Generating pancreatic β-cells from embryonic stem cells by manipulating signaling pathways

Journal of Endocrinology

Volumn 206, Issue 1, 2010, Pages 13-26

  Champeris Tsaniras, Spyridon ^a   Jones, Peter M ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BETA CATENIN; NOTCH RECEPTOR; PHOSPHATIDYLINOSITOL 3 KINASE; SONIC HEDGEHOG PROTEIN; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEIN;

CELL DIFFERENTIATION; EMBRYONIC STEM CELL; ENDODERM; HUMAN; INTRACELLULAR SIGNALING; NONHUMAN; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; REVIEW;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; BETA CATENIN; CELL DIFFERENTIATION; DIABETES MELLITUS, TYPE 1; EMBRYONIC STEM CELLS; HEDGEHOG PROTEINS; HUMANS; INSULIN; INSULIN-SECRETING CELLS; ISLETS OF LANGERHANS TRANSPLANTATION; RECEPTORS, NOTCH; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEINS;

EID: 77953862208     PISSN: 00220795     EISSN: 14796805     Source Type: Journal    
DOI: 10.1677/JOE-10-0073     Document Type: Review

References (187)

1. Almeida M, Han L, Bellido T, Manolagas SC & Kousteni S 2005 Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. Journal of Biological Chemistry 280 41342-41351.
2. Apelqvist E, Ahlgren U & Edlund H 1997 Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Current Biology 7 801-804. (Pubitemid 27441836)
3. Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, de Angelis MH, Lendahl U & Edlund H 1999 Notch signalling controls pancreatic cell differentiation. Nature 400 877-881.
4. Bai L, Meredith G & Tuch BE 2005 Glucagon-like peptide-1 enhances production of insulin in insulin-producing cells derived from mouse embryonic stem cells. Journal of Endocrinology 186 343-352.
5. Bakre MM, Hoi A, Mong JC, Koh YY, Wong KY & Stanton LW 2007 Generation of multipotential mesendodermal progenitors from mouse embryonic stem cells via sustained Wnt pathway activation. Journal of Biological Chemistry 282 31703-31712.
6. Barnett SF, Defeo-Jones D, Fu S, Hancock PJ, Haskell KM, Jones RE, Kahana JA, Kral AM, Leander K, Lee LL et al. 2005 Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. Biochemical Journal 385 399-408.
7. Beck CW & Slack JMW 2002 Notch is required for outgrowth of the Xenopus tail bud. International Journal of Developmental Biology 46 255-258.
8. Beher D, Wrigley JDJ, Nadin A, Evin G, Masters CL, Harrison T, Castro JL & Shearman MS 2001 Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma-secretase inhibitor: implications for presenilin biology. Journal of Biological Chemistry 276 45394-45402.
9. Bhat R, Xue Y, Berg S, Hellberg S, Ormö M, Nilsson Y, Radesäter AC, Jerning E, Markgren PO, Borgegård T et al. 2003 Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. Journal of Biological Chemistry 278 45937-45945.
10. Blyszczuk P & Wobus AM 2007 In vitro differentiation of embryonic stem cells into the pancreatic lineage. Methods in Molecular Biology 330 373-385.
11. Blyszczuk P, Czyz J, Kania G, Wagner M, Roll U, St-Onge L & Wobus AM 2003 Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. PNAS 100 998-1003.
12. Bodine PVN, Stauffer B, Ponce-de-Leon H, Bhat RA, Mangine A, Seestaller-Wehr LM, Moran RA, Billiard J, Fukayama S, Komm BS et al. 2009 A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation. Bone 44 1063-1068.
13. Borowiak M, Maehr R, Chen S, Chen AE, Tang W, Fox JL, Schreiber SL & Melton DA 2009 Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells. Cell Stem Cell 4 348-358.
14. Bray SJ 2006 Notch signalling: a simple pathway becomes complex. Nature Reviews. Molecular Cell Biology 7 678-689.
15. Buteau J, Roduit R, Susini S & Prentki M 1999 Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetologia 42 856-864.
16. Butler LM, Webb Y, Agus DB, Higgins B, Tolentino TR, Kutko MC, LaQuaglia MP, Drobnjak M, Cordon-Cardo C, Scher HI et al. 2001 Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase. Clinical Cancer Research 7 962-970.
17. Calderari S, Gangnerau MN, Thibault M, Meile MJ, Kassis N, Alvarez C, Portha B & Serradas P 2007 Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto-Kakizaki rat model of type 2 diabetes. Diabetologia 50 1463-1471.
18. Chen JK, Taipale J, Young KE, Maiti T & Beachy PA 2002 Small molecule modulation of Smoothened activity. PNAS 99 14071-14076.
19. Chen YG, Wang Q, Lin SL, Chang CD, Chung J & Ying SY 2006 Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis. Experimental Biology and Medicine 231 534-544.
20. Chen C, Zhang Y, Sheng X, Huang C & Zang YQ 2008 Differentiation of embryonic stem cells towards pancreatic progenitor cells and their transplantation into streptozotocin-induced diabetic mice. Cell Biology International 32 456-461.
21. Chen S, Borowiak M, Fox JL, Maehr R, Osafune K, Davidow L, Lam K, Peng LF, Schreiber SL, Rubin LL et al. 2009 A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nature Chemical Biology 5 258-265.
22. Cho YM, Lim JM, Yoo DH, Kim JH, Chung SS, Park SG, Kim TH, Oh SK, Choi YM, Moon SY et al. 2008 Betacellulin and nicotinamide sustain PDX1 expression and induce pancreatic beta-cell differentiation in human embryonic stem cells. Biochemical and Biophysical Research Communications 366 129-134.
23. Chuang PT & McMahon AP 1999 Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397 617-621. (Pubitemid 129613567)
24. Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L et al. 2000 Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chemistry & Biology 7 793-803.
25. Cooper MK, Porter JA, Young KE & Beachy PA 1998 Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280 1603-1607.
26. D'Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E & Baetge EE 2005 Efficient differentiation of human embryonic stem cells to definitive endoderm. Nature Biotechnology 23 1534-1541.
27. D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK & Baetge EE 2006 Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nature Biotechnology 24 1392-1401.
28. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ et al. 1999 A presenilin-1- dependent [gamma]-secretase-like protease mediates release of Notch intracellular domain. Nature 398 518-522.
29. Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ et al. 2001 Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. Journal of Neurochemistry 76 173-181.
30. Dyer MA, Farrington SM, Mohn D, Munday JR & Baron MH 2001 Indian Hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development 128 1717-1730. (Pubitemid 32514853)
31. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA & McMahon AP 1993 Sonic Hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75 1417-1430.
32. Eiselein L, Schwartz HJ & Rutledge JC 2004 The challenge of type 1 diabetes mellitus. ILAR 45 231-236.
33. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, Moon RT, Teo JL, Oh SW, Kim HY et al. 2004 A small molecule inhibitor of beta-catenin/CREB-binding protein transcription. PNAS 101 12682-12687.
34. Esler WP, Kimberly WT, Ostaszewski BL, Ye W, Diehl TS, Selkoe DJ & Wolfe MS 2002 Activity-dependent isolation of the presenilin- gamma-secretase complex reveals nicastrin and a gamma substrate. PNAS 99 2720-2725.
35. Evans MJ & Kaufman MH 1981 Establishment in culture of pluripotential cells from mouse embryos. Nature 292 154-156.
36. Frandsen U, Porneki AD, Floridon C, Abdallah BM & Kassem M 2007 Activin B mediated induction of Pdx1 in human embryonic stem cell derived embryoid bodies. Biochemical and Biophysical Research Communications 362 568-574.
37. Frank-Kamenetsky M, Zhang X, Bottega S, Guicherit O, Wichterle H, Dudek H, Bumcrot D, Wang F, Jones S, Shulok J et al. 2002 Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. Journal of Biology 1 10.
38. Fujii N, You L, Xu Z, Uematsu K, Shan J, He B, Mikami I, Edmondson LR, Neale G, Zheng J et al. 2007 An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth. Cancer Research 67 573-579.
39. Fukumoto S, Hsieh CM, Maemura K, Layne MD, Yet SF, Lee KH, Matsui T, Rosenzweig A, Taylor WG, Rubin JS et al. 2001 Akt participation in the Wnt signaling pathway through dishevelled. Journal of Biological Chemistry 276 17479-17483.
40. van Gijn ME, Daemen MJAP, Smits JFM & Blankesteijn WM 2002 The wntfrizzled cascade in cardiovascular disease. Cardiovascular Research 55 16-24.
41. Glaser KB, Staver MJ, Waring JF, Stender J, Ulrich RG & Davidsen SK 2003 Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Molecular Cancer Therapeutics 2 151-163.
42. Goicoa S, Alvarez S, Ricordi C, Inverardi L & Dominguez-Bendala J 2006 Sodium butyrate activates genes of early pancreatic development in embryonic stem cells. Cloning and Stem Cells 8 140-149.
43. Gradwohl G, Dierich A, LeMeur M & Guillemot F 2000 Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. PNAS 97 1607-1611.
44. Gregorieff A, Grosschedl R & Clevers H 2004 Hindgut defects and transformation of the gastro-intestinal tract in Tcf4K/K/Tcf1K/K embryos. EMBO Journal 23 1825-1833.
45. Gu G, Dubauskaite J & Melton DA 2002 Direct evidence for the pancreatic lineage: Ngn3+ cells are islet progenitors and are distinct from duct progenitors. Development 129 2447-2457. (Pubitemid 34863851)
46. Hald J, Hjorth JP, German MS, Madsen OD, Serup P & Jensen J 2003 Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development. Developmental Biology 260 426-437.
47. Hansson M, Tonning A, Frandsen U, Petri A, Rajagopal J, Englund MCO, Heller RS, Hakansson J, Fleckner J, Skold HN et al. 2004 Artifactual insulin release from differentiated embryonic stem cells. Diabetes 53 2603-2609.
48. Haumaitre C, Lenoir O & Scharfmann R 2008 Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Molecular Cell Biology 28 6373-6383.
49. He XC, Yin T, Grindley JC, Tian Q, Sato T, Tao WA, Dirisina R, Porter-Westpfahl KS, Hembree M, Johnson T et al. 2007 PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nature Genetics 39 189-198.
50. Hebrok M, Kim SK & Melton DA 1998 Notochord repression of endodermal Sonic Hedgehog permits pancreas development. Genes and Development 12 1705-1713. (Pubitemid 28299520)
51. Hebrok M, Kim SK, St Jacques B, McMahon AP & Melton DA 2000 Regulation of pancreas development by Hedgehog signaling. Development 127 4905-4913.
52. Heller RS, Dichmann DS, Jensen J, Miller C, Wong G, Madsen OD & Serup P 2002 Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic mice suggesting a role for Wnts in pancreas and foregut pattern formation. Developmental Dynamics 225 260-270.
53. Higaki J, Quon D, Zhong Z & Cordell B 1995 Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 14 651-659.
54. Hisinaga E, Park KY, Yamada S, Hashimoto H, Takeuchi T, Mori M, Seno M, Umezawa K, Takei I & Kojima I 2008 A simple method to induce differentiation of murine bone marrow mesenchymal cells to insulin-producing cells using conophylline and betacellulin-delta4. Endocrine Journal 55 535-543.
55. Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD & Kim SK 2002 Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. PNAS 99 16105-16110.
56. Hori Y, Gu X, Xie X & Kim SK 2005 Differentiation of insulin-producing cells from human neural progenitor cells. PLoS Medicine 2 e103.
57. Huang L & Pardee AB 2000 Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. Molecular Medicine 6 849-866.
58. Hui H, Tang Y, Zhu L, Khoury N, Hui Z, Wang K, Perfetti R & Go V 2009 Glucagon like peptide-1-directed human embryonic stem cells differentiation into insulin-producing cells via Hedgehog, cAMP, and PI3K pathways. Pancreas 39 315-322.
59. Incardona JP, Gaffield W, Lange Y, Cooney A, Pentchev PG, Liu S, Watson JA, Kapur RP & Roelink H 2000 Cyclopamine inhibition of Sonic Hedgehog signal transduction is not mediated through effects on cholesterol transport. Developmental Biology 224 440-452.
60. Ishiyama N, Kanzaki M, Seno M, Yamada H, Kobayashi I & Kojima I 1998 Studies on the betacellulin receptor in pancreatic AR42J cells. Diabetologia 41 623-628.
61. Itäranta P, Chi L, SeppSnen T, Niku M, Tuukkanen J, Peltoketo H & Vainio S 2006 Wnt-4 signaling is involved in the control of smooth muscle cell fate via Bmp-4 in the medullary stroma of the developing kidney. Developmental Biology 293 473-483.
62. Ito K, Caramori G & Adcock IM 2007 Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease. Journal of Pharmacology and Experimental Therapeutics 321 1-8.
63. Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, Kageyama R, Guillemot F, Serup P & Madsen OD 2000 Control of endodermal endocrine development by Hes-1. Nature Genetics 24 36-44.
64. Jiang J, Au M, Lu K, Eshpeter A, Korbutt G, Fisk G & Majumdar AS 2007a Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25 1940-1953. (Pubitemid 47258172) (Pubitemid 47258172)
65. Jiang W, Shi Y, Zhao D, Chen S, Yong J, Zhang J, Qing T, Sun X, Zhang P, Ding M et al. 2007b In vitro derivation of functional insulin-producing cells from human embryonic stem cells. Cell Research 17 333-344.
66. Johannesson M, Ståhlberg A, Ameri J, Sand FW, Norrman K & Semb H 2009 FGF4 and retinoic acid direct differentiation of hESCs into PDX1-expressing foregut endoderm in a time- and concentration-dependent manner. PLoS ONE 4 e4794.
67. Kawahira H, Scheel DW, Smith SB, German MS & Hebrok M 2005 Hedgehog signaling regulates expansion of pancreatic epithelial cells. Developmental Biology 280 111-121.
68. Kawano Y & Kypta R 2003 Secreted antagonists of the Wnt signalling pathway. Journal of Cell Science 116 2627-2634.
69. Kim SK & Melton DA 1998 Pancreas development is promoted by cyclopamine, a Hedgehog signaling inhibitor. PNAS 95 13036-13041.
70. Kispert A, Vainio S & McMahon AP 1998 Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney. Development 125 4225-4234. (Pubitemid 28528930)
71. Kitamura K, Hoshi S, Koike M, Kiyoi H, Saito H & Naoe T 2000 Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid. British Journal of Haematology 108 696-702.
72. Kitamura RI, Ogata T, Tanaka Y, Motoyoshi K, Seno M, Takei I, Umezawa K & Kojima I 2007 Conophylline and betacellulin-delta4: an effective combination of differentiation factors for pancreatic beta cells. Endocrine Journal 54 255-264.
73. Kopan R, Schroeter EH, Weintraub H & Nye JS 1996 Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. PNAS 93 1683-1688.
74. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J et al. 2008 Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nature Biotechnology 26 443-452.
75. Ku HT, Zhang N, Kubo A, O'Connor R, Mao M, Keller G & Bromberg JS 2004 Committing embryonic stem cells to early endocrine pancreas in vitro. Stem Cells 22 1205-1217. (Pubitemid 39636399) (Pubitemid 39636399)
76. Kubo A, Shinozaki K, Shannon JM, Kouskoff V, Kennedy M, Woo S, Fehling HJ & Keller G 2004 Development of definitive endoderm from embryonic stem cells in culture. Development 131 651-1662.
77. Kuo GH, Prouty C, DeAngelis A, Shen L, O'Neill DJ, Shah C, Connolly PJ, Murray WV, Conway BR, Cheung P et al. 2003 Synthesis and discovery of macrocyclic polyoxygenated bis-7-azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-3beta inhibitors. Journal of Medicinal Chemistry 46 4021-4031.
78. Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM et al. 2001 Indirubins inhibit glycogen synthase kinase-3beta and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? Journal of Biological Chemistry 276 251-260.
79. Lee J, Wu X, di Magliano MP, Peters EC, Wang Y, Hong J, Hebrok M, Ding S, Cho CY & Schultz PG 2007 A small-molecule antagonist of the hedgehog signaling pathway. Chembiochem 8 1916-1919.
80. Lepourcelet M, Chen YN, France DS, Wang H, Crews P, Petersen F, Bruseo C, Wood AW & Shivdasani RA 2004 Small-molecule antagonists of the oncogenic Tcf/[beta]-catenin protein complex. Cancer Cell 5 91-102.
81. Lester L, Kuo HC, Andrews L, Nauert B & Wolf D 2004 Directed differentiation of rhesus monkey ES cells into pancreatic cell phenotypes. Reproductive Biology and Endocrinology 2 42.
82. Li YM, Xu M, Lai MT, Huang Q, Castro JL, Muzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG et al. 2000 Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405 689-694.
83. Liu J, Wu X, Mitchell B, Kintner C, Ding S & Schultz PG 2005 A small-molecule agonist of the Wnt signaling pathway. Angewandte Chemie (International ed. in English) 44 1987-1990.
84. Logan CY & Nusse R 2004 The Wnt signaling pathway in development and disease. Annual Review of Cell and Developmental Biology 20 781.
85. Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R & McKay R 2001 Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292 1389-1394. (Pubitemid 32476228) (Pubitemid 32476228)
86. Lundkvist J & Näslund J 2007 Gamma-secretase: a complex target for Alzheimer's disease. Current Opinion in Pharmacology 7 112-118.
87. Mandrup-Poulsen T 2003 Beta cell death and protection. Annals of the New York Academy of Sciences 1005 32-42.
88. Marigo V, Roberts DJ, Lee SMK, Tsukurov O, Levi T, Gastier JM, Epstein DJ, Gilbert DJ, Copeland NG, Seidman CE et al. 1995 Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog. Genomics 28 44-51.
89. Marikawa Y, Tamashiro DAA, Fujita TC & Alarcon VB 2008 Regulation of mesendoderm formation and axial elongation by Wnt signaling in mouse embryonal carcinoma cells. Biology of Reproduction 78 331.
90. Martín M, Gallego-Llamas J, Ribes V, Kedinger M, Niederreither K, Chambon P, Dollé P & Gradwohl G 2005 Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice. Developmental Biology 284 399-411.
91. Massagué J 1998 TGF-beta signal transduction. Annual Review of Biochemistry 67 753.
92. Massagué J & Chen YG 2000 Controlling TGF-beta signaling. Genes and Development 14 627-644.
93. McLean AB, D'Amour KA, Jones KL, Krishnamoorthy M, Kulik MJ, Reynolds DM, Sheppard AM, Liu H, Xu Y, Baetge EE et al. 2007 Activin A efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed. Stem Cells 25 29-38.
94. McLin VA, Rankin SA & Zorn AM 2007 Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development 134 2207-2217.
95. McMahon AP & Bradley A 1990 The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62 1073-1085. (Pubitemid 120035024)
96. McMahon AP, Joyner AL, Bradley A & McMahon JA 1992 The midbrain-hindbrain phenotype of Wnt-1K/Wnt-1K mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum. Cell 69 581-595.
97. Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Knockaert M, Leost M, Ryan XP, Vonica CA, Brivanlou A, Dajani R et al. 2003 GSK-3-selective inhibitors derived from tyrian purple indirubins. Chemistry & Biology 10 1255-1266.
98. Merrill BJ, Pasolli HA, Polak L, Rendl M, Garcia-Garcia MJ, Anderson KV & Fuchs E 2004 Tcf3: a transcriptional regulator of axis induction in the early embryo. Development 131 263-274.
99. Mfopou JK, Willems E, Leyns L & Bouwens L 2005 Expression of regulatory genes for pancreas development during murine embryonic stem cell differentiation. International Journal of Developmental Biology 49 915-922.
100. Mfopou JK, De Groote V, Xu X, Heimberg H & Bouwens L 2007 Sonic Hedgehog and other soluble factors from differentiating embryoid bodies inhibit pancreas development. Stem Cells 25 1156-1165.
101. Micallef SJ, Janes ME, Knezevic K, Davis RP, Elefanty AG & Stanley EG 2005 Retinoic acid induces Pdx1-positive endoderm in differentiating mouse embryonic stem cells. Diabetes 54 301-305.
102. Mielnicki LM, Ying AM, Head KL, Asch HL & Asch B 1999 Epigenetic regulation of gelsolin expression in human breast cancer cells. Experimental Cell Research 249 161-176.
103. Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R, Jacobs RT, Zacco A, Greenberg B & Ciaccio PJ 2004 Modulation of Notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicological Sciences 82 341-358.
104. Miyazaki S, Yamato E & Miyazaki JI 2004 Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Diabetes 53 1030-1037.
105. Molotkov A, Molotkova N & Duester G 2005 Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. Developmental Dynamics 232 950-957.
106. Montrose-Rafizadeh C, Avdonin P, Garant MJ, Rodgers BD, Kole S, Yang H, Levine MA, Schwindinger W & Bernier M 1999 Pancreatic glucagon-like peptide-1 receptor couples to multiple G proteins and activates mitogen-activated protein kinase pathways in Chinese hamster ovary cells. Endocrinology 140 1132-1140.
107. Munster PN, Troso-Sandoval T, Rosen N, Rifkind R, Marks PA & Richon VM 2001 The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Research 61 8492-8497. (Pubitemid 33131130)
108. Murtaugh LC, Stanger BZ, Kwan KM & Melton DA 2003 Notch signaling controls multiple steps of pancreatic differentiation. PNAS 100 14920-14925.
109. Nakanishi M, Hamazaki TS, Komazaki S, Okochi H & Asashima M 2007 Pancreatic tissue formation from murine embryonic stem cells in vitro. Differentiation 75 1-11.
110. Naujok O, Francini F, Jörns A & Lenzen S 2008a An efficient experimental strategy for mouse embryonic stem cell differentiation and separation of a cytokeratin-19-positive population of insulin-producing cells. Cell Proliferation 41 607-624.
111. Naujok O, Francini F, Picton S, Jörns A, Bailey CJ & Lenzen S 2008b A new experimental protocol for preferential differentiation of mouse embryonic stem cells into insulin-producing cells. Cell Transplantation 17 1231-1242.
112. Naylor S, Smalley MJ, Robertson D, Gusterson BA, Edwards PA & Dale TC 2000 Retroviral expression of Wnt-1 and Wnt-7b produces different effects in mouse mammary epithelium. Journal of Cell Science 113 2129-2138. (Pubitemid 30426828)
113. Ng SS, Mahmoudi T, Danenberg E, Bejaoui I, de Lau W, Korswagen HC, Schutte M & Clevers H 2009 Phosphatidylinositol 3-kinase (PI3K) signaling does not activate the Wnt cascade. Journal of Biological Chemistry 284 35308-35313.
114. Nusslein-Volhard C & Wieschaus E 1980 Mutations affecting segment number and polarity in Drosophila. Nature 287 795-801.
115. Ogata T, Li L, Yamada S, Yamamoto Y, Tanaka Y, Takei I, Umezawa K & Kojima I 2004 Promotion of beta-cell differentiation by conophylline in fetal and neonatal rat pancreas. Diabetes 53 2596-2602.
116. Onkamo P, Väänänen S, Karvonen M & Tuomilehto J 1999 Worldwide increase in incidence of type I diabetes - the analysis of the data on published incidence trends. Diabetologia 42 1395-1403.
117. Öström M, Loffler KA, Edfalk S, Selander L, Dahl U, Ricordi C, Jeon J, Correa-Medina M, Diez J & Edlund H 2008 Retinoic acid promotes the generation of pancreatic endocrine progenitor cells and their further differentiation into beta-cells. PLoS ONE 3 e2841.
118. Otonkoski T, Beattie GM, Mally MI, Ricordi C & Hayek A 1993 Nicotinamide is a potent inducer of endocrine differentiation in cultured human fetal pancreatic cells. Journal of Clinical Investigation 92 1459-1466.
119. Paek HJ, Morgan JR & Lysaght MJ 2005 Sequestration and synthesis: the source of insulin in cell clusters differentiated from murine embryonic stem cells. Stem Cells 23 862-867.
120. Paling NRD, Wheadon H, Bone HK & Welham MJ 2004 Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling. Journal of Biological Chemistry 279 48063-48070.
121. Peat AJ, Boucheron JA, Dickerson SH, Garrido D, Mills W, Peckham J, Preugschat F, Smalley T, Schweiker SL, Wilson JR et al. 2004a Novel pyrazolopyrimidine derivatives as GSK-3 inhibitors. Bioorganic & Medicinal Chemistry Letters 14 2121-2125. (Pubitemid 38481374) (Pubitemid 38481374)
122. Peat AJ, Garrido D, Boucheron JA, Schweiker SL, Dickerson SH,Wilson JR, Wang TY & Thomson SA 2004b Novel GSK-3 inhibitors with improved cellular activity. Bioorganic & Medicinal Chemistry Letters 14 2127-2130. (Pubitemid 38481375) (Pubitemid 38481375)
123. Peifer M & Polakis P 2000 Wnt signaling in oncogenesis and embryogenesis - a look outside the nucleus. Science 287 1606-1609.
124. Petrik J, Pell JM, Arany E, McDonald TJ, Dean WL, ReikW& Hill DJ 1999 Overexpression of insulin-like growth factor-II in transgenic mice is associated with pancreatic islet cell hyperplasia. Endocrinology 140 2353-2363. (Pubitemid 30636477)
125. Phillips BW, Hentze H, Rust WL, Chen QP, Chipperfield H, Tan EK, Abraham S, Sadasivam A, Soong PL, Wang ST et al. 2007 Directed differentiation of human embryonic stem cells into the pancreatic endocrine lineage. Stem Cells and Development 16 561-578.
126. Piper SC, Amtul Z, Galiranes-Garcia L, Howard VG, Ziani-Cherif C, McLendon C, Rochette MJ, Fauq A, Golde TE & Paul Murphy M 2003 Peptide-based, irreversible inhibitors of gamma-secretase activity. Biochemical and Biophysical Research Communications 305 529-533.
127. Ptasznik A, Beattie GM, Mally MI, Cirulli V, Lopez A & Hayek A 1997 Phosphatidylinositol 3-kinase is a negative regulator of cellular differentiation. Journal of Cell Biology 137 1127-1136.
128. Rada-Iglesias A, Enroth S, Ameur A, Koch CM, Clelland GK, Respuela-Alonso P, Wilcox S, Dovey OM, Ellis PD, Langford CF et al. 2007 Butyrate mediates decrease of histone acetylation centered on transcription start sites and down-regulation of associated genes. Genome Research 17 708-719.
129. Rajagopal J, Anderson WJ, Kume S, Martinez OI & Melton DA 2003 Insulin staining of ES cell progeny from insulin uptake. Science 299 363.
130. Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T et al. 2003 Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 52 588-595.
131. Rombouts K, Knittel T, Machesky L, Braet F, Wielant A, Hellemans K, De Bleser P, Gelman I, Ramadori G & Geerts A 2002 Actin filament formation, reorganization and migration are impaired in hepatic stellate cells under influence of trichostatin A, a histone deacetylase inhibitor. Journal of Hepatology 37 788-796.
132. Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JRT & Shapiro AMJ 2005 Five-year follow-up after clinical islet transplantation. Diabetes 54 2060-2069. (Pubitemid 40911269) (Pubitemid 40911269)
133. Sanvito F, Herrera PL, Huarte J, Nichols A, Montesano R, Orci L & Vassalli JD 1994 TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro. Development 120 3451-3462.
134. Schier AF & Shen MM 2000 Nodal signalling in vertebrate development. Nature 403 385-389.
135. Schroeder IS, Rolletschek A, Blyszczuk P, Kania G & Wobus AM 2006 Differentiation of mouse embryonic stem cells to insulin-producing cells. Nature Protocols 1 495-507.
136. Seaberg RM, Smukler SR, Kieffer TJ, Enikolopov G, Asghar Z, Wheeler MB, Korbutt G & van der Kooy D 2004 Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nature Biotechnology 22 1115-1124.
137. Segev H, Fishman B, Ziskind A, Shulman M & Itskovitz-Eldor J 2004 Differentiation of human embryonic stem cells into insulin-producing clusters. Stem Cells 22 265-274. (Pubitemid 38736611) (Pubitemid 38736611)
138. Seiffert D, Bradley JD, Rominger CM, Rominger DH, Yang F, Meredith JE Jr, Wang Q, Roach AH, Thompson LA, Spitz SM et al. 2000 Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors. Journal of Biological Chemistry 275 34086-34091.
139. Serafimidis I, Rakatzi I, Episkopou V, Gouti M & Gavalas A 2008 Novel effectors of directed and Ngn3-mediated differentiation of mouse embryonic stem cells into endocrine pancreas progenitors. Stem Cells 26 3-16.
140. Sernee FM, Evin G, Culvenor JG, Villadangos JA, Beyreuther K, Masters CL & Cappai R 2003 Selecting cells with different Alzheimer's disease gamma-secretase activity using FACS. Differential effect on presenilin exon 9 gamma- and epsilon-cleavage. European Journal of Biochemistry 270 495-506.
141. Shan J, Shi D-L, Wang J & Zheng J 2005 Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 44 15495-15503.
142. Shapiro AMJ, Lakey JRT, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM & Rajotte RV 2000 Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. New England Journal of Medicine 343 230-238.
143. Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, Hunt P, Nadin A, Smith AL, Stevenson G & Castro JL 2000 L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry 39 8698-8704.
144. Shi Y, Hou L, Tang F, Jiang W, Wang P, Ding M & Deng H 2005 Inducing embryonic stem cells to differentiate into pancreatic beta cells by a novel three-step approach with activin A and all-trans retinoic acid. Stem Cells 23 656-662.
145. Shim JH, Kim SE, Woo DH, Kim SK, Oh CH, McKay R & Kim JH 2007 Directed differentiation of human embryonic stem cells towards a pancreatic cell fate. Diabetologia 50 1228-1238.
146. Shiraki N, Lai CJ, Hishikari Y & Kume S 2005 TGF-beta signaling potentiates differentiation of embryonic stem cells to Pdx1 expressing endodermal cells. Genes to Cells 10 503-516.
147. Shiroi A, Ueda S, Ouji Y, Moriya K, Sugie Y, Fukui H, Ishizaka S & Yoshikawa M 2005 Differentiation of embryonic stem cells into insulin-producing cells promoted by Nkx2-2 gene transfer. World Journal of Gastroenterology 11 4161-4166.
148. Sipione S, Eshpeter A, Lyon JG, Korbutt GS & Bleackley RC 2004 Insulin expressing cells from differentiated embryonic stem cells are not beta cells. Diabetologia 47 499-508.
149. Skoudy A, Rovira M, Savatier P, Martin F, León-Quinto T, Soria B & Real FX 2004 Transforming growth factor (TGF) beta, fibroblast growth factor (FGF) and retinoid signalling pathways promote pancreatic exocrine gene expression in mouse embryonic stem cells. Biochemical Journal 379 749-756.
150. Soria B, Roche E, Berná G, León-Quinto T, Reig JA & Martín F 2000 Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49 157-162. (Pubitemid 30070992)
151. Stambolic V, Ruel L & Woodgett JR 1996 Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Current Biology 6 1664-1669.
152. Strulovici Y, Leopold PL, O'Connor TP, Pergolizzi RG & Crystal RG 2007 Human embryonic stem cells and gene therapy. Molecular Therapy 15 850-866.
153. Suzuki A, Nakauchi H & Taniguchi H 2004 Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. Diabetes 53 2143-2152.
154. Tada S, Era T, Furusawa C, Sakurai H, Nishikawa S, Kinoshita M, Nakao K, Chiba T & Nishikawa SI 2005 Characterization of mesendoderm: a diverging point of the definitive endoderm and mesoderm in embryonic stem cell differentiation culture. Development 132 4363-4374.
155. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP & Beachy PA 2000 Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406 1005-1009.
156. Taniguchi Y, Karlstrom H, Lundkvist J, Mizutani T, Otaka A, Vestling M, Bernstein A, Donoviel D, Lendahl U & Honjo T 2002 Notch receptor cleavage depends on but is not directly executed by presenilins. PNAS 99 4014-4019.
157. Tayaramma T, Ma B, Rohde M & Mayer H 2006 Chromatin-remodeling factors allow differentiation of bone marrow cells into insulin-producing cells. Stem Cells 24 2858-2867.
158. Tei E, Mehta S, Tulachan SS, Yew H, Hembree M, Preuett B, Snyder C, Yamataka A, Miyano T & Gittes G 2005 Synergistic endocrine induction by GLP-1 and TGF-[beta] in the developing pancreas. Pancreas 31 138-141.
159. Thomas MK, Rastalsky N, Lee JH & Habener JF 2000 Hedgehog signaling regulation of insulin production by pancreatic beta-cells. Diabetes 49 2039-2047.
160. Thomas MK, Lee JH, Rastalsky N & Habener JF 2001 Hedgehog signaling regulation of homeodomain protein islet duodenum homeobox-1 expression in pancreatic beta-cells. Endocrinology 142 1033-1040.
161. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS & Jones JM 1998 Embryonic stem cell lines derived from human blastocysts. Science 282 1145-1147.
162. Tremblay KD, Hoodless PA, Bikoff EK & Robertson EJ 2000 Formation of the definitive endoderm in mouse is a Smad2-dependent process. Development 127 3079-3090.
163. Trosset J-Y, Dalvit C, Knapp S, Fasolini M, Veronesi M, Mantegani S, Gianellini LM, Catana C, Sundström M, Stouten PFW et al. 2006 Inhibition of protein-protein interactions: the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening. Proteins 64 60-67.
164. Tsang CK, Qi H, Liu LF & Zheng XFS 2007 Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discovery Today 12 112-124.
165. Uchida H, Maruyama T, Nagashima T, Asada H & Yoshimura Y 2005 Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin. Endocrinology 146 5365-5373.
166. Umezawa K, Ohse T, Yamamoto T, Koyano T & Takahashi Y 1994 Isolation of a new vinca alkaloid from the leaves of Ervatamia microphylla as an inhibitor of ras functions. Anticancer Research 14 2413-2417.
167. Umezawa K, Hiroki A, Kawakami M, Naka H, Takei I, Ogata T, Kojima I, Koyano T, Kowithayakorn T, Pang H-S et al. 2003 Induction of insulin production in rat pancreatic acinar carcinoma cells by conophylline. Biomedicine & Pharmacotherapy 57 341-350.
168. Vaca P, Berná G, Martín F & Soria B 2003 Nicotinamide induces both proliferation and differentiation of embryonic stem cells into insulin-producing cells. Transplantation Proceedings 35 2021-2023.
169. Vaca P, Berná G, Araujo R, Carneiro EM, Bedoya FJ, Soria B & Martín F 2008 Nicotinamide induces differentiation of embryonic stem cells into insulin-secreting cells. Experimental Cell Research 314 969-974.
170. Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ & Waterfield MD 2001 Synthesis and function of 3-phosphorylated inositol lipids. Annual Review of Biochemistry 70 535.
171. Villavicencio EH, Walterhouse DO & Iannaccone PM 2000 The sonic Hedgehog-Patched-Gli pathway in human development and disease. American Journal of Human Genetics 67 1047-1054.
172. Vincent SD, Dunn NR, Hayashi S, Norris DP & Robertson EJ 2003 Cell fate decisions within the mouse organizer are governed by graded Nodal signals. Genes and Development 17 1646-1662.
173. Wang X, Cahill CM, Pineyro MA, Zhou J, Doyle ME & Egan JM 1999 Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells. Endocrinology 140 4904-4907. (Pubitemid 30666159)
174. Ward S, Sotsios Y, Dowden J, Bruce I & Finan P 2003 Therapeutic potential of phosphoinositide 3-kinase inhibitors. Chemistry & Biology 10 207-213. (Pubitemid 36380277) (Pubitemid 36380277)
175. Watanabe S, Umehara H, Murayama K, Okabe M, Kimura T & Nakano T 2006 Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells. Oncogene 25 2697-2707.
176. Wells J, Esni F, Boivin G, Aronow B, Stuart W, Combs C, Sklenka A, Leach S & Lowy A 2007 Wnt/beta-catenin signaling is required for development of the exocrine pancreas. BMC Developmental Biology 7 4.
177. Williams JA, Guicherit OM, Zaharian BI, Xu Y, Chai L, Wichterle H, Kon C, Gatchalian C, Porter JA, Rubin LL et al. 2003 Identification of a small molecule inhibitor of the Hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. PNAS 100 4616-4621.
178. Wolfe MS, Citron M, Diehl TS, Xia W, Donkor IO & Selkoe DJ 1998 A substrate-based difluoro ketone selectively inhibits Alzheimer's gamma-secretase activity. Journal of Medicinal Chemistry 41 6-9. (Pubitemid 128719273)
179. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ et al. 2004 Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. Journal of Biological Chemistry 279 12876-12882.
180. Wu X, Walker J, Zhang J, Ding S & Schultz PG 2004 Purmorphamine induces osteogenesis by activation of the Hedgehog signaling pathway. Chemistry and Biology 11 1229-1238.
181. Yasunaga M, Tada S, Torikai-Nishikawa S, Nakano Y, Okada M, Jakt LM, Nishikawa S, Chiba T, Era T & Nishikawa SI 2005 Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nature Biotechnology 23 1542-1550.
182. Yoon J-W & Jun H-S 2005 Autoimmune destruction of pancreatic beta cells. American Journal of Therapeutics 12 580-591.
183. Yue F, Cui L, Johkura K, Ogiwara N & Sasaki K 2006 Glucagon-like peptide-1 differentiation of primate embryonic stem cells into insulin-producing cells. Tissue Engineering 12 2105-2116. (Pubitemid 44734970) (Pubitemid 44734970)
184. Zhang Q, Major MB, Takanashi S, Camp ND, Nishiya N, Peters EC, Ginsberg MH, Jian X, Randazzo PA, Schultz PG et al. 2007 Smallmolecule synergist of the Wnt/beta-catenin signaling pathway. PNAS 104 7444-7448.
185. Zhang D, Jiang W, Liu M, Sui X, Yin X, Chen S, Shi Y & Deng H 2009 Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Research 19 429-438.
186. Zhou J, Pineyro MA, Wang X, Doyle ME & Egan JM 2002 Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors. Journal of Cell Physiology 192 304-314.
187. Zhu S, Wurdak H, Wang J, Lyssiotis CA, Peters EC, Cho CY, Wu X & Schultz PG 2009 A small molecule primes embryonic stem cells for differentiation. Cell Stem Cell 4 416-426.