,Chao KF,Fu YS,Liu SH.Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes.PLo S One 2008;3(1):e1451.
25陈燕,汪珊珊,刘尚全,陈明卫,王佑民.体外诱导人脐带间充质干细胞向胰岛素分泌细胞分化.安徽医药(Chen Yan,Wang Shanshan,Liu Shangquan,Chen Mingwei,Wang Youmin.Inducing the differentiation of human umbilical cord mesenchymal stem cells into insulin secreting cells in vitro.Anhui Medical and Pharmaceutical Journal)2014;18(1):63-6.
26 Tsai PJ,Wang HS,Shyr YM,Weng ZC,Tai LC,Shyu JF,et al.Transplantation of insulin-producing cells from umbilical cord mesenchymal stem cells for the treatment of streptozotocininduced diabetic rats.J Biomed Sci 2012;19(1):47.
27孔德晓.间充质干细胞及胰岛素分泌细胞治疗糖尿病的临床及应用基础研究(博士论文).山东大学(Kong Dexiao.Study on mesenchymal stern cell and insulin producing cell therapy for diabetes mellitus.Shandong University)2015.
28 Sánchez L,Gutierrez A I,Ligero G,Martín M,Ayllón V,Real PJ,et al.Maintenance of human embryonic stem cells in media conditioned by human mesenchymal stem cells obviates the requirement of exogenous basic fibroblast growth factor supplementation.Tissue Eng Part C Methods 2012;18(5):387-96.
29 Lin W,Anna O,Zhen H,Leif J,Hongfen C,Xin G,et al.GLP-1,exendin-4 and C-peptide regulate pancreatic islet microcirculation,insulin secretion and glucose tolerance in rats.Clin Sci 2011;122(8):375-84.
30 Malm-Erjef?lt M,Bj?rnsdotti I,Vanggaar J,Helleberg H,Larsen U,Oosterhuis B,et al.Metabolism and excretion of the oncedaily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase.Drug Metab Dispos 2010;38(11):1944-53.
31 Yu YB,Bian JM,Gu DH.Transplantation of insulin-producing cells to treat diabetic rats after 90%pancreatectomy.World JGastroenterol 2015;21(21):6582.
32 Wang HW,Lin LM,He HY,You F,Li WZ,Huang TH,et al.Human umbilical cord mesenchymal stem cells derived from Wharton’s jelly differentiate into insulin-producing cells in vitro.Chin Med J 2011;124(10):1534.
33马桂霞,何红燕,罗敏洁,黄天华,肖升平,崔冰琳,等.人脐带间充质干细胞分化为胰岛β细胞的实验研究.中华实用儿科临床杂志(Ma Guixia,He Hongyan,Luo Minjie,Huang Tianhua,Xiao Shengping,Cui Binglin,et al.Experimental research on human umbilical cord whartons jelly-derived mesenchymal stem cells differentiate into insulin producing cells in vitro.Chinese Journal of Applied Clinical Pediatrics)2008;23(8):618-20.
34 Nekoei SM,Azarpira N,Sadeghi L,Kamalifar S.In vitro differentiation of human umbilical cord Wharton’s jelly mesenchymal stromal cells to insulin producing clusters.World JClin Cases 2015;3(7):640.
35 Woltjen K,Michael IP,Mohseni P,Desai R,Mileikovsky M,H?m?l?inen R,et al.Piggy Bac transposition reprograms fibroblasts to induced pluripotent stem cells.Nature 2009;458(7239):766-70.
36 Qu H,Liu X,Ni Y,Jiang Y,Feng X,Xiao J,et al.Laminin 411acts as a potent inducer of umbilical cord mesenchymal stem cell differentiation into insulin-producing cells.J Transl Med 2014;12(1):1.
37 Bouchea C,Lopeza X,Fleischmana A,Aaron MC,Sheila OS,Darko S,et al.Insulin enhances glucose-stimulated insulin secretion in healthy humans.Proc Natl Acad Sci USA 2010;107(10):4770-5.
38 Ryang HL,Min JS,Roxanne LR,Jeffrey LS,Andrey AP,Scott DO,et al.Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice.Proc Natl Acad Sci USA 2006;103(46):17438-43.
39柴树宏,鲍艳春.人脐带间充质干细胞向胰岛素分泌细胞分化的研究.实用医学杂志(Cai Shuhong,Bao Yanchun.Differentiation of human umbilical cord mesenchymal stem cells into insulin secreting cells.The Journal of Practical Medicine)2014;30(23):3752-4.
40 He D,Wang J,Gao Y,Zhang Y.Differentiation of PDX1 genemodified human umbilical cord mesenchymal stem cells into insulin-producing cells in vitro.Int J Mol Med 2011;28(6):1019.
41王爱红,何红燕,罗敏洁,黄天华,马廉,马桂霞,等.人脐带间充质干细胞向胰岛样细胞的分化.中国组织工程研究与临床康复(Wang Aihong,He Hongyan,Luo Minjie,Huang Tianhua,Ma Lian,Ma Guixia,et al.Differentiation of human umbilical cord mesenchymal stem cells into islet-like cells.Journal of Clinical Rehabilitative Tissue Engineering Research)2008;12(21):4102-6.
42朱旅云,赵芳,郝永蕾,李晓玲,孙蕾蕾.人脐带间充质干细胞向胰岛样分泌细胞的诱导分化及胰岛样分泌细胞治疗效果评价.临床误诊误治(Zhu Lvyun,Zhao Fang,Hao Yonglei,Li Xiaoling,Sun Leilei.Differentiation of islet like cells from the umbilical cord mesenchymal stem cells in vitro and its function evaluation.Clinical Misdiagnosis&Mistherapy)2015;28(8):91-5.
43 Zhou Y,Hu Q,Chen F,Zhang J,Guo J,Wang H,et al.Human umbilical cord matrix-derived stem cells exert trophic effects onβ-cell survival in diabetic rats and isolated islets.Dis Model Mech 2015;8(12):1625-33.
44 Kunisada Y,Tsubooka YN,Shoji M,Hosoya M.Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells.Stem Cell Res 2012;8(2):274-84.
45 Seyedi F,Farsinejad A,Eslaminejad T.Suspension culture alters insulin secretion in induced human umbilical cord matrix-derived mesenchymal cells.Cell J 2016;18(1):52-61.
46 Bai C,Li X,Gao Y,Wang K,Fan Y,Zhang S,et al.Role of micro RNA-21 in the formation of insulin-producing cells from pancreatic progenitor cells.Biochim Biophys Acta 2016;1859(2):280-93.
2 Russ HA,Efrat S.Development of human insulin-producing cells for cell therapy of diabetes.Pediatr Endocrinol Rev 2011;9(2):590-7.
3 Calafiore R,Montanucci P,Basta G.Stem cells for pancreaticβ-cell replacement in diabetes mellitus:Actual perspectives.Curr Opin Organ Transplant 2014;19(2):162-8.
4 Gioviale MC,Bellavia M,Damiano G,Lo Monte AI.Beyond islet transplantation in diabetes cell therapy:From embryonic stem cells to transdifferentiation of adult cells.Transplant Proc2013;45(5):2019-24.
5 Gabr MM,Zakaria MM,Refaie AF,Ismail AM,Abou-ElMahasen MA,Ashamallah SA,et al.Insulin-producing cells from adult human bone marrow mesenchymal stem cells control streptozotocin-induced diabetes in nude mice.Cell Transplant2013;22(1):133-45.
6 Rezania A,Bruin JE,Arora P,Rubin A,Batushansky I,Asadi A,et al.Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells.Nat Biotechnol 2014;32(11):1121-33.
7 Fu YS,Cheng YC,Lin MYA,Cheng H,Chu PM,Chou SC,et al.Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro:Potential therapeutic application for Parkinsonism.Stem Cells 2006;24(1):115-24.
8 Weiss ML,Medicetty S,Bledsoe AR,Rachakatla RS,Choi M,Merchav S,et al.Human umbilical cord matrix stem cells:Preliminary characterization and effect of transplantation in a rodent model of Parkinson’s disease.Stem Cells 2006;24(3):781-92.
9 Smith JR,Pfeifer K,Petry F,Powell N,Delzeit J,Weiss ML.Standardizing umbilical cord mesenchymal stromal cells for translation to clinical use:Selection of GMP-compliant medium and a simplified isolation method.Stem Cells Int 2016;2016:1-14.
10 Wang L,Ott L,Seshareddy K,Weiss ML,Detamore MS.Musculoskeletal tissue engineering with human umbilical cord mesenchymal stromal cells.Regen Med 2011;6(1):95-109.
11 Kim DW,Staples M,Shinozuka K,Pantcheva P,Kang SD,Borlongan CV.Wharton’s jelly-derived mesenchymal stem cells:Phenotypic characterization and optimizing their therapeutic potential for clinical applications.Int J Mol Sci 2013;14(6):11692-712.
12 Cai H,Wu LL,Sun XC,Zhu W,Qian H,Hu JB,et al.Effects of puerarin on proliferation and differentiation of umbilical cord mesenchymal stem cells into osteoblasts in vitro.Acta Pharm Sin B 2011;46(6):738-41.
13 Li N,Pan S,Zhu H,Mu H,Liu W,Hua J.BMP4 promotes SSEA-1+h UC-MSC differentiation into male germ-like cells in vitro.Cell Prolif 2014;47(4):299-309.
14 Xue G,Han X,Ma X,Wu H,Qin Y,Liu J,et al.Effect of microenvironment on differentiation of human umbilical cord mesenchymal stem cells into hepatocytes in vitro and in vivo.Biomed Res Int 2016;2016(5):1-13.
15 Chen S,Zhang W,Wang JM,Duan HT,Kong JH,Wang YX,et al.Differentiation of isolated human umbilical cord mesenchymal stem cells into neural stem cells.Int J Ophthalmol 2016;9(1):41-7.
16 Jiang L,Wang Y,Pan F,Zhao X,Zhang H,Lei M,et al.Synergistic effect of bioactive lipid and condition medium on cardiac differentiation of human mesenchymal stem cells from different tissues.Cell Biochem Funct 2016;34(3):163-72.
17 Chen Y,Yu Y,Chen L,Ye L,Cui J,Sun Q,et al.Human umbilical cord mesenchymal stem cells:A new therapeutic option for tooth regeneration.Stem Cells Int 2015;2015:1-11.
18 Yuan H,Liu L,Zheng S,Liu Z,Yang L,Pu C,et al.Experimental study of differentiation of umbilical cord mesenchymal stem cells into smooth muscle cells induced by bladder smooth muscle cells conditioned medium.Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2013;27(12):1506-11.
19 Slack JM.Developmental biology of the pancreas.Development1995;121(6):1569-80.
20 Kaneto H,Miyatsuka T,Nakatani Y,Matsuoka TA.PDX-1 and Maf A:Key transcription factors in pancreas.Am J Biochem Biotechnol 2005;1(2):54-63.
21陈桃,王云帅,谷乐辉,周淑艳,叶剑,简优强,等.胰岛新生相关蛋白肽在促进脐带间充质干细胞分化为胰岛素分泌细胞中的作用.细胞与分子免疫学杂志(Chen Tao,Wang Yunshuai,Gu Lehui,Zhou Shuyan,Ye Jian,Jian Youqiang.Role of INGAP-pp in the differentiation of h UCMSCs into insulin producing cells.Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi)2013;29(2):141-5.
22 Kim SJ,Choi YS,Ko ES,Lim SM,Lee CW,Kim DI.Glucosestimulated insulin secretion of various mesenchymal stem cells after insulin-producing cell differentiation.J Biosci Bioeng 2012;113(6):771-7.
23 Limbert C,P?th G,Ebert R,Rothhammer V,Kassem M,Jakob F,et al.PDX1and NGN3mediated in vitro reprogramming of human bone marrow-derived mesenchymal stromal cells into pancreatic endocrine lineages.Cytotherapy 2011;13(7):802-13.
24 Chao KC,Chao KF,Fu YS,Liu SH.Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes.PLo S One 2008;3(1):e1451.
25陈燕,汪珊珊,刘尚全,陈明卫,王佑民.体外诱导人脐带间充质干细胞向胰岛素分泌细胞分化.安徽医药(Chen Yan,Wang Shanshan,Liu Shangquan,Chen Mingwei,Wang Youmin.Inducing the differentiation of human umbilical cord mesenchymal stem cells into insulin secreting cells in vitro.Anhui Medical and Pharmaceutical Journal)2014;18(1):63-6.
26 Tsai PJ,Wang HS,Shyr YM,Weng ZC,Tai LC,Shyu JF,et al.Transplantation of insulin-producing cells from umbilical cord mesenchymal stem cells for the treatment of streptozotocininduced diabetic rats.J Biomed Sci 2012;19(1):47.
27孔德晓.间充质干细胞及胰岛素分泌细胞治疗糖尿病的临床及应用基础研究(博士论文).山东大学(Kong Dexiao.Study on mesenchymal stern cell and insulin producing cell therapy for diabetes mellitus.Shandong University)2015.
28 Sánchez L,Gutierrez A I,Ligero G,Martín M,Ayllón V,Real PJ,et al.Maintenance of human embryonic stem cells in media conditioned by human mesenchymal stem cells obviates the requirement of exogenous basic fibroblast growth factor supplementation.Tissue Eng Part C Methods 2012;18(5):387-96.
29 Lin W,Anna O,Zhen H,Leif J,Hongfen C,Xin G,et al.GLP-1,exendin-4 and C-peptide regulate pancreatic islet microcirculation,insulin secretion and glucose tolerance in rats.Clin Sci 2011;122(8):375-84.
30 Malm-Erjef?lt M,Bj?rnsdotti I,Vanggaar J,Helleberg H,Larsen U,Oosterhuis B,et al.Metabolism and excretion of the oncedaily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase.Drug Metab Dispos 2010;38(11):1944-53.
31 Yu YB,Bian JM,Gu DH.Transplantation of insulin-producing cells to treat diabetic rats after 90%pancreatectomy.World JGastroenterol 2015;21(21):6582.
32 Wang HW,Lin LM,He HY,You F,Li WZ,Huang TH,et al.Human umbilical cord mesenchymal stem cells derived from Wharton’s jelly differentiate into insulin-producing cells in vitro.Chin Med J 2011;124(10):1534.
33马桂霞,何红燕,罗敏洁,黄天华,肖升平,崔冰琳,等.人脐带间充质干细胞分化为胰岛β细胞的实验研究.中华实用儿科临床杂志(Ma Guixia,He Hongyan,Luo Minjie,Huang Tianhua,Xiao Shengping,Cui Binglin,et al.Experimental research on human umbilical cord whartons jelly-derived mesenchymal stem cells differentiate into insulin producing cells in vitro.Chinese Journal of Applied Clinical Pediatrics)2008;23(8):618-20.
34 Nekoei SM,Azarpira N,Sadeghi L,Kamalifar S.In vitro differentiation of human umbilical cord Wharton’s jelly mesenchymal stromal cells to insulin producing clusters.World JClin Cases 2015;3(7):640.
35 Woltjen K,Michael IP,Mohseni P,Desai R,Mileikovsky M,H?m?l?inen R,et al.Piggy Bac transposition reprograms fibroblasts to induced pluripotent stem cells.Nature 2009;458(7239):766-70.
36 Qu H,Liu X,Ni Y,Jiang Y,Feng X,Xiao J,et al.Laminin 411acts as a potent inducer of umbilical cord mesenchymal stem cell differentiation into insulin-producing cells.J Transl Med 2014;12(1):1.
37 Bouchea C,Lopeza X,Fleischmana A,Aaron MC,Sheila OS,Darko S,et al.Insulin enhances glucose-stimulated insulin secretion in healthy humans.Proc Natl Acad Sci USA 2010;107(10):4770-5.
38 Ryang HL,Min JS,Roxanne LR,Jeffrey LS,Andrey AP,Scott DO,et al.Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice.Proc Natl Acad Sci USA 2006;103(46):17438-43.
39柴树宏,鲍艳春.人脐带间充质干细胞向胰岛素分泌细胞分化的研究.实用医学杂志(Cai Shuhong,Bao Yanchun.Differentiation of human umbilical cord mesenchymal stem cells into insulin secreting cells.The Journal of Practical Medicine)2014;30(23):3752-4.
40 He D,Wang J,Gao Y,Zhang Y.Differentiation of PDX1 genemodified human umbilical cord mesenchymal stem cells into insulin-producing cells in vitro.Int J Mol Med 2011;28(6):1019.
41王爱红,何红燕,罗敏洁,黄天华,马廉,马桂霞,等.人脐带间充质干细胞向胰岛样细胞的分化.中国组织工程研究与临床康复(Wang Aihong,He Hongyan,Luo Minjie,Huang Tianhua,Ma Lian,Ma Guixia,et al.Differentiation of human umbilical cord mesenchymal stem cells into islet-like cells.Journal of Clinical Rehabilitative Tissue Engineering Research)2008;12(21):4102-6.
42朱旅云,赵芳,郝永蕾,李晓玲,孙蕾蕾.人脐带间充质干细胞向胰岛样分泌细胞的诱导分化及胰岛样分泌细胞治疗效果评价.临床误诊误治(Zhu Lvyun,Zhao Fang,Hao Yonglei,Li Xiaoling,Sun Leilei.Differentiation of islet like cells from the umbilical cord mesenchymal stem cells in vitro and its function evaluation.Clinical Misdiagnosis&Mistherapy)2015;28(8):91-5.
43 Zhou Y,Hu Q,Chen F,Zhang J,Guo J,Wang H,et al.Human umbilical cord matrix-derived stem cells exert trophic effects onβ-cell survival in diabetic rats and isolated islets.Dis Model Mech 2015;8(12):1625-33.
44 Kunisada Y,Tsubooka YN,Shoji M,Hosoya M.Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells.Stem Cell Res 2012;8(2):274-84.
45 Seyedi F,Farsinejad A,Eslaminejad T.Suspension culture alters insulin secretion in induced human umbilical cord matrix-derived mesenchymal cells.Cell J 2016;18(1):52-61.
46 Bai C,Li X,Gao Y,Wang K,Fan Y,Zhang S,et al.Role of micro RNA-21 in the formation of insulin-producing cells from pancreatic progenitor cells.Biochim Biophys Acta 2016;1859(2):280-93.