人羊水来源干细胞的实验研究
|
摘要
糖尿病是由多种病因引起的以慢性高血糖为特征的代谢性疾病，严重危害着人类健康。目前胰岛素注射是临床上治疗糖尿病的主要方法，可以短期内控制血糖。不足之处是需要频繁监测血糖及胰岛素注射，而且不能阻止糖尿病所引起的肾衰、心脏病变、眼底病变、坏疽等并发症。近年来胰腺移植和胰岛细胞移植治疗糖尿病取得了很大进展，可有效改善患者内源性胰岛素的分泌，改善患者生活状态。胰岛移植最大的问题就是胰岛供体来源不足和终身使用免疫抑制剂。目前解决细胞移植供体不足最有可能的就是干细胞。利用干细胞体外诱导分化为胰岛素分泌细胞，不仅可以从根本上解决细胞来源问题，还可以克服免疫排斥问题。
羊水中存在着多潜能干细胞。人羊水干细胞易于获取，可以从产前诊断的少量羊水中提取；也可以从产后的羊水中分离。而且抽取羊水不会损害母体，也不会对胚胎造成影响，也就不存在伦理和道德上的问题。羊水中的细胞是一群处于胚胎发育早期的细胞群。从中分离的人羊水干细胞(amniotic fluid-derived stemcells, hAFS)细胞是介于胚胎干细胞(embryonic stem cells, ES)和成体干细胞之间的细胞类型，表达ES细胞和成体干细胞的标志，具有相似的多向分化潜能，可以分化为三个胚层的细胞。hAFS细胞体外比较容易培养，其增殖较快，动物体内移植不会形成畸胎瘤，成为干细胞研究的热点。
本实验从羊水中分离hAFS细胞，以hAFS细胞为研究对象。研究hAFS细胞的生物学特性，以及多向分化潜能，重点研究其分化为胰岛素分泌细胞的能力。建立及优化hAFS细胞诱导分化的实验方案，探讨诱导后细胞的功能和活性，为其临床应用提供依据。
1. hAFS细胞的分离培养和生物学特性
从羊水中分离获得hAFS细胞。通过流式细胞仪和免疫荧光测定，hAFS细胞具有ES细胞和间充质干细胞(mesenchymal stem cells, MSCs)的标志，同时也首次检测到SSEA-1在hAFS细胞中的表达。hAFS在体外可以大量扩增，具有较强的增殖能力。通过细胞周期和端粒酶测定，也证实细胞具有典型干细胞的特点。超微结构发现细胞表面大量的微绒毛，胞内富含丰富的细胞器，说明获得的hAFS细胞功能活跃，具有强蛋白合成的能力，维持自身的增殖和分化。
2. hAFS细胞的多向分化潜能
本实验对hAFS向脂肪细胞、成骨细胞和神经细胞三个方向进行诱导分化。通过油红O染色、茜素红染色、Von Kossa’s染色、RT-PCR和免疫组化等实验证实了hAFS细胞在体外特定诱导条件下可以分化为脂肪细胞、成骨细胞和神经细胞。
同时本实验也分析了hAFS细胞的致瘤性。将第3代，第5代，第8代细胞以5×10~6、1×10~7、2×10~7个细胞注射BALB/C裸鼠皮下，观察两个月，未发现肿瘤的形成。说明hAFS细胞动物体内移植不具有致瘤性，这也为临床应用提供可能。
3. hAFS细胞分化为胰岛素分泌细胞
本实验以胰腺体内发育为依据，诱导hAFS细胞分化为胰岛素分泌细胞。首先bFGF和尼克酰胺联合诱导hAFS细胞分化为胰腺祖细胞。通过检测，这些细胞表达胰腺前体细胞相关的转录因子，例如Pdx-1、Nng3、Pax4。之后加入EGF和exendin-4联合诱导胰腺祖细胞分化为胰岛素分泌细胞。EGF可以有效促进Pdx-1阳性的胰腺祖细胞增殖，exendin-4可促进细胞内分泌方向分化。这些胰岛素分泌细胞表达胰岛相关的转录因子，如Pdx-1、Nkx6.1等，同时表达胰岛功能相关的功能基因，如胰岛素、葡萄糖转运因子和葡萄糖激酶等。最后对这些胰岛素分泌细胞进行葡萄糖刺激试验，发现这些细胞对葡萄糖刺激敏感，根据葡萄糖浓度释放相应的胰岛素。
总之，本实验从羊水中分离得到一种新的hAFS细胞，hAFS细胞具有较强的增殖能力和多向分化潜能，体内移植不具有致瘤性。同时高效诱导hAFS细胞分化为胰岛素分泌细胞，这些细胞具有类似成人胰岛的功能和体内发育模式。这为糖尿病临床治疗提供重要的理论和实验基础。
Diabetes is a metabolic diseases which is characterized by chronic hyperglycemia,seriously threaten the human health. Insulin injection is currently the main method totreat diabetes mellitus in clinical, which can control the blood glucose level in theshort term. The disadvantage of this treatment is that it requires frequent bloodglucose monitoring and insulin injection. Most importantly, it cannot prevent thecomplications caused by diabetes such as kidney failure, heart disease, retinopathy,gangrene and so on. In recent years, pancreatic transplantation and islet celltransplantation have made great progresses in the treatment of diabetes. Thesemethods can effectively improve the secretion of endogenous insulin and improve thequality of patients’ life. Two of the most important limitations of islet transplantationare the insufficient source of islet donor and patients undergoing life-longimmunosuppression. At present, stem cell technology is one of the most possible ways tosolve the shortage of donor cells. Stem cells can be induced to differentiate intoinsulin-producing cells in vitro. This not only fundamentally solves the problem ofcell source, but also surmounts the problem of immunological rejection.
Amniotic fluid contains a lot of stem cells. Human amniotic fluid stem cells(hAFS) can be easily acquired from amniotic fluid which could be for prenataldiagnosis or from the postnatal amniotic fluid. Extracting amniotic fluid is notharmful for mother and has no impact on the embryo. So there are not ethical andmoral problems.
Amniotic fluid cells are a group of cells at the early stage of embryogenesis andhAFS cells can be isolated from them. They are a type of cells between embryonicstem cells (ES) and adult stem cells, which can express markers for both ES cell andadult stem cell. hAFS cells possess similar potentials to differentiate into cells of threegerm layers when properly induced. In recent years, hAFS cells become the focus ofstem cell research because they are easy to be cultured and proliferated rapidly, even more important, they do not cause teratomas when transplanted in animals.
In this study, hAFS cells were isolated from amniotic fluid. We studied theirbiological features and pluripotent differentiating potential. This research focuses onthe capability of hAFS cells differentiating into insulin secreting cells. We establishedand optimized the method of inducing hAFS cells into insulin-producing cells,discussed the function and activity of hAFS cell after differentiation. Therefore thisstudy provided important evidence for its clinical application.
1. Biological features of hAFS cells
hAFS cells were isolated from amniotic fluid, were determined by flow cytometerand immunocytochemistry. We find that hAFS cells possess markers for both ES andMSCs. For the first time, we observed that SSEA-1expressed in hAFS cells. hAFScells are very active and proliferate extensively in vitro. hAFS cells are confirmed tohave the typical characteristics of stem cells by cell cycle analysis and telomerasedetermination. Ultrastructure shows there are a large amount of microvilli on thesurface of hAFS cells and abundant intracellular organelles, which indicated thathAFS cells function actively and have strong capacity of synthesizing to maintaintheir proliferation and differentiation.
2. Differentiation potential of hAFS cells
In order to study the differentiation potential of hAFS cells, we tried to inducethem to differentiate into adipocytes, osteoblasts and neural cells. Using Oil-red Ostaining, Von Kossa’s staining, Alizarin red staining, RT-PCR andimmunohistochemistry, we proved that hAFS cells can differentiate into adipocytes,osteoblasts and nerve cell in vitro under specified conditions.
In addition, we analyzed the tumorigenicity of hAFS cell. Different densities ofP3, P5, P8cells were injected into immunodeficient Balb/c mice and no tumors wereformed after two month, which indicated that hAFS cells are not tumorigenic aftertransplanted into animals, and also provide possibility for its clinical application.
3. Differentiation of hAFS cells into insulin-producing cells
In this study, hAFS cells were induced to differentiate into insulin-producing cells according to pancreas growth in vivo. First, hAFs cells were induced todifferentiate into pancreatic progenitor cells with bFGF and nicotinamide. These cellsexpressed pancreatic precursor cells related transcription factors, such as Pdx-1, Ngn3and Pax4. After that we induce pancreatic progenitor cells into insulin secreting cellswith EGF and exendin-4. EGF is able to promote the proliferation of Pdx-1positivepancreatic progenitor cells and exendin-4can promote its differentiation towardendocrine fate. These insulin-producing cells expressed islet functions relatedtranscription factors, such as Pdx-1and Nkx6.1. Moreover, these cells are able toexpress islet function related functional genes such as insulin, Glut2and glucokinase.Finally, these insulin-producing cells were tested by glucose stimulated experiment.We find that these cells are sensitive to glucose stimulation and they are able torelease certain amount of insulin according to the corresponding glucoseconcentration.
In conclusion, we isolated a new kind of hAFS cells from amniotic fluid. hAFScells show strong ability to proliferate, pluripotent differentiation potential and notumorigenic after transplanting into animal. Moreover, hAFS cells can be efficientlyinduced to differentiate into insulin-producing cells which exhibit similardevelopmental mode and function with pancreatic islet of adult. This study willprovide important theoretical and experimental evidence for clinical treatment ofdiabetes.
羊水中存在着多潜能干细胞。人羊水干细胞易于获取，可以从产前诊断的少量羊水中提取；也可以从产后的羊水中分离。而且抽取羊水不会损害母体，也不会对胚胎造成影响，也就不存在伦理和道德上的问题。羊水中的细胞是一群处于胚胎发育早期的细胞群。从中分离的人羊水干细胞(amniotic fluid-derived stemcells, hAFS)细胞是介于胚胎干细胞(embryonic stem cells, ES)和成体干细胞之间的细胞类型，表达ES细胞和成体干细胞的标志，具有相似的多向分化潜能，可以分化为三个胚层的细胞。hAFS细胞体外比较容易培养，其增殖较快，动物体内移植不会形成畸胎瘤，成为干细胞研究的热点。
本实验从羊水中分离hAFS细胞，以hAFS细胞为研究对象。研究hAFS细胞的生物学特性，以及多向分化潜能，重点研究其分化为胰岛素分泌细胞的能力。建立及优化hAFS细胞诱导分化的实验方案，探讨诱导后细胞的功能和活性，为其临床应用提供依据。
1. hAFS细胞的分离培养和生物学特性
从羊水中分离获得hAFS细胞。通过流式细胞仪和免疫荧光测定，hAFS细胞具有ES细胞和间充质干细胞(mesenchymal stem cells, MSCs)的标志，同时也首次检测到SSEA-1在hAFS细胞中的表达。hAFS在体外可以大量扩增，具有较强的增殖能力。通过细胞周期和端粒酶测定，也证实细胞具有典型干细胞的特点。超微结构发现细胞表面大量的微绒毛，胞内富含丰富的细胞器，说明获得的hAFS细胞功能活跃，具有强蛋白合成的能力，维持自身的增殖和分化。
2. hAFS细胞的多向分化潜能
本实验对hAFS向脂肪细胞、成骨细胞和神经细胞三个方向进行诱导分化。通过油红O染色、茜素红染色、Von Kossa’s染色、RT-PCR和免疫组化等实验证实了hAFS细胞在体外特定诱导条件下可以分化为脂肪细胞、成骨细胞和神经细胞。
同时本实验也分析了hAFS细胞的致瘤性。将第3代，第5代，第8代细胞以5×10~6、1×10~7、2×10~7个细胞注射BALB/C裸鼠皮下，观察两个月，未发现肿瘤的形成。说明hAFS细胞动物体内移植不具有致瘤性，这也为临床应用提供可能。
3. hAFS细胞分化为胰岛素分泌细胞
本实验以胰腺体内发育为依据，诱导hAFS细胞分化为胰岛素分泌细胞。首先bFGF和尼克酰胺联合诱导hAFS细胞分化为胰腺祖细胞。通过检测，这些细胞表达胰腺前体细胞相关的转录因子，例如Pdx-1、Nng3、Pax4。之后加入EGF和exendin-4联合诱导胰腺祖细胞分化为胰岛素分泌细胞。EGF可以有效促进Pdx-1阳性的胰腺祖细胞增殖，exendin-4可促进细胞内分泌方向分化。这些胰岛素分泌细胞表达胰岛相关的转录因子，如Pdx-1、Nkx6.1等，同时表达胰岛功能相关的功能基因，如胰岛素、葡萄糖转运因子和葡萄糖激酶等。最后对这些胰岛素分泌细胞进行葡萄糖刺激试验，发现这些细胞对葡萄糖刺激敏感，根据葡萄糖浓度释放相应的胰岛素。
总之，本实验从羊水中分离得到一种新的hAFS细胞，hAFS细胞具有较强的增殖能力和多向分化潜能，体内移植不具有致瘤性。同时高效诱导hAFS细胞分化为胰岛素分泌细胞，这些细胞具有类似成人胰岛的功能和体内发育模式。这为糖尿病临床治疗提供重要的理论和实验基础。
Diabetes is a metabolic diseases which is characterized by chronic hyperglycemia,seriously threaten the human health. Insulin injection is currently the main method totreat diabetes mellitus in clinical, which can control the blood glucose level in theshort term. The disadvantage of this treatment is that it requires frequent bloodglucose monitoring and insulin injection. Most importantly, it cannot prevent thecomplications caused by diabetes such as kidney failure, heart disease, retinopathy,gangrene and so on. In recent years, pancreatic transplantation and islet celltransplantation have made great progresses in the treatment of diabetes. Thesemethods can effectively improve the secretion of endogenous insulin and improve thequality of patients’ life. Two of the most important limitations of islet transplantationare the insufficient source of islet donor and patients undergoing life-longimmunosuppression. At present, stem cell technology is one of the most possible ways tosolve the shortage of donor cells. Stem cells can be induced to differentiate intoinsulin-producing cells in vitro. This not only fundamentally solves the problem ofcell source, but also surmounts the problem of immunological rejection.
Amniotic fluid contains a lot of stem cells. Human amniotic fluid stem cells(hAFS) can be easily acquired from amniotic fluid which could be for prenataldiagnosis or from the postnatal amniotic fluid. Extracting amniotic fluid is notharmful for mother and has no impact on the embryo. So there are not ethical andmoral problems.
Amniotic fluid cells are a group of cells at the early stage of embryogenesis andhAFS cells can be isolated from them. They are a type of cells between embryonicstem cells (ES) and adult stem cells, which can express markers for both ES cell andadult stem cell. hAFS cells possess similar potentials to differentiate into cells of threegerm layers when properly induced. In recent years, hAFS cells become the focus ofstem cell research because they are easy to be cultured and proliferated rapidly, even more important, they do not cause teratomas when transplanted in animals.
In this study, hAFS cells were isolated from amniotic fluid. We studied theirbiological features and pluripotent differentiating potential. This research focuses onthe capability of hAFS cells differentiating into insulin secreting cells. We establishedand optimized the method of inducing hAFS cells into insulin-producing cells,discussed the function and activity of hAFS cell after differentiation. Therefore thisstudy provided important evidence for its clinical application.
1. Biological features of hAFS cells
hAFS cells were isolated from amniotic fluid, were determined by flow cytometerand immunocytochemistry. We find that hAFS cells possess markers for both ES andMSCs. For the first time, we observed that SSEA-1expressed in hAFS cells. hAFScells are very active and proliferate extensively in vitro. hAFS cells are confirmed tohave the typical characteristics of stem cells by cell cycle analysis and telomerasedetermination. Ultrastructure shows there are a large amount of microvilli on thesurface of hAFS cells and abundant intracellular organelles, which indicated thathAFS cells function actively and have strong capacity of synthesizing to maintaintheir proliferation and differentiation.
2. Differentiation potential of hAFS cells
In order to study the differentiation potential of hAFS cells, we tried to inducethem to differentiate into adipocytes, osteoblasts and neural cells. Using Oil-red Ostaining, Von Kossa’s staining, Alizarin red staining, RT-PCR andimmunohistochemistry, we proved that hAFS cells can differentiate into adipocytes,osteoblasts and nerve cell in vitro under specified conditions.
In addition, we analyzed the tumorigenicity of hAFS cell. Different densities ofP3, P5, P8cells were injected into immunodeficient Balb/c mice and no tumors wereformed after two month, which indicated that hAFS cells are not tumorigenic aftertransplanted into animals, and also provide possibility for its clinical application.
3. Differentiation of hAFS cells into insulin-producing cells
In this study, hAFS cells were induced to differentiate into insulin-producing cells according to pancreas growth in vivo. First, hAFs cells were induced todifferentiate into pancreatic progenitor cells with bFGF and nicotinamide. These cellsexpressed pancreatic precursor cells related transcription factors, such as Pdx-1, Ngn3and Pax4. After that we induce pancreatic progenitor cells into insulin secreting cellswith EGF and exendin-4. EGF is able to promote the proliferation of Pdx-1positivepancreatic progenitor cells and exendin-4can promote its differentiation towardendocrine fate. These insulin-producing cells expressed islet functions relatedtranscription factors, such as Pdx-1and Nkx6.1. Moreover, these cells are able toexpress islet function related functional genes such as insulin, Glut2and glucokinase.Finally, these insulin-producing cells were tested by glucose stimulated experiment.We find that these cells are sensitive to glucose stimulation and they are able torelease certain amount of insulin according to the corresponding glucoseconcentration.
In conclusion, we isolated a new kind of hAFS cells from amniotic fluid. hAFScells show strong ability to proliferate, pluripotent differentiation potential and notumorigenic after transplanting into animal. Moreover, hAFS cells can be efficientlyinduced to differentiate into insulin-producing cells which exhibit similardevelopmental mode and function with pancreatic islet of adult. This study willprovide important theoretical and experimental evidence for clinical treatment ofdiabetes.
引文
[1] Zhang D, Jiang W, Liu M, et al. Highly efficient differentiation of human ES cellsand iPS cells into mature pancreatic insulin-producing cells [J]. Cell Res,2009,19(4):429-438.
[2] Shim JH, Kim SE, Woo DH, et al. Directed differentiation of human embryonicstem cells towards a pancreatic cell fate [J]. Diabetologia,2007,50(6):1228-1238.
[3] Lumelsky N, Blondel O, Laeng P, et al. Differentiation of embryonic stem cells toinsulin-secreting structures similar to pancreatic islets [J]. Science,2001,292(5520):1389-1394.
[4] Hori Y, Rulifson IC, Tsai BC, et al. Growth inhibitors promote differentiation ofinsulin-producing tissue from embryonic stem cells [J]. Proc Natl Acad Sci USA,2002,99(25):16105-16110.
[5] Jiang J, Au M, Lu K, et al. Generation of insulin-producing islet-like clusters fromhuman embryonic stem cells [J]. Stem Cells,2007,25(8):1940-1953.
[6] Shi Y, Hou L, Tang F, et al. Inducing embryonic stem cells to differentiate intopancreatic cells by a novel three-step approach with activin A and all-trans retinoicacid[J]. Stem Cells,2005,23(5):656-662.
[7] Bonner-Weir S, Taneja M, Weir GC, et al. In vitro cultivation of human islets fromexpanded ductal tissue [J]. Proc Natl Acad Sci USA,2000,97(14):7999-8004.
[8] Kajiyama H, Hamazaki TS, Tokuhara M, et al. Pdx1-transfected adiposetissue-derived stem cells differentiate into insulin-producing cells in vivo andreduce hyperglycemia in diabetic mice [J]. Int J Dev Biol,2010,54(4):699-705.
[9] Sun Y, Chen L, Hou XG, et al. Differentiation of bone marrow-derivedmesenchymal stem cells from diabetic patients into insulin-producing cells in vitro[J]. Clin Med J,2007,120(9):771-776.
[10] Yuan H, Li J, Xin N, et al. Expression of Pdx1mediates differentiation frommesenchymal stem cells into insulin-producing cells[J]. Mol Biol Rep,2010,37(8):4023-4031.
[11] Hess D, Li L, Martin M. Bone marrow-derived stem cells initiate pancreaticregeneration [J]. Nat Biotechnol,2003,21(7):763-770.
[12] Perin L, Sedrakyan S, Da Sacco S,et al. Characterization of human amnioticfluid stem cells and their pluripotential capability [J]. Methods Cell Biol,2008,86:85-99.
[13] Bossolasco P, Montemurro T, Cova L, et al. Molecular and phenotypiccharacterization of human amniotic fluid cells and their differentiation potential[J]. Cell Res,2006,16(4):329-336.
[14] Kim J, Lee Y, Kim H, et al. Human amniotic fluid-derived stem cells havecharacteristics of multipotent stem cells [J]. Cell Prolif,2007,40(1):75-90.
[15] Pfeiffer S, McLaughlin D. In vitro differentiation of human amnioticfluid-derived cells: augmentation towards a neuronal dopaminergic phenotype [J].Cell Biol Int,2010,34(9):959-967.
[16] Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell linesderived from human blastocysts [J]. Science,1998,282(5391):1145-1147.
[17] Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells[J]. Cell,2008,134(5):877-886.
[18] Dimos JT, Rodolfa KT, Niakan KK, et al. Induced pluripotent stem cellsgenerated from patients with ALS can be differentiated into motor neurons [J].Science,2008,321(5893):1218-1221.
[19] Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms andapplications [J]. Genes Dev,2010,24(20):2239-2263.
[20] Zhu H, Lensch MW, Cahan P, et al. Investigating monogenic and complexdiseases with pluripotent stem cells [J]. Nat Rev Genet,2011,12(4):266-275.
[21] Kaviani A, Perry TE, Dzakovic A, et al. The amniotic fluid as a source of cellsfor fetal tissue engineering [J]. J Pediatr Surg,2001,36(11):1662-1665.
[22] Prusa AR, Marton E, Rosner M, et al.Oct-4-expressing cells in human amnioticfluid: a new source for stem cell research [J]? Hum Reprod,2003,18(7):1489-1493.
[23] Mosquera A, Fernández JL, Campos A, et al. Simultaneous decrease of telomerelength and telomerase activity with ageing of human amniotic fluid cells [J]. JMed Genet,1999,36(6):494-496.
[24] Tsai MS, Lee JL, Chang YJ, et al. Isolation of human multipotent mesenchymalstem cells from second-trimester amniotic fluid using a novel two-stage cultureprotocol [J]. Hum Reprod,2004,19(6):1450-1456.
[25] De Coppi P, Bartsch G Jr, Siddiqui MM, et al. Isolation of amniotic stem celllines with potential for therapy [J]. Nat Biotechnol,2007,25(1):100-106.
[26] Kaviani A, Guleserian K, Perry TE, et al. Fetal tissue engineering from amnioticfluid [J]. J Am Coll Surg,2003,196(4):592-597.
[27] Tsai MS, Hwang SM, Chen KD, et al. Functional network analysis of thetranscriptomes of mesenchymal stem cells derived from amniotic fluid, amnioticmembrane, cord blood, and bone marrow [J]. Stem Cells,2007,25(10):2511-2523.
[28] Schmidt D, Achermann J, Odermatt B, et al. Prenatally fabricated autologoushuman living heart valves based on amniotic fluid derived progenitor cells assingle cell source [J]. Circulation,2007,116(11Suppl): I64-70.
[29] Ditadi A, de Coppi P, Picone O, et al. Human and murine amniotic fluidc-Kit+Lin-cells display hematopoietic activity [J]. Blood,2009,113(17):3953-3960.
[30] Prusa AR, Hengstschlager M. Amniotic fluid cells and human stem cell research:a new connection [J]. Med Sci Monit,2002,8(11): RA253-257.
[31] Chambers I, Silva J, Colby D, et al. Nanog safeguards pluripotency and mediatesgermline development [J]. Nature,2007,450(7173):1230-1234.
[32] Zhang P, Baxter J, Vinod K, et al. Endothelial differentiation of amnioticfluid-derived stem cells: synergism of biochemical and shear force stimuli [J].Stem Cells Dev,2009,18(9):1299-1308.
[33] Sessarego N, Parodi A, Podestà M, et al. Multipotent mesenchymal stromal cellsfrom amniotic fluid: solid perspectives for clinical application [J].Haematologica,2008,93(3):339-346.
[34] Tsai MS, Hwang SM, Tsai YL, et al. Clonal amniotic fluid-derived stem cellsexpress characteristics of both mesenchymal and neural stem cells [J]. BiolReprod,2006,74(3):545-551.
[35] Prusa AR, Marton E, Rosner M, et al. Neurogenic cells in human amniotic fluid[J]. Am J Obstet Gynecol,2004,191(1):309-314.
[36] Kakishita K, Nakao N, Sakuragawa N, et al. Implantation of human amnioticepithelial cells prevents the degeneration of nigral dopamine neurons in rats with6-hydroxydopamine lesions [J]. Brain Res,2003,980(1):48-56.
[37] Yeh YC, Wei HJ, Lee WY, et al. Cellular cardiomyoplasty with human amnioticfluid stem cells: in vitro and in vivo studies [J]. Tissue Eng Part A,2010,16(6):1925-1936.
[38] Bollini S, Pozzobon M, Nobles M, et al. In vitro and in vivo cardiomyogenicdifferentiation of amniotic fluid stem cells [J]. Stem Cell Rev,2011,7(2):364-380.
[39] Bollini S, Cheung KK, Riegler J, et al. Amniotic fluid stem cells arecardioprotective following acute myocardial infarction [J]. Stem Cells Dev,2011,20(11):1985-1994.
[40] Delo DM, De Coppi P, Bartsch G Jr, et al. Amniotic fluid and placental stemcells [J]. Methods Enzymol,2006,419:426-438.
[41] Rota C, Imberti B, Pozzobon M, et al. Human amniotic fluid stem cellpreconditioning improves their regenerative potential [J]. Stem Cells Dev,2011Dec23.
[42] Perin L, Giuliani S, Jin D, et al. Renal differentiation of amniotic fluid stem cells[J]. Cell Prolif,2007,40(6):936-948.
[43] Li B, Wang S, Liu H, et al. Neuronal restrictive silencing factor silencing induceshuman amniotic fluid-derived stem cells differentiation into insulin-producingcells [J]. Stem Cells Dev,2011,20(7):1223-1231.
[44] Ghaderi S, Soheili ZS, Ahmadieh H, et al. Human amniotic fluid promotesretinal pigmented epithelial cells' trans-differentiation into rod photoreceptorsand retinal ganglion cells [J]. Stem Cells Dev,2011,20(9):1615-1625.
[45] Decembrini S, Cananzi M, Gualdoni S, et al. Comparative analysis of the retinalpotential of embryonic stem cells and amniotic fluid-derived stem cells [J]. StemCells Dev,2011,20(5):851-863.
[46] Rosner M, Dolznig H, Schipany K, et al. Human amniotic fluid stem cells as amodel for functional studies of genes involved in human genetic diseases oroncogenesis [J]. Oncotarget,2011,2(9):705-712.
[47] Parolini O, Alviano F, Bagnara GP, et al. Concise review: isolation andcharacterization of cells from human term placenta: outcome of the firstinternational Workshop on Placenta Derived Stem Cells [J]. Stem Cells,2008,26(2):300-311.
[48] Porada CD, Zanjani ED, Almeida-Porad G. Adult mesenchymal stem cells: apluripotent population with multiple applications [J]. Curr Stem Cell Res Ther,2006,1(3):365-369.
[49] Hotta Y. Ethical issues of the research on human embryonic stem cells [J]. J IntBioethique,2008,19(3):77-85.
[50] Wood A. Ethics and embryonic stem cell research [J]. Stem Cell Rev,2005,1(4):317-324.
[51] Wu SM, Hochedlinger K. Harnessing the potential of induced pluripotent stemcells for regenerative medicine [J]. Nat Cell Biol,2011,13(5):497-505.
[52] Mattis VB, Svendsen CN. Induced pluripotent stem cells: a new revolution forclinical neurology?[J] Lancet Neurol,2011,10(4):383-394.
[53] Stadtfeld M, Apostolou E, Akutsu H, et al. Aberrant silencing of imprinted geneson chromosome12qF1in mouse induced pluripotent stem cells [J]. Nature,2010,465(7295):175-181.
[54] Kim K, Doi A, Wen B, et al. Epigenetic memory in induced pluripotent stemcells [J]. Nature,2010,467(7313):285-290.
[55] Laurent LC, Ulitsky I, Slavin I, et al. Dynamic changes in the copy number ofpluripotency and cell proliferation genes in human ESCs and iPSCs duringreprogramming and time in culture [J]. Cell Stem Cell,2011,8(1):106-118.
[56] Gore A, Li Z, Fung HL, et al. Somatic coding mutations in human inducedpluripotent stem cells [J]. Nature,2011,471(7336):63-67.
[57] Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increasedbeta-cell apoptosis in humans with type2diabetes [J]. Diabetes,2003,52(1):102-110.
[58] Yoon KH, Ko SH, Cho JH, et al. Selective beta-cell loss and alpha-cellexpansion in patients with type2diabetes mellitus in Korea [J]. J ClinEndocrinol Metab,2003,88(5):2300-2308.
[59] Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patientswith type1diabetes mellitus using a glucocorticoid-free immunosuppressiveregimen [J]. N Engl J Med,2000,343(4):230-238.
[60] Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmontonprotocol for islet transplantation [J].N Engl J Med,2006,355(13):1318-1330.
[61] Ricordi C, Hering BJ, Shapiro AM，et al. Beta-cell transplantation for diabetestherapy [J]. Lancet,2008,372(9632):27-28.
[62] Groth CG, Korsgren O, Wennberg L, et al. Pig-to-human islet transplantation [J].Transplant Proc,1998,30(7):3809-3810.
[63] Zalzman M, Gupta S, Giri RK, et al. Reversal of hyperglycemia in mice by usinghuman expandable insulin-producing cells differentiated from fetal liverprogenitor cells[J]. Proc Natl Acad Sci USA,2003,100(12):7253-7258.
[64] Horb ME, Shen CN, Tosh D, et al. Experimental conversion of liver to pancreas[J]. Curr Biol,2003,13(2):105-115.
[65] Hogan A, Pileggi A, Ricordi C. Transplantation: current developments and futuredirections; the future of clinical islet transplantation as a cure for diabetes [J].Front Biosci,2008,13:1192-1205.
[66] Jiang W, Shi Y, Zhao D, et al. In vitro derivation of functional insulin-producingcells from human embryonic stem cells [J]. Cell Res,2007,17(4):333-344.
[67] Phillips BW, Hentze H, Rust WL,et al. Directed differentiation of humanembryonic stem cells into the pancreatic endocrine lineage [J]. Stem Cells Dev,2007,16(4):561-578.
[68] Ramiya VK, Lan MS, Wasserfall CH, et al. Immunization therapies in theprevention of diabetes [J]. J Autoimmun,1997,10(3):287-292.
[69] Assady S, Maor G, Amit M, et al. Insulin production by human embryonic stemcells [J]. Diabetes,2001,50(8):1691-1697.
[70] Blyszczuk P, Czyz J, Kania G, et al. Expression of Pax4in embryonic stem cellspromotes differentiation of nestin-positive progenitor and insulin-producing cells[J]. Proc Natl Acad Sci U S A,2003,100(3):998-1003.
[71] Taniguchi H, Yamato E, Tashiro F,et al. beta-cell neogenesis induced byadenovirus-mediated gene delivery of transcription factor pdx-1into mousepancreas [J]. Gene Ther,2003,10(1):15-23.
[72] Sakuraba H, Mizukami H, Yagihashi N, Reduced beta-cell mass and expressionof oxidative stress-related DNA damage in the islet of Japanese Type II diabeticpatients [J]. Diabetologia,2002,45(1):85-96.
[73] Brissova M, Fowler MJ, Nicholson WE, et al. Assessment of human pancreaticislet architecture and composition by laser scanning confocal microscopy [J]. JHistochem Cytochem,2005,53(9):1087-1097.
[74] Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics [J]. Nat RevCancer,2002,2(12):897-909.
[75] Oliver-Krasinski JM, Stoffers DA. On the origin of the beta cell [J]. Genes Dev,2008,22(15):1998-2021.
[76] Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containingtransactivator of the insulin gene [J]. EMBO J,1993,12(11):4251-4259.
[77] Stoffers DA, Heller RS, Miller CP, et al. Developmental expression of thehomeodomain protein IDX-1in mice transgenic for an IDX-1promoter/lacZtranscriptional reporter [J]. Endocrinology,1999,140(11):5374-5381.
[78] Jacquemin P, Yoshitomi H, Kashima Y, et al. An endothelial-mesenchymal relaypathway regulates early phases of pancreas development [J]. Dev Biol,2006,290(1):189-199.
[79] Yoshitomi H, Zaret KS.Endothelial cell interactions initiate dorsal pancreasdevelopment by selectively inducing the transcription factor Ptf1a [J].Development,2004,131(4):807-817.
[80] Wiebe PO, Kormish JD, Roper VT, et al. Ptf1a binds to and activates area III, ahighly conserved region of the Pdx1promoter that mediates early pancreas-widePdx1expression [J]. Mol Cell Biol,2007,27(11):4093-4104.
[81] Kawahira H, Scheel DW, Smith SB, et al. Hedgehog signaling regulatesexpansion of pancreatic epithelial cells [J]. Dev Biol,2005,280(1):111-121.
[82] Hebrok M, Kim SK, St Jacques B, et al. Regulation of pancreas development byhedgehog signaling [J]. Development,2000,127(22):4905-4913.
[83] Deutsch G, Jung J, Zheng M, et al. A bipotential precursor population forpancreas and liver within the embryonic endoderm [J]. Development,2001,128(6):871-881.
[84] Rossi JM, Dunn NR, Hogan BL, et al. Distinct mesodermal signals, includingBMPs from the septum transversum mesenchyme, are required in combinationfor hepatogenesis from the endoderm [J]. Genes Dev,2001,15(15):1998-2009.
[85] Zhou Q, Law AC, Rajagopal J, et al. A multipotent progenitor domain guidespancreatic organogenesis [J]. Dev Cell,2007,13(1):103-114.
[86] Georgia S, Soliz R, Li M, et al. p57and Hes1coordinate cell cycle exit withself-renewal of pancreatic progenitors [J]. Dev Biol,2006,298(1):22-31.
[87] Hald J, Hjorth JP, German MS, et al. Activated Notch1prevents differentiationof pancreatic acinar cells and attenuate endocrine development [J]. Dev Biol,2003,260(2):426-437.
[88] Murtaugh LC, Stanger BZ, Kwan KM, et al. Notch signaling controls multiplesteps of pancreatic differentiation [J]. Proc Natl Acad Sci U S A,2003,100(25):14920-14925.
[89] J rgensen MC, Ahnfelt-R nne J, Hald J, et al. An illustrated review of earlypancreas development in the mouse [J]. Endocr Rev,2007,28(6):685-705.
[90] Servitja JM, Ferrer J. Transcriptional networks controlling pancreaticdevelopment and beta cell function [J]. Diabetologia,2004,47(4):597-613.
[91] Jensen J. Gene regulatory factors in pancreatic development [J]. Dev Dyn,2004,229(1):176-200.
[92] Guz Y, Montminy MR, Stein R, et al. Expression of murine STF-1, a putativeinsulin gene transcription factor, in beta cells of pancreas, duodenal epitheliumand pancreatic exocrine and endocrine progenitors during ontogeny [J].Development,1995,121(1):11-18.
[93] Stoffel M, Duncan SA. The maturity-onset diabetes of the young (MODY1)transcription factor HNF4alpha regulates expression of genes required forglucose transport and metabolism [J]. Proc Natl Acad Sci U S A,1997,94(24):13209-13214.
[94] Stoffers DA, Ferrer J, Clarke WL,et al. Early-onset type-II diabetes mellitus(MODY4) linked to IPF1[J]. Nat Genet,1997,17(2):138-139.
[95] Miller CP, McGehee RE Jr, Habener JF. IDX-1: a new homeodomaintranscription factor expressed in rat pancreatic islets and duodenum thattransactivates the somatostatin gene [J]. EMBO J,1994,13(5):1145-1156.
[96] Gerrish K, Gannon M, Shih D, et al. Pancreatic beta cell-specific transcription ofthe pdx-1gene. The role of conserved upstream control regions and their hepaticnuclear factor3beta sites [J]. J Biol Chem,2000,275(5):3485-3492.
[97] Stoffers DA，Stanojevic V，Habener J F. Insulin promoter factor-1gene mutationlinked to early-onset type2diabetes mellitus directs expression of a dominantnegative isoprotien [J]. J Clin Invest,1998,102(1):232-241.
[98] Peshabaria M，Cissell MA，Henderson E，et al.The PDX-1activation domainprovides specific functions necessary for transcriptional stimulation inpancreaticβ-cell [J].Molecular Endocrinology,2000,14(12):1907-1917.
[99] Kulkarni RN，Jhala US，Winnay JN，et al. PDX-1haploinsufficiency limits thecompensatory islet hyperplasia that occurs in response to insulin resistance [J]. JClin Invest,2004,114(6):828-836.
[100] Jonsson J, Carlsson L, Edlund T, et al. Insulin-promoter-factor1is required forpancreas development in mice [J]. Nature,1994,371(6498):606-609.
[101] Offield MF, Jetton TL, Labosky PA, et al. PDX-1is required for pancreaticoutgrowth and differentiation of the rostral duodenum [J]. Development,1996,122(3):983-995.
[102] Grapin-Botton A, Majithia AR, Melton DA. Key events of pancreas formationare triggered in gut endoderm by ectopic expression of pancreatic regulatorygenes [J]. Genes Dev,2001,15(4):444-454.
[103] Gu G, Brown JR, Melton DA. Direct lineage tracing reveals the ontogeny ofpancreatic cell fates during mouse embryogenesis [J]. Mech Dev,2003,120(1):35-43.
[104] Gradwohl G, Dierich A, LeMeur M, et al. neurogenin3is required for thedevelopment of the four endocrine cell lineages of the pancreas [J]. Proc NatlAcad Sci U S A,2000,97(4):1607-1611.
[105] Jensen JN, Rosenberg LC, Hecksher-S rensen J, et al. Mutant neurogenin-3incongenital malabsorptive diarrhea [J]. N Engl J Med,2007,356(17):1781-1782.
[106] Wang J, Cortina G, Wu SV, et al. Mutant neurogenin-3in congenitalmalabsorptive diarrhea [J]. N Engl J Med,2006,355(3):270-280.
[107] Apelqvist A, Li H, Sommer L, et al. Notch signalling controls pancreatic celldifferentiation [J]. Nature,1999,400(6747):877-881.
[108] Gu G, Dubauskaite J, Melton DA. Direct evidence for the pancreatic lineage:NGN3+cells are islet progenitors and are distinct from duct progenitors [J].Development,2002,129(10):2447-2457.
[109] Glick E, Leshkowitz D, Walker MD.Transcription factor BETA2actscooperatively with E2A and PDX1to activate the insulin gene promoter [J]. JBiol Chem,2000,275(3):2199-2204.
[110] Qiu Y, Guo M, Huang S, et al. Insulin gene transcription is mediated byinteractions between the p300coactivator and PDX-1, BETA2, and E47[J].Mol Cell Biol,2002,22(2):412-420.
[111] Schwitzgebel VM, Scheel DW, Conners JR, et al. Expression of neurogenin3reveals an islet cell precursor population in the pancreas [J]. Development,2000,127(16):3533-3542.
[112] Sussel L, Kalamaras J, Hartigan-O'Connor DJ, et al.Mice lacking thehomeodomain transcription factor Nkx2.2have diabetes due to arresteddifferentiation of pancreatic beta cells [J]. Development,1998,125(12):2213-2221.
[113] Doyle MJ, Sussel L.Nkx2.2regulates beta-cell function in the mature islet [J].Diabetes,2007,56(8):1999-2007.
[114] Doyle MJ, Loomis ZL, Sussel L. Nkx2.2-repressor activity is sufficient tospecify alpha-cells and a small number of beta-cells in the pancreatic islet [J].Development,2007,134(3):515-523.
[115] Nelson SB, Schaffer AE, Sander M. The transcription factors Nkx6.1andNkx6.2possess equivalent activities in promoting beta-cell fate specification inPdx1+pancreatic progenitor cells [J]. Development,2007,134(13):2491-2500.
[116] Henseleit KD, Nelson SB, Kuhlbrodt K, et al. NKX6transcription factoractivity is required for alpha-and beta-cell development in the pancreas [J].Development,2005,132(13):3139-3149.
[117] Schisler JC, Jensen PB, Taylor DG, et al. The Nkx6.1homeodomaintranscription factor suppresses glucagon expression and regulatesglucose-stimulated insulin secretion in islet beta cells [J]. Proc Natl Acad Sci US A,2005,102(20):7297-302.
[118] Gauthier BR, Gosmain Y, Mamin A, et al. The beta-cell specific transcriptionfactor Nkx6.1inhibits glucagon gene transcription by interfering with Pax6[J].Biochem J,2007,403(3):593-601.
[119] Murtaugh LC. Pancreas and beta-cell development: from the actual to thepossible [J]. Development,2007,134(3):427-438.
[120] Soria B, Skoudy A, Martín F. From stem cells to beta cells: new strategies incell therapy of diabetes mellitus [J]. Diabetologia,2001,44(4):407-415.
[121] León-Quinto T, Jones J, Skoudy A, et al. In vitro directed differentiation ofmouse embryonic stem cells into insulin-producing cells [J]. Diabetologia,2004,47(8):1442-1451.
[122] Lumelsky N, Blondel O, Laeng P, et al. Differentiation of embryonic stem cellsto insulin-secreting structures similar to pancreatic islets [J]. Science,2001,292(5520):1389-1394.
[123] Kroon E, Martinson LA, Kadoya K, et al. Pancreatic endoderm derived fromhuman embryonic stem cells generates glucose-responsive insulin-secretingcells in vivo[J]. Nat Biotechnol,2008,26(4):443-452.
[124] Van Hoof D, D'Amour KA, German MS. Derivation of insulin-producing cellsfrom human embryonic stem cells [J]. Stem Cell Res,2009,3(2-3):73-87.
[125] Santamaria X, Massasa EE, Feng Y,et al. Derivation of insulin producing cellsfrom human endometrial stromal stem cells and use in the treatment of murinediabetes[J]. Mol Ther,2011,19(11):2065-2071.
[126] Naujok O, Burns C, Jones PM, et al. Insulin-producing surrogate β-cells fromembryonic stem cells: are we there yet [J]? Mol Ther,2011,19(10):1759-1768.
[127] D’Amour KA, Bang AG, Eliazer S, et al. Production of pancreatichormone-expressing endocrine cells from human embryonic stem cells[J]. NatBiotechnol,2006,24(11):1392-1401.
[128] Zhang D, Jiang W, Liu M, et al. Highly efficient differentiation of human EScells and iPS cells into mature pancreatic insulin-producing cells [J]. Cell Res,2009,19(4):429-438.
[129] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouseembryonic and adult fibroblast cultures by defined factors [J]. Cell,2006,126(4):663-676.
[130] Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cellsfrom adult human fibroblasts by defined factors [J]. Cell,2007,131(5):861-872.
[131] Aoi T, Yae K, Nakagawa M, et al. Generation of pluripotent stem cells fromadult mouse liver and stomach cells [J]. Science,2008,321(5889):699-702.
[132] Li W, Wei W, Zhu S, et al. Generation of rat and human induced pluripotentstem cells by combining genetic reprogramming and chemical inhibitors [J].Cell Stem Cell,2009,4(1):16-19.
[133] Cantz T, Bleidissel M, Stehling M, et al. In vitro differentiation ofreprogrammed murine somatic cells into hepatic precursor cells [J]. Biol Chem,2008,389(7):889-896.
[134] Hu BY, Weick JP, Yu J, et al. Neural differentiation of human inducedpluripotent stem cells follows developmental principles but with variablepotency [J]. Proc Natl Acad Sci USA,2010,107(9):4335-4340.
[135] Soldner F, Hockemeyer D, Beard C, et al. Parkinson's disease patient-derivedinduced pluripotent stem cells free of viral reprogramming factors [J]. Cell,2009,136(5):964-977.
[136] Kunisada Y, Tsubooka-Yamazoe N, Shoji M, et al. Small molecules induceefficient differentiation into insulin-producing cells from human inducedpluripotent stem cells [J]. Stem Cell Res,2012,8(2):274-284.
[137] Maehr R, Chen S, Snitow M, et al. Generation of pluripotent stem cells frompatients with type1diabetes [J]. Proc Natl Acad Sci U S A,2009,106(37):15768-15773.
[138] Okita K, Nakagawa M, Hyenjong H, et al. Generation of mouse inducedpluripotent stem cells without viral vectors [J]. Science,2008,322(5903):949-953.
[139] Kim D, Kim CH, Moon JI, et al. Generation of human induced pluripotent stemcells by direct delivery of reprogramming proteins [J]. Cell Stem Cell,2009,4(6):472-476.
[140] Zhou H, Wu S, Joo JY, et al. Generation of induced pluripotent stem cells usingrecombinant proteins [J]. Cell Stem Cell,2009,4(5):381-384.
[141] Sun Y, Chen L, Hou XG, et al. Differentiation of bone marrow-derivedmesenchymal stem cells from diabetic patients into insulin-producing cells invitro [J]. Chin Med J (Engl),2007,120(9):771-776.
[142] Xie QP, Huang H, Xu B, et al. Human bone marrow mesenchymal stem cellsdifferentiate into insulin-producing cells upon microenvironmentalmanipulation in vitro [J]. Differentiation,2009,77(5):483-491.
[143] Zhang YH, Wang HF, Liu W, et al. Insulin-producing cells derived from ratbone marrow and their autologous transplantation in the duodenal wall fortreating diabetes [J]. Anat Rec (Hoboken),2009,292(5):728-735.
[144] Oh SH, Witek RP, Bae SH, et al. Detection of transketolase in bonemarrow-derived insulin-producing cells: benfotiamine enhances insulinsynthesis and glucose metabolism [J]. Stem Cells Dev,2009,18(1):37-46.
[145] Neshati Z, Matin MM, Bahrami AR, et al. Differentiation of mesenchymal stemcells to insulin-producing cells and their impact on type1diabetic rats [J]. JPhysiol Biochem,2010,66(2):181-187.
[146] Li L, Seno M, Yamada H, et al. Promotion of β-Cell regeneration bybetacellulin in ninety percent-pancreatectomized rats [J]. Endocrinology,2001,142(10):5379-5385.
[147] Peck AB, Ramiya V. In vitro-generation of surrogate islets from adult stemcells [J]. Transpl Immunol,2004,12(3-4):259-272.
[148] Jiang Y, Jahagirdar BN, Reinhard RL, et al. Pluripotency of mesenchymal stemcells derived from adult marrow [J]. Nature,2002,418(6893):41-49.
[149] Yang L, Li S, Hatch H, et al. In vitro trans-differentiation of adult hepatic stemcells into pancreatic endocrine hormone-producing cells [J]. Proc Natl Acad SciUSA,2002,99(12):8078-8083.
[150] Okura H, Komoda H, Fumimoto Y, et al. Transdifferentiation of human adiposetissue-derived stromal cells into insulin-producing clusters [J]. J Artif Organs,2009,12(2):123-130.
[151] Timper K, Seboek D, Eberhardt M, et al. Human adipose tissue-derivedmesenchymal stem cells differentiate into insulin, somatostatin, and glucagonexpressing cells [J]. Biochem Biophys Res Commun,2006,341(4):1135-1140.
[152] Thakar N, Priest RE, Priest JH. Estrogen production by cultured amniotic fluidcells [J]. Clinical Research,1982,30,888A.
[153] Gosden CM. Amniotic fluid cell types and culture [J]. Br Med Bull,1983,39(4):348-354.
[154] Gosden C, Brock DJ. Combined use of alphafetoprotein and amniotic fluid cellmorphology in early prenatal diagnosis of fetal abnormalities [J]. J Med Genet,1978,15(4):262-270.
[155] Hoehn H, Bryant EM, Karp LE, et al. Cultivated cells from diagnosticamniocentesis in second trimester pregnancies. II. Cytogenetic parameters asfunctions of clonal type and preparative technique [J]. Clin Genet,1975,7(1):29-36.
[156] von Koskull H, Aula P, Trejdosiewicz LK, et al. Identification of cells fromfetal bladder epithelium in human amniotic fluid [J]. Hum Genet,1984,65(3):262-267.
[157] Kolambkar YM, Peister A, Soker S, et al. Chondrogenic differentiation ofamniotic fluid-derived stem cells [J]. J Mol Histol,2007,38(5):405-413.
[158] Nadri S, Soleimani M. Comparative analysis of mesenchymal stromal cellsfrom murine bone marrow and amniotic fluid [J]. Cytotherapy,2007,9(8):729-737.
[159] Roubelakis MG, Pappa KI, Bitsika V, et al. Molecular and proteomiccharacterization of human mesenchymal stem cells derived from amniotic fluid:comparison to bone marrow mesenchymal stem cells [J]. Stem Cells Dev,2007,16(6):931-52.
[160] Kern S, Eichler H, Stoeve J, et al. Comparative analysis of mesenchymal stemcells from bone marrow, umbilical cord blood, or adipose tissue [J]. Stem Cells,2006,24(5):1294-1301.
[161] Bieback K, Kern S, Klüter H, et al. Critical parameters for the isolation ofmesenchymal stem cells from umbilical cord blood [J]. Stem Cells,2004,22(4):625-634.
[162] Carraro G, Perin L, Sedrakyan S, et al. Human amniotic fluid stem cells canintegrate and differentiate into epithelial lung lineages [J]. Stem Cells,2008,26(11):2902-2911.
[163] Chiavegato A, Bollini S, Pozzobon M, et al. Human amniotic fluid-derivedstem cells are rejected after transplantation in the myocardium of normal,ischemic, immuno-suppressed or immuno-deficient rat [J]. J Mol Cell Cardiol,2007,42(4):746-759.
[164] Dai W, Kloner RA. Myocardial regeneration by human amniotic fluid stemcells: challenges to be overcome [J]. J Mol Cell Cardiol,2007,42(4):730-732.
[165] Wei AH, Wang WJ, Mu XP, et al. Enhanced differentiation of human adiposetissue-derived stromal cells into insulin-producing cells with glucagon-likepeptide-1[J]. Exp Clin Endocrinol Diabetes,2012,120(1):28-34.
[166] Cipriani S, Bonini D, Marchina E, et al. Mesenchymal cells from humanamniotic fluid survive and migrate after transplantation into adult rat brain [J].Cell Biol Int,2007,31(8):845-850.
[167] Shetty AK. Progenitor cells from the CA3region of the embryonic day19rathippocampus generate region-specific neuronal phenotypes in vitro [J].Hippocampus,2004,14(5):595-614.
[168] Pan HC, Cheng FC, Chen CJ, et al. Post-injury regeneration in rat sciatic nervefacilitated by neurotrophic factors secreted by amniotic fluid mesenchymalstem cells [J]. J Clin Neurosci,2007,14(11):1089-1098.
[169] Pan HC, Yang DY, Chiu YT, et al. Enhanced regeneration in injured sciaticnerve by human amniotic mesenchymal stem cell [J]. J Clin Neurosci,2006,13(5):570-575.
[170] Hui H, Wright C, Perfetti R. Glucagon-like peptide1induces differentiation ofislet duodenal homeobox-1-positive pancreatic ductal cells intoinsulin-secreting cells [J]. Diabetes,2001,50(4):785-796.
[171] Abraham EJ, Leech CA, Lin JC, et al. Insulinotropic hormone glucagon-likepeptide-1differentiation of human pancreatic islet-derived progenitor cells intoinsulin-producing cells [J]. Endocrinology,2002,143(8):3152-3161.
[172] Xu G, Stoffers DA, Habener JF, et al. Exendin-4stimulates both beta-cellreplication and neogenesis, resulting in increased beta-cell mass and improvedglucose tolerance in diabetic rats [J]. Diabetes,1999,48(12):2270-2276.
[173] Stoffers DA, Kieffer TJ, Hussain MA, et al. Insulinotropic glucagon-likepeptide1agonists stimulate expression of homeodomain protein IDX-1andincrease islet size in mouse pancreas [J]. Diabetes,2000,49(5):741-748.
[174] Habener JF. Glucagon-like peptide1agonist stimulation of β-cell growth anddifferentiation [J]. Current Opinion in Endocrinology and Diabetes,2001,8(2):74-81.
[2] Shim JH, Kim SE, Woo DH, et al. Directed differentiation of human embryonicstem cells towards a pancreatic cell fate [J]. Diabetologia,2007,50(6):1228-1238.
[3] Lumelsky N, Blondel O, Laeng P, et al. Differentiation of embryonic stem cells toinsulin-secreting structures similar to pancreatic islets [J]. Science,2001,292(5520):1389-1394.
[4] Hori Y, Rulifson IC, Tsai BC, et al. Growth inhibitors promote differentiation ofinsulin-producing tissue from embryonic stem cells [J]. Proc Natl Acad Sci USA,2002,99(25):16105-16110.
[5] Jiang J, Au M, Lu K, et al. Generation of insulin-producing islet-like clusters fromhuman embryonic stem cells [J]. Stem Cells,2007,25(8):1940-1953.
[6] Shi Y, Hou L, Tang F, et al. Inducing embryonic stem cells to differentiate intopancreatic cells by a novel three-step approach with activin A and all-trans retinoicacid[J]. Stem Cells,2005,23(5):656-662.
[7] Bonner-Weir S, Taneja M, Weir GC, et al. In vitro cultivation of human islets fromexpanded ductal tissue [J]. Proc Natl Acad Sci USA,2000,97(14):7999-8004.
[8] Kajiyama H, Hamazaki TS, Tokuhara M, et al. Pdx1-transfected adiposetissue-derived stem cells differentiate into insulin-producing cells in vivo andreduce hyperglycemia in diabetic mice [J]. Int J Dev Biol,2010,54(4):699-705.
[9] Sun Y, Chen L, Hou XG, et al. Differentiation of bone marrow-derivedmesenchymal stem cells from diabetic patients into insulin-producing cells in vitro[J]. Clin Med J,2007,120(9):771-776.
[10] Yuan H, Li J, Xin N, et al. Expression of Pdx1mediates differentiation frommesenchymal stem cells into insulin-producing cells[J]. Mol Biol Rep,2010,37(8):4023-4031.
[11] Hess D, Li L, Martin M. Bone marrow-derived stem cells initiate pancreaticregeneration [J]. Nat Biotechnol,2003,21(7):763-770.
[12] Perin L, Sedrakyan S, Da Sacco S,et al. Characterization of human amnioticfluid stem cells and their pluripotential capability [J]. Methods Cell Biol,2008,86:85-99.
[13] Bossolasco P, Montemurro T, Cova L, et al. Molecular and phenotypiccharacterization of human amniotic fluid cells and their differentiation potential[J]. Cell Res,2006,16(4):329-336.
[14] Kim J, Lee Y, Kim H, et al. Human amniotic fluid-derived stem cells havecharacteristics of multipotent stem cells [J]. Cell Prolif,2007,40(1):75-90.
[15] Pfeiffer S, McLaughlin D. In vitro differentiation of human amnioticfluid-derived cells: augmentation towards a neuronal dopaminergic phenotype [J].Cell Biol Int,2010,34(9):959-967.
[16] Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell linesderived from human blastocysts [J]. Science,1998,282(5391):1145-1147.
[17] Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells[J]. Cell,2008,134(5):877-886.
[18] Dimos JT, Rodolfa KT, Niakan KK, et al. Induced pluripotent stem cellsgenerated from patients with ALS can be differentiated into motor neurons [J].Science,2008,321(5893):1218-1221.
[19] Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms andapplications [J]. Genes Dev,2010,24(20):2239-2263.
[20] Zhu H, Lensch MW, Cahan P, et al. Investigating monogenic and complexdiseases with pluripotent stem cells [J]. Nat Rev Genet,2011,12(4):266-275.
[21] Kaviani A, Perry TE, Dzakovic A, et al. The amniotic fluid as a source of cellsfor fetal tissue engineering [J]. J Pediatr Surg,2001,36(11):1662-1665.
[22] Prusa AR, Marton E, Rosner M, et al.Oct-4-expressing cells in human amnioticfluid: a new source for stem cell research [J]? Hum Reprod,2003,18(7):1489-1493.
[23] Mosquera A, Fernández JL, Campos A, et al. Simultaneous decrease of telomerelength and telomerase activity with ageing of human amniotic fluid cells [J]. JMed Genet,1999,36(6):494-496.
[24] Tsai MS, Lee JL, Chang YJ, et al. Isolation of human multipotent mesenchymalstem cells from second-trimester amniotic fluid using a novel two-stage cultureprotocol [J]. Hum Reprod,2004,19(6):1450-1456.
[25] De Coppi P, Bartsch G Jr, Siddiqui MM, et al. Isolation of amniotic stem celllines with potential for therapy [J]. Nat Biotechnol,2007,25(1):100-106.
[26] Kaviani A, Guleserian K, Perry TE, et al. Fetal tissue engineering from amnioticfluid [J]. J Am Coll Surg,2003,196(4):592-597.
[27] Tsai MS, Hwang SM, Chen KD, et al. Functional network analysis of thetranscriptomes of mesenchymal stem cells derived from amniotic fluid, amnioticmembrane, cord blood, and bone marrow [J]. Stem Cells,2007,25(10):2511-2523.
[28] Schmidt D, Achermann J, Odermatt B, et al. Prenatally fabricated autologoushuman living heart valves based on amniotic fluid derived progenitor cells assingle cell source [J]. Circulation,2007,116(11Suppl): I64-70.
[29] Ditadi A, de Coppi P, Picone O, et al. Human and murine amniotic fluidc-Kit+Lin-cells display hematopoietic activity [J]. Blood,2009,113(17):3953-3960.
[30] Prusa AR, Hengstschlager M. Amniotic fluid cells and human stem cell research:a new connection [J]. Med Sci Monit,2002,8(11): RA253-257.
[31] Chambers I, Silva J, Colby D, et al. Nanog safeguards pluripotency and mediatesgermline development [J]. Nature,2007,450(7173):1230-1234.
[32] Zhang P, Baxter J, Vinod K, et al. Endothelial differentiation of amnioticfluid-derived stem cells: synergism of biochemical and shear force stimuli [J].Stem Cells Dev,2009,18(9):1299-1308.
[33] Sessarego N, Parodi A, Podestà M, et al. Multipotent mesenchymal stromal cellsfrom amniotic fluid: solid perspectives for clinical application [J].Haematologica,2008,93(3):339-346.
[34] Tsai MS, Hwang SM, Tsai YL, et al. Clonal amniotic fluid-derived stem cellsexpress characteristics of both mesenchymal and neural stem cells [J]. BiolReprod,2006,74(3):545-551.
[35] Prusa AR, Marton E, Rosner M, et al. Neurogenic cells in human amniotic fluid[J]. Am J Obstet Gynecol,2004,191(1):309-314.
[36] Kakishita K, Nakao N, Sakuragawa N, et al. Implantation of human amnioticepithelial cells prevents the degeneration of nigral dopamine neurons in rats with6-hydroxydopamine lesions [J]. Brain Res,2003,980(1):48-56.
[37] Yeh YC, Wei HJ, Lee WY, et al. Cellular cardiomyoplasty with human amnioticfluid stem cells: in vitro and in vivo studies [J]. Tissue Eng Part A,2010,16(6):1925-1936.
[38] Bollini S, Pozzobon M, Nobles M, et al. In vitro and in vivo cardiomyogenicdifferentiation of amniotic fluid stem cells [J]. Stem Cell Rev,2011,7(2):364-380.
[39] Bollini S, Cheung KK, Riegler J, et al. Amniotic fluid stem cells arecardioprotective following acute myocardial infarction [J]. Stem Cells Dev,2011,20(11):1985-1994.
[40] Delo DM, De Coppi P, Bartsch G Jr, et al. Amniotic fluid and placental stemcells [J]. Methods Enzymol,2006,419:426-438.
[41] Rota C, Imberti B, Pozzobon M, et al. Human amniotic fluid stem cellpreconditioning improves their regenerative potential [J]. Stem Cells Dev,2011Dec23.
[42] Perin L, Giuliani S, Jin D, et al. Renal differentiation of amniotic fluid stem cells[J]. Cell Prolif,2007,40(6):936-948.
[43] Li B, Wang S, Liu H, et al. Neuronal restrictive silencing factor silencing induceshuman amniotic fluid-derived stem cells differentiation into insulin-producingcells [J]. Stem Cells Dev,2011,20(7):1223-1231.
[44] Ghaderi S, Soheili ZS, Ahmadieh H, et al. Human amniotic fluid promotesretinal pigmented epithelial cells' trans-differentiation into rod photoreceptorsand retinal ganglion cells [J]. Stem Cells Dev,2011,20(9):1615-1625.
[45] Decembrini S, Cananzi M, Gualdoni S, et al. Comparative analysis of the retinalpotential of embryonic stem cells and amniotic fluid-derived stem cells [J]. StemCells Dev,2011,20(5):851-863.
[46] Rosner M, Dolznig H, Schipany K, et al. Human amniotic fluid stem cells as amodel for functional studies of genes involved in human genetic diseases oroncogenesis [J]. Oncotarget,2011,2(9):705-712.
[47] Parolini O, Alviano F, Bagnara GP, et al. Concise review: isolation andcharacterization of cells from human term placenta: outcome of the firstinternational Workshop on Placenta Derived Stem Cells [J]. Stem Cells,2008,26(2):300-311.
[48] Porada CD, Zanjani ED, Almeida-Porad G. Adult mesenchymal stem cells: apluripotent population with multiple applications [J]. Curr Stem Cell Res Ther,2006,1(3):365-369.
[49] Hotta Y. Ethical issues of the research on human embryonic stem cells [J]. J IntBioethique,2008,19(3):77-85.
[50] Wood A. Ethics and embryonic stem cell research [J]. Stem Cell Rev,2005,1(4):317-324.
[51] Wu SM, Hochedlinger K. Harnessing the potential of induced pluripotent stemcells for regenerative medicine [J]. Nat Cell Biol,2011,13(5):497-505.
[52] Mattis VB, Svendsen CN. Induced pluripotent stem cells: a new revolution forclinical neurology?[J] Lancet Neurol,2011,10(4):383-394.
[53] Stadtfeld M, Apostolou E, Akutsu H, et al. Aberrant silencing of imprinted geneson chromosome12qF1in mouse induced pluripotent stem cells [J]. Nature,2010,465(7295):175-181.
[54] Kim K, Doi A, Wen B, et al. Epigenetic memory in induced pluripotent stemcells [J]. Nature,2010,467(7313):285-290.
[55] Laurent LC, Ulitsky I, Slavin I, et al. Dynamic changes in the copy number ofpluripotency and cell proliferation genes in human ESCs and iPSCs duringreprogramming and time in culture [J]. Cell Stem Cell,2011,8(1):106-118.
[56] Gore A, Li Z, Fung HL, et al. Somatic coding mutations in human inducedpluripotent stem cells [J]. Nature,2011,471(7336):63-67.
[57] Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increasedbeta-cell apoptosis in humans with type2diabetes [J]. Diabetes,2003,52(1):102-110.
[58] Yoon KH, Ko SH, Cho JH, et al. Selective beta-cell loss and alpha-cellexpansion in patients with type2diabetes mellitus in Korea [J]. J ClinEndocrinol Metab,2003,88(5):2300-2308.
[59] Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patientswith type1diabetes mellitus using a glucocorticoid-free immunosuppressiveregimen [J]. N Engl J Med,2000,343(4):230-238.
[60] Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmontonprotocol for islet transplantation [J].N Engl J Med,2006,355(13):1318-1330.
[61] Ricordi C, Hering BJ, Shapiro AM，et al. Beta-cell transplantation for diabetestherapy [J]. Lancet,2008,372(9632):27-28.
[62] Groth CG, Korsgren O, Wennberg L, et al. Pig-to-human islet transplantation [J].Transplant Proc,1998,30(7):3809-3810.
[63] Zalzman M, Gupta S, Giri RK, et al. Reversal of hyperglycemia in mice by usinghuman expandable insulin-producing cells differentiated from fetal liverprogenitor cells[J]. Proc Natl Acad Sci USA,2003,100(12):7253-7258.
[64] Horb ME, Shen CN, Tosh D, et al. Experimental conversion of liver to pancreas[J]. Curr Biol,2003,13(2):105-115.
[65] Hogan A, Pileggi A, Ricordi C. Transplantation: current developments and futuredirections; the future of clinical islet transplantation as a cure for diabetes [J].Front Biosci,2008,13:1192-1205.
[66] Jiang W, Shi Y, Zhao D, et al. In vitro derivation of functional insulin-producingcells from human embryonic stem cells [J]. Cell Res,2007,17(4):333-344.
[67] Phillips BW, Hentze H, Rust WL,et al. Directed differentiation of humanembryonic stem cells into the pancreatic endocrine lineage [J]. Stem Cells Dev,2007,16(4):561-578.
[68] Ramiya VK, Lan MS, Wasserfall CH, et al. Immunization therapies in theprevention of diabetes [J]. J Autoimmun,1997,10(3):287-292.
[69] Assady S, Maor G, Amit M, et al. Insulin production by human embryonic stemcells [J]. Diabetes,2001,50(8):1691-1697.
[70] Blyszczuk P, Czyz J, Kania G, et al. Expression of Pax4in embryonic stem cellspromotes differentiation of nestin-positive progenitor and insulin-producing cells[J]. Proc Natl Acad Sci U S A,2003,100(3):998-1003.
[71] Taniguchi H, Yamato E, Tashiro F,et al. beta-cell neogenesis induced byadenovirus-mediated gene delivery of transcription factor pdx-1into mousepancreas [J]. Gene Ther,2003,10(1):15-23.
[72] Sakuraba H, Mizukami H, Yagihashi N, Reduced beta-cell mass and expressionof oxidative stress-related DNA damage in the islet of Japanese Type II diabeticpatients [J]. Diabetologia,2002,45(1):85-96.
[73] Brissova M, Fowler MJ, Nicholson WE, et al. Assessment of human pancreaticislet architecture and composition by laser scanning confocal microscopy [J]. JHistochem Cytochem,2005,53(9):1087-1097.
[74] Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics [J]. Nat RevCancer,2002,2(12):897-909.
[75] Oliver-Krasinski JM, Stoffers DA. On the origin of the beta cell [J]. Genes Dev,2008,22(15):1998-2021.
[76] Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containingtransactivator of the insulin gene [J]. EMBO J,1993,12(11):4251-4259.
[77] Stoffers DA, Heller RS, Miller CP, et al. Developmental expression of thehomeodomain protein IDX-1in mice transgenic for an IDX-1promoter/lacZtranscriptional reporter [J]. Endocrinology,1999,140(11):5374-5381.
[78] Jacquemin P, Yoshitomi H, Kashima Y, et al. An endothelial-mesenchymal relaypathway regulates early phases of pancreas development [J]. Dev Biol,2006,290(1):189-199.
[79] Yoshitomi H, Zaret KS.Endothelial cell interactions initiate dorsal pancreasdevelopment by selectively inducing the transcription factor Ptf1a [J].Development,2004,131(4):807-817.
[80] Wiebe PO, Kormish JD, Roper VT, et al. Ptf1a binds to and activates area III, ahighly conserved region of the Pdx1promoter that mediates early pancreas-widePdx1expression [J]. Mol Cell Biol,2007,27(11):4093-4104.
[81] Kawahira H, Scheel DW, Smith SB, et al. Hedgehog signaling regulatesexpansion of pancreatic epithelial cells [J]. Dev Biol,2005,280(1):111-121.
[82] Hebrok M, Kim SK, St Jacques B, et al. Regulation of pancreas development byhedgehog signaling [J]. Development,2000,127(22):4905-4913.
[83] Deutsch G, Jung J, Zheng M, et al. A bipotential precursor population forpancreas and liver within the embryonic endoderm [J]. Development,2001,128(6):871-881.
[84] Rossi JM, Dunn NR, Hogan BL, et al. Distinct mesodermal signals, includingBMPs from the septum transversum mesenchyme, are required in combinationfor hepatogenesis from the endoderm [J]. Genes Dev,2001,15(15):1998-2009.
[85] Zhou Q, Law AC, Rajagopal J, et al. A multipotent progenitor domain guidespancreatic organogenesis [J]. Dev Cell,2007,13(1):103-114.
[86] Georgia S, Soliz R, Li M, et al. p57and Hes1coordinate cell cycle exit withself-renewal of pancreatic progenitors [J]. Dev Biol,2006,298(1):22-31.
[87] Hald J, Hjorth JP, German MS, et al. Activated Notch1prevents differentiationof pancreatic acinar cells and attenuate endocrine development [J]. Dev Biol,2003,260(2):426-437.
[88] Murtaugh LC, Stanger BZ, Kwan KM, et al. Notch signaling controls multiplesteps of pancreatic differentiation [J]. Proc Natl Acad Sci U S A,2003,100(25):14920-14925.
[89] J rgensen MC, Ahnfelt-R nne J, Hald J, et al. An illustrated review of earlypancreas development in the mouse [J]. Endocr Rev,2007,28(6):685-705.
[90] Servitja JM, Ferrer J. Transcriptional networks controlling pancreaticdevelopment and beta cell function [J]. Diabetologia,2004,47(4):597-613.
[91] Jensen J. Gene regulatory factors in pancreatic development [J]. Dev Dyn,2004,229(1):176-200.
[92] Guz Y, Montminy MR, Stein R, et al. Expression of murine STF-1, a putativeinsulin gene transcription factor, in beta cells of pancreas, duodenal epitheliumand pancreatic exocrine and endocrine progenitors during ontogeny [J].Development,1995,121(1):11-18.
[93] Stoffel M, Duncan SA. The maturity-onset diabetes of the young (MODY1)transcription factor HNF4alpha regulates expression of genes required forglucose transport and metabolism [J]. Proc Natl Acad Sci U S A,1997,94(24):13209-13214.
[94] Stoffers DA, Ferrer J, Clarke WL,et al. Early-onset type-II diabetes mellitus(MODY4) linked to IPF1[J]. Nat Genet,1997,17(2):138-139.
[95] Miller CP, McGehee RE Jr, Habener JF. IDX-1: a new homeodomaintranscription factor expressed in rat pancreatic islets and duodenum thattransactivates the somatostatin gene [J]. EMBO J,1994,13(5):1145-1156.
[96] Gerrish K, Gannon M, Shih D, et al. Pancreatic beta cell-specific transcription ofthe pdx-1gene. The role of conserved upstream control regions and their hepaticnuclear factor3beta sites [J]. J Biol Chem,2000,275(5):3485-3492.
[97] Stoffers DA，Stanojevic V，Habener J F. Insulin promoter factor-1gene mutationlinked to early-onset type2diabetes mellitus directs expression of a dominantnegative isoprotien [J]. J Clin Invest,1998,102(1):232-241.
[98] Peshabaria M，Cissell MA，Henderson E，et al.The PDX-1activation domainprovides specific functions necessary for transcriptional stimulation inpancreaticβ-cell [J].Molecular Endocrinology,2000,14(12):1907-1917.
[99] Kulkarni RN，Jhala US，Winnay JN，et al. PDX-1haploinsufficiency limits thecompensatory islet hyperplasia that occurs in response to insulin resistance [J]. JClin Invest,2004,114(6):828-836.
[100] Jonsson J, Carlsson L, Edlund T, et al. Insulin-promoter-factor1is required forpancreas development in mice [J]. Nature,1994,371(6498):606-609.
[101] Offield MF, Jetton TL, Labosky PA, et al. PDX-1is required for pancreaticoutgrowth and differentiation of the rostral duodenum [J]. Development,1996,122(3):983-995.
[102] Grapin-Botton A, Majithia AR, Melton DA. Key events of pancreas formationare triggered in gut endoderm by ectopic expression of pancreatic regulatorygenes [J]. Genes Dev,2001,15(4):444-454.
[103] Gu G, Brown JR, Melton DA. Direct lineage tracing reveals the ontogeny ofpancreatic cell fates during mouse embryogenesis [J]. Mech Dev,2003,120(1):35-43.
[104] Gradwohl G, Dierich A, LeMeur M, et al. neurogenin3is required for thedevelopment of the four endocrine cell lineages of the pancreas [J]. Proc NatlAcad Sci U S A,2000,97(4):1607-1611.
[105] Jensen JN, Rosenberg LC, Hecksher-S rensen J, et al. Mutant neurogenin-3incongenital malabsorptive diarrhea [J]. N Engl J Med,2007,356(17):1781-1782.
[106] Wang J, Cortina G, Wu SV, et al. Mutant neurogenin-3in congenitalmalabsorptive diarrhea [J]. N Engl J Med,2006,355(3):270-280.
[107] Apelqvist A, Li H, Sommer L, et al. Notch signalling controls pancreatic celldifferentiation [J]. Nature,1999,400(6747):877-881.
[108] Gu G, Dubauskaite J, Melton DA. Direct evidence for the pancreatic lineage:NGN3+cells are islet progenitors and are distinct from duct progenitors [J].Development,2002,129(10):2447-2457.
[109] Glick E, Leshkowitz D, Walker MD.Transcription factor BETA2actscooperatively with E2A and PDX1to activate the insulin gene promoter [J]. JBiol Chem,2000,275(3):2199-2204.
[110] Qiu Y, Guo M, Huang S, et al. Insulin gene transcription is mediated byinteractions between the p300coactivator and PDX-1, BETA2, and E47[J].Mol Cell Biol,2002,22(2):412-420.
[111] Schwitzgebel VM, Scheel DW, Conners JR, et al. Expression of neurogenin3reveals an islet cell precursor population in the pancreas [J]. Development,2000,127(16):3533-3542.
[112] Sussel L, Kalamaras J, Hartigan-O'Connor DJ, et al.Mice lacking thehomeodomain transcription factor Nkx2.2have diabetes due to arresteddifferentiation of pancreatic beta cells [J]. Development,1998,125(12):2213-2221.
[113] Doyle MJ, Sussel L.Nkx2.2regulates beta-cell function in the mature islet [J].Diabetes,2007,56(8):1999-2007.
[114] Doyle MJ, Loomis ZL, Sussel L. Nkx2.2-repressor activity is sufficient tospecify alpha-cells and a small number of beta-cells in the pancreatic islet [J].Development,2007,134(3):515-523.
[115] Nelson SB, Schaffer AE, Sander M. The transcription factors Nkx6.1andNkx6.2possess equivalent activities in promoting beta-cell fate specification inPdx1+pancreatic progenitor cells [J]. Development,2007,134(13):2491-2500.
[116] Henseleit KD, Nelson SB, Kuhlbrodt K, et al. NKX6transcription factoractivity is required for alpha-and beta-cell development in the pancreas [J].Development,2005,132(13):3139-3149.
[117] Schisler JC, Jensen PB, Taylor DG, et al. The Nkx6.1homeodomaintranscription factor suppresses glucagon expression and regulatesglucose-stimulated insulin secretion in islet beta cells [J]. Proc Natl Acad Sci US A,2005,102(20):7297-302.
[118] Gauthier BR, Gosmain Y, Mamin A, et al. The beta-cell specific transcriptionfactor Nkx6.1inhibits glucagon gene transcription by interfering with Pax6[J].Biochem J,2007,403(3):593-601.
[119] Murtaugh LC. Pancreas and beta-cell development: from the actual to thepossible [J]. Development,2007,134(3):427-438.
[120] Soria B, Skoudy A, Martín F. From stem cells to beta cells: new strategies incell therapy of diabetes mellitus [J]. Diabetologia,2001,44(4):407-415.
[121] León-Quinto T, Jones J, Skoudy A, et al. In vitro directed differentiation ofmouse embryonic stem cells into insulin-producing cells [J]. Diabetologia,2004,47(8):1442-1451.
[122] Lumelsky N, Blondel O, Laeng P, et al. Differentiation of embryonic stem cellsto insulin-secreting structures similar to pancreatic islets [J]. Science,2001,292(5520):1389-1394.
[123] Kroon E, Martinson LA, Kadoya K, et al. Pancreatic endoderm derived fromhuman embryonic stem cells generates glucose-responsive insulin-secretingcells in vivo[J]. Nat Biotechnol,2008,26(4):443-452.
[124] Van Hoof D, D'Amour KA, German MS. Derivation of insulin-producing cellsfrom human embryonic stem cells [J]. Stem Cell Res,2009,3(2-3):73-87.
[125] Santamaria X, Massasa EE, Feng Y,et al. Derivation of insulin producing cellsfrom human endometrial stromal stem cells and use in the treatment of murinediabetes[J]. Mol Ther,2011,19(11):2065-2071.
[126] Naujok O, Burns C, Jones PM, et al. Insulin-producing surrogate β-cells fromembryonic stem cells: are we there yet [J]? Mol Ther,2011,19(10):1759-1768.
[127] D’Amour KA, Bang AG, Eliazer S, et al. Production of pancreatichormone-expressing endocrine cells from human embryonic stem cells[J]. NatBiotechnol,2006,24(11):1392-1401.
[128] Zhang D, Jiang W, Liu M, et al. Highly efficient differentiation of human EScells and iPS cells into mature pancreatic insulin-producing cells [J]. Cell Res,2009,19(4):429-438.
[129] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouseembryonic and adult fibroblast cultures by defined factors [J]. Cell,2006,126(4):663-676.
[130] Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cellsfrom adult human fibroblasts by defined factors [J]. Cell,2007,131(5):861-872.
[131] Aoi T, Yae K, Nakagawa M, et al. Generation of pluripotent stem cells fromadult mouse liver and stomach cells [J]. Science,2008,321(5889):699-702.
[132] Li W, Wei W, Zhu S, et al. Generation of rat and human induced pluripotentstem cells by combining genetic reprogramming and chemical inhibitors [J].Cell Stem Cell,2009,4(1):16-19.
[133] Cantz T, Bleidissel M, Stehling M, et al. In vitro differentiation ofreprogrammed murine somatic cells into hepatic precursor cells [J]. Biol Chem,2008,389(7):889-896.
[134] Hu BY, Weick JP, Yu J, et al. Neural differentiation of human inducedpluripotent stem cells follows developmental principles but with variablepotency [J]. Proc Natl Acad Sci USA,2010,107(9):4335-4340.
[135] Soldner F, Hockemeyer D, Beard C, et al. Parkinson's disease patient-derivedinduced pluripotent stem cells free of viral reprogramming factors [J]. Cell,2009,136(5):964-977.
[136] Kunisada Y, Tsubooka-Yamazoe N, Shoji M, et al. Small molecules induceefficient differentiation into insulin-producing cells from human inducedpluripotent stem cells [J]. Stem Cell Res,2012,8(2):274-284.
[137] Maehr R, Chen S, Snitow M, et al. Generation of pluripotent stem cells frompatients with type1diabetes [J]. Proc Natl Acad Sci U S A,2009,106(37):15768-15773.
[138] Okita K, Nakagawa M, Hyenjong H, et al. Generation of mouse inducedpluripotent stem cells without viral vectors [J]. Science,2008,322(5903):949-953.
[139] Kim D, Kim CH, Moon JI, et al. Generation of human induced pluripotent stemcells by direct delivery of reprogramming proteins [J]. Cell Stem Cell,2009,4(6):472-476.
[140] Zhou H, Wu S, Joo JY, et al. Generation of induced pluripotent stem cells usingrecombinant proteins [J]. Cell Stem Cell,2009,4(5):381-384.
[141] Sun Y, Chen L, Hou XG, et al. Differentiation of bone marrow-derivedmesenchymal stem cells from diabetic patients into insulin-producing cells invitro [J]. Chin Med J (Engl),2007,120(9):771-776.
[142] Xie QP, Huang H, Xu B, et al. Human bone marrow mesenchymal stem cellsdifferentiate into insulin-producing cells upon microenvironmentalmanipulation in vitro [J]. Differentiation,2009,77(5):483-491.
[143] Zhang YH, Wang HF, Liu W, et al. Insulin-producing cells derived from ratbone marrow and their autologous transplantation in the duodenal wall fortreating diabetes [J]. Anat Rec (Hoboken),2009,292(5):728-735.
[144] Oh SH, Witek RP, Bae SH, et al. Detection of transketolase in bonemarrow-derived insulin-producing cells: benfotiamine enhances insulinsynthesis and glucose metabolism [J]. Stem Cells Dev,2009,18(1):37-46.
[145] Neshati Z, Matin MM, Bahrami AR, et al. Differentiation of mesenchymal stemcells to insulin-producing cells and their impact on type1diabetic rats [J]. JPhysiol Biochem,2010,66(2):181-187.
[146] Li L, Seno M, Yamada H, et al. Promotion of β-Cell regeneration bybetacellulin in ninety percent-pancreatectomized rats [J]. Endocrinology,2001,142(10):5379-5385.
[147] Peck AB, Ramiya V. In vitro-generation of surrogate islets from adult stemcells [J]. Transpl Immunol,2004,12(3-4):259-272.
[148] Jiang Y, Jahagirdar BN, Reinhard RL, et al. Pluripotency of mesenchymal stemcells derived from adult marrow [J]. Nature,2002,418(6893):41-49.
[149] Yang L, Li S, Hatch H, et al. In vitro trans-differentiation of adult hepatic stemcells into pancreatic endocrine hormone-producing cells [J]. Proc Natl Acad SciUSA,2002,99(12):8078-8083.
[150] Okura H, Komoda H, Fumimoto Y, et al. Transdifferentiation of human adiposetissue-derived stromal cells into insulin-producing clusters [J]. J Artif Organs,2009,12(2):123-130.
[151] Timper K, Seboek D, Eberhardt M, et al. Human adipose tissue-derivedmesenchymal stem cells differentiate into insulin, somatostatin, and glucagonexpressing cells [J]. Biochem Biophys Res Commun,2006,341(4):1135-1140.
[152] Thakar N, Priest RE, Priest JH. Estrogen production by cultured amniotic fluidcells [J]. Clinical Research,1982,30,888A.
[153] Gosden CM. Amniotic fluid cell types and culture [J]. Br Med Bull,1983,39(4):348-354.
[154] Gosden C, Brock DJ. Combined use of alphafetoprotein and amniotic fluid cellmorphology in early prenatal diagnosis of fetal abnormalities [J]. J Med Genet,1978,15(4):262-270.
[155] Hoehn H, Bryant EM, Karp LE, et al. Cultivated cells from diagnosticamniocentesis in second trimester pregnancies. II. Cytogenetic parameters asfunctions of clonal type and preparative technique [J]. Clin Genet,1975,7(1):29-36.
[156] von Koskull H, Aula P, Trejdosiewicz LK, et al. Identification of cells fromfetal bladder epithelium in human amniotic fluid [J]. Hum Genet,1984,65(3):262-267.
[157] Kolambkar YM, Peister A, Soker S, et al. Chondrogenic differentiation ofamniotic fluid-derived stem cells [J]. J Mol Histol,2007,38(5):405-413.
[158] Nadri S, Soleimani M. Comparative analysis of mesenchymal stromal cellsfrom murine bone marrow and amniotic fluid [J]. Cytotherapy,2007,9(8):729-737.
[159] Roubelakis MG, Pappa KI, Bitsika V, et al. Molecular and proteomiccharacterization of human mesenchymal stem cells derived from amniotic fluid:comparison to bone marrow mesenchymal stem cells [J]. Stem Cells Dev,2007,16(6):931-52.
[160] Kern S, Eichler H, Stoeve J, et al. Comparative analysis of mesenchymal stemcells from bone marrow, umbilical cord blood, or adipose tissue [J]. Stem Cells,2006,24(5):1294-1301.
[161] Bieback K, Kern S, Klüter H, et al. Critical parameters for the isolation ofmesenchymal stem cells from umbilical cord blood [J]. Stem Cells,2004,22(4):625-634.
[162] Carraro G, Perin L, Sedrakyan S, et al. Human amniotic fluid stem cells canintegrate and differentiate into epithelial lung lineages [J]. Stem Cells,2008,26(11):2902-2911.
[163] Chiavegato A, Bollini S, Pozzobon M, et al. Human amniotic fluid-derivedstem cells are rejected after transplantation in the myocardium of normal,ischemic, immuno-suppressed or immuno-deficient rat [J]. J Mol Cell Cardiol,2007,42(4):746-759.
[164] Dai W, Kloner RA. Myocardial regeneration by human amniotic fluid stemcells: challenges to be overcome [J]. J Mol Cell Cardiol,2007,42(4):730-732.
[165] Wei AH, Wang WJ, Mu XP, et al. Enhanced differentiation of human adiposetissue-derived stromal cells into insulin-producing cells with glucagon-likepeptide-1[J]. Exp Clin Endocrinol Diabetes,2012,120(1):28-34.
[166] Cipriani S, Bonini D, Marchina E, et al. Mesenchymal cells from humanamniotic fluid survive and migrate after transplantation into adult rat brain [J].Cell Biol Int,2007,31(8):845-850.
[167] Shetty AK. Progenitor cells from the CA3region of the embryonic day19rathippocampus generate region-specific neuronal phenotypes in vitro [J].Hippocampus,2004,14(5):595-614.
[168] Pan HC, Cheng FC, Chen CJ, et al. Post-injury regeneration in rat sciatic nervefacilitated by neurotrophic factors secreted by amniotic fluid mesenchymalstem cells [J]. J Clin Neurosci,2007,14(11):1089-1098.
[169] Pan HC, Yang DY, Chiu YT, et al. Enhanced regeneration in injured sciaticnerve by human amniotic mesenchymal stem cell [J]. J Clin Neurosci,2006,13(5):570-575.
[170] Hui H, Wright C, Perfetti R. Glucagon-like peptide1induces differentiation ofislet duodenal homeobox-1-positive pancreatic ductal cells intoinsulin-secreting cells [J]. Diabetes,2001,50(4):785-796.
[171] Abraham EJ, Leech CA, Lin JC, et al. Insulinotropic hormone glucagon-likepeptide-1differentiation of human pancreatic islet-derived progenitor cells intoinsulin-producing cells [J]. Endocrinology,2002,143(8):3152-3161.
[172] Xu G, Stoffers DA, Habener JF, et al. Exendin-4stimulates both beta-cellreplication and neogenesis, resulting in increased beta-cell mass and improvedglucose tolerance in diabetic rats [J]. Diabetes,1999,48(12):2270-2276.
[173] Stoffers DA, Kieffer TJ, Hussain MA, et al. Insulinotropic glucagon-likepeptide1agonists stimulate expression of homeodomain protein IDX-1andincrease islet size in mouse pancreas [J]. Diabetes,2000,49(5):741-748.
[174] Habener JF. Glucagon-like peptide1agonist stimulation of β-cell growth anddifferentiation [J]. Current Opinion in Endocrinology and Diabetes,2001,8(2):74-81.