Cell and Tissue Research

, Volume 331, Issue 1, pp 5–22 | Cite as

Pluripotency of embryonic stem cells

  • Satoshi Yamanaka
  • Jinliang Li
  • Gabriela Kania
  • Steve Elliott
  • Robert P. Wersto
  • Jennifer Van Eyk
  • Anna M. Wobus
  • Kenneth R. BohelerEmail author


Embryonic stem (ES) cells derived from pre-implantation embryos have the potential to differentiate into any cell type derived from the three germ layers of ectoderm (epidermal tissues and nerves), mesoderm (muscle, bone, blood), and endoderm (liver, pancreas, gastrointestinal tract, lungs), including fetal and adult cells. Alone, these cells do not develop into a viable fetus or adult animal because they do not retain the potential to contribute to extraembryonic tissue, and in vitro, they lack spatial and temporal signaling cues essential to normal in vivo development. The basis of pluripotentiality resides in conserved regulatory networks composed of numerous transcription factors and multiple signaling cascades. Together, these regulatory networks maintain ES cells in a pluripotent and undifferentiated form; however, alterations in the stoichiometry of these signals promote differentiation. By taking advantage of this differentiation capacity in vitro, ES cells have clearly been shown to possess the potential to generate multipotent stem and progenitor cells capable of differentiating into a limited number of cell fates. These latter types of cells may prove to be therapeutically viable, but perhaps more importantly, the studies of these cells have led to a greater understanding of mammalian development.


Embryonic stem cells Pluripotency Differentiation Development 


  1. Ambrosetti DC, Basilico C, Dailey L (1997) Synergistic activation of the fibroblast growth factor 4 enhancer by Sox2 and Oct-3 depends on protein-protein interactions facilitated by a specific spatial arrangement of factor binding sites. Mol Cell Biol 17:6321–6329PubMedGoogle Scholar
  2. Amit M, Shariki C, Margulets V, Itskovitz-Eldor J (2004) Feeder layer- and serum-free culture of human embryonic stem cells. Biol Reprod 70:837–845PubMedGoogle Scholar
  3. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823–826PubMedGoogle Scholar
  4. Anger M, Bryja V, Jirmanova L, Hampl A, Carrington M, Motlik J, Dvorak P, Kubelka M (2003) The appearance of truncated cyclin A2 correlates with differentiation of mouse embryonic stem cells. Biochem Biophys Res Commun 302:825–830PubMedGoogle Scholar
  5. Aubert J, Dunstan H, Chambers I, Smith A (2002) Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat Biotechnol 20:1240–1245PubMedGoogle Scholar
  6. Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17:126–140PubMedGoogle Scholar
  7. Bagutti C, Wobus AM, Fassler R, Watt FM (1996) Differentiation of embryonal stem cells into keratinocytes: comparison of wild-type and beta 1 integrin-deficient cells. Dev Biol 179:184–196PubMedGoogle Scholar
  8. Bhagavati S, Xu W (2005) Generation of skeletal muscle from transplanted embryonic stem cells in dystrophic mice. Biochem Biophys Res Commun 333:644–649PubMedGoogle Scholar
  9. 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. Proc Natl Acad Sci USA 100:998–1003PubMedGoogle Scholar
  10. Blyszczuk P, Asbrand C, Rozzo A, Kania G, St-Onge L, Rupnik M, Wobus AM (2004) Embryonic stem cells differentiate into insulin-producing cells without selection of nestin-expressing cells. Int J Dev Biol 48:1095–1104PubMedGoogle Scholar
  11. Boeuf H, Hauss C, Graeve FD, Baran N, Kedinger C (1997) Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells. J Cell Biol 138:1207–1217PubMedGoogle Scholar
  12. Boheler KR, Czyz J, Tweedie D, Yang HT, Anisimov SV, Wobus AM (2002) Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res 91:189–201PubMedGoogle Scholar
  13. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956PubMedGoogle Scholar
  14. Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441:349–353PubMedGoogle Scholar
  15. Buehr M, Smith A (2003) Genesis of embryonic stem cells. Philos Trans R Soc Lond Biol 358:1397–1402PubMedGoogle Scholar
  16. Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H, Meng S, Chen Y, Zhou R, Song X, Guo Y, Ding M, Deng H (2007) Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 45:1229–1239PubMedGoogle Scholar
  17. Cartwright P, McLean C, Sheppard A, Rivett D, Jones K, Dalton S (2005) LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 132:885–896PubMedGoogle Scholar
  18. Catena R, Tiveron C, Ronchi A, Porta S, Ferri A, Tatangelo L, Cavallaro M, Favaro R, Ottolenghi S, Reinbold R, Scholer H, Nicolis SK (2004) Conserved POU binding DNA sites in the Sox2 upstream enhancer regulate gene expression in embryonic and neural stem cells. J Biol Chem 279:41846–41857PubMedGoogle Scholar
  19. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643–655PubMedGoogle Scholar
  20. Chang KH, Zandstra PW (2004) Quantitative screening of embryonic stem cell differentiation: endoderm formation as a model. Biotechnol Bioeng 88:287–298PubMedGoogle Scholar
  21. Chapman G, Remiszewski JL, Webb GC, Schulz TC, Bottema CD, Rathjen PD (1997) The mouse homeobox gene, Gbx2: genomic organization and expression in pluripotent cells in vitro and in vivo. Genomics 46:223–233PubMedGoogle Scholar
  22. Choi D, Lee HJ, Jee S, Jin S, Koo SK, Paik SS, Jung SC, Hwang SY, Lee KS, Oh B (2005) In vitro differentiation of mouse embryonic stem cells: enrichment of endodermal cells in the embryoid body. Stem Cells 23:817–827PubMedGoogle Scholar
  23. Coraux C, Hilmi C, Rouleau M, Spadafora A, Hinnrasky J, Ortonne JP, Dani C, Aberdam D (2003) Reconstituted skin from murine embryonic stem cells. Curr Biol 13:849–853PubMedGoogle Scholar
  24. Daley GQ (2007) Gametes from embryonic stem cells: a cup half empty or half full? Science 316:409–410PubMedGoogle Scholar
  25. D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE (2005) Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23:1534–1541PubMedGoogle Scholar
  26. 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. Nat Biotechnol 24:1392–1401PubMedGoogle Scholar
  27. Damelin M, Sun YE, Sodja VB, Bestor TH (2005) Decatenation checkpoint deficiency in stem and progenitor cells. Cancer Cell 8:479–484PubMedGoogle Scholar
  28. Dang SM, Zandstra PW (2005) Scalable production of embryonic stem cell-derived cells. Methods Mol Biol 290:353–364PubMedGoogle Scholar
  29. Darr H, Mayshar Y, Benvenisty N (2006) Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features. Development 133:1193–1201PubMedGoogle Scholar
  30. Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R (1985) The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol 87:27–45PubMedGoogle Scholar
  31. Drab M, Haller H, Bychkov R, Erdmann B, Lindschau C, Haase H, Morano I, Luft FC, Wobus AM (1997) From totipotent embryonic stem cells to spontaneously contracting smooth muscle cells: a retinoic acid and db-cAMP in vitro differentiation model. FASEB J 11:905–915PubMedGoogle Scholar
  32. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156PubMedGoogle Scholar
  33. Fan Y, Melhem MF, Chaillet JR (1999) Forced expression of the homeobox-containing gene Pem blocks differentiation of embryonic stem cells. Dev Biol 210:481–496PubMedGoogle Scholar
  34. Fehling HJ, Lacaud G, Kubo A, Kennedy M, Robertson S, Keller G, Kouskoff V (2003) Tracking mesoderm induction and its specification to the hemangioblast during embryonic stem cell differentiation. Development 130:4217–4227PubMedGoogle Scholar
  35. Fraser ST, Yamashita J, Jakt LM, Okada M, Ogawa M, Nishikawa S (2003) In vitro differentiation of mouse embryonic stem cells: hematopoietic and vascular cell types. Methods Enzymol 365:59–72PubMedCrossRefGoogle Scholar
  36. Fujii-Yamamoto H, Kim JM, Arai K, Masai H (2005) Cell cycle and developmental regulations of replication factors in mouse embryonic stem cells. J Biol Chem 280:12976–12987PubMedGoogle Scholar
  37. Galan-Caridad JM, Harel S, Arenzana TL, Hou ZE, Doetsch FK, Mirny LA, Reizis B (2007) Zfx controls the self-renewal of embryonic and hematopoietic stem cells. Cell 129:345–357PubMedGoogle Scholar
  38. Gardner RL (1985) Clonal analysis of early mammalian development. Philos Trans R Soc Lond Biol 312:163–178PubMedGoogle Scholar
  39. Gottlieb DI, Huettner JE (1999) An in vitro pathway from embryonic stem cells to neurons and glia. Cells Tissues Organs 165:165–172PubMedGoogle Scholar
  40. Gouon-Evans V, Boussemart L, Gadue P, Nierhoff D, Koehler CI, Kubo A, Shafritz DA, Keller G (2006) BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol 24:1402–1411PubMedGoogle Scholar
  41. Halban PA (2004) Cellular sources of new pancreatic beta cells and therapeutic implications for regenerative medicine. Nat Cell Biol 6:1021–1025PubMedGoogle Scholar
  42. Hansson M, Tonning A, Frandsen U, Petri A, Rajagopal J, Englund MC, Heller RS, Hakansson J, Fleckner J, Skold HN, Melton D, Semb H, Serup P (2004) Artifactual insulin release from differentiated embryonic stem cells. Diabetes 53:2603–2609PubMedGoogle Scholar
  43. Heo J, Factor VM, Uren T, Takahama Y, Lee JS, Major M, Feinstone SM, Thorgeirsson SS (2006) Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver. Hepatology 44:1478–1486PubMedGoogle Scholar
  44. Hosler BA, Rogers MB, Kozak CA, Gudas LJ (1993) An octamer motif contributes to the expression of the retinoic acid-regulated zinc finger gene Rex-1 (Zfp-42) in F9 teratocarcinoma cells. Mol Cell Biol 13:2919–2928PubMedGoogle Scholar
  45. Humphrey RK, Beattie GM, Lopez AD, Bucay N, King CC, Firpo MT, Rose-John S, Hayek A (2004) Maintenance of pluripotency in human embryonic stem cells is STAT3 independent. Stem Cells 22:522–530PubMedGoogle Scholar
  46. Ishii T, Yasuchika K, Fujii H, Hoppo T, Baba S, Naito M, Machimoto T, Kamo N, Suemori H, Nakatsuji N, Ikai I (2005) In vitro differentiation and maturation of mouse embryonic stem cells into hepatocytes. Exp Cell Res 309:68–77PubMedGoogle Scholar
  47. Kattman SJ, Huber TL, Keller GM (2006) Multipotent Flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. Dev Cell 11:723–732PubMedGoogle Scholar
  48. Kania G, Blyszczuk P, Jochheim A, Ott M, Wobus AM (2004) Generation of glycogen and albumin producing hepatocyte like cells from embryonic stem cells. Biol Chem 385:943–953PubMedGoogle Scholar
  49. Kawasaki H, Mizuseki K, Nishikawa S, Kaneko S, Kuwana Y, Nakanishi S, Nishikawa SI, Sasai Y (2000) Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28:31–40PubMedGoogle Scholar
  50. Kennedy M, D’Souza SL, Lynch-Kattman M, Schwantz S, Keller G (2007) Development of the hemangioblast defines the onset of hematopoiesis in human ES cell differentiation cultures. Blood 109:2679–2687PubMedGoogle Scholar
  51. Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 418:50–56PubMedGoogle Scholar
  52. Kimelman D, Griffin KJ (2000) Vertebrate mesendoderm induction and patterning. Curr Opin Genet Dev 10:350–356PubMedGoogle Scholar
  53. Koban MU, Brugh SA, Riordon DR, Dellow KA, Yang HT, Tweedie D, Boheler KR (2001) A distant upstream region of the rat multipartite Na(+)-Ca(2+) exchanger NCX1 gene promoter is sufficient to confer cardiac-specific expression. Mech Dev 109:267–279PubMedGoogle Scholar
  54. Kouskoff V, Lacaud G, Schwantz S, Fehling HJ, Keller G (2005) Sequential development of hematopoietic and cardiac mesoderm during embryonic stem cell differentiation. Proc Natl Acad Sci USA 102:13170–13175PubMedGoogle Scholar
  55. 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 131:1651–1662PubMedGoogle Scholar
  56. Kuroda T, Tada M, Kubota H, Kimura H, Hatano SY, Suemori H, Nakatsuji N, Tada T (2005) Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Mol Cell Biol 25:2475–2485PubMedGoogle Scholar
  57. Lako M, Lindsay S, Lincoln J, Cairns PM, Armstrong L, Hole N (2001) Characterisation of Wnt gene expression during the differentiation of murine embryonic stem cells in vitro: role of Wnt3 in enhancing haematopoietic differentiation. Mech Dev 103:49–59PubMedGoogle Scholar
  58. Lavon N, Yanuka O, Benvenisty N (2004) Differentiation and isolation of hepatic-like cells from human embryonic stem cells. Differentiation 72:230–238PubMedGoogle Scholar
  59. Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD (2000) Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 18:675–679PubMedGoogle Scholar
  60. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP, Melton DA, Gifford DK, Jaenisch R, Young RA (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125:301–313PubMedGoogle Scholar
  61. Lee JP, Jeyakumar M, Gonzalez R, Takahashi H, Lee PJ, Baek RC, Clark D, Rose H, Fu G, Clarke J, McKercher S, Meerloo J, Muller FJ, Park KI, Butters TD, Dwek RA, Schwartz P, Tong G, Wenger D, Lipton SA, Seyfried TN, Platt FM, Snyder EY (2007) Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med 13:439–447PubMedGoogle Scholar
  62. Leon-Quinto T, Jones J, Skoudy A, Burcin M, Soria B (2004) In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells. Diabetologia 47:1442–1451PubMedGoogle Scholar
  63. Li J, Pan G, Cui K, Liu Y, Xu S, Pei D (2007) A dominant negative form of mouse Sox2 induces trophectoderm differentiation and progressive polyploidy in mouse ES cells. J Biol Chem 15:15Google Scholar
  64. Lim LS, Loh YH, Zhang W, Li Y, Chen X, Wang Y, Bakre M, Ng HH, Stanton LW (2007) Zic3 is required for maintenance of pluripotency in embryonic stem cells. Mol Biol Cell 18:1348–1358PubMedGoogle Scholar
  65. Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y (2005) p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 7:165–171PubMedGoogle Scholar
  66. Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong KY, Sung KW, Lee CW, Zhao XD, Chiu KP, Lipovich L, Kuznetsov VA, Robson P, Stanton LW, Wei CL, Ruan Y, Lim B, Ng HH (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38:431–440PubMedGoogle Scholar
  67. Louvi A, Artavanis-Tsakonas S (2006) Notch signalling in vertebrate neural development. Nat Rev Neurosci 7:93–102PubMedGoogle Scholar
  68. Lowell S, Benchoua A, Heavey B, Smith AG (2006) Notch promotes neural lineage entry by pluripotent embryonic stem cells. PLoS Biol 4:e121PubMedGoogle Scholar
  69. 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 292:1389–1394PubMedGoogle Scholar
  70. Maguire T, Novik E, Schloss R, Yarmush M (2006) Alginate-PLL microencapsulation: effect on the differentiation of embryonic stem cells into hepatocytes. Biotechnol Bioeng 93:581–591PubMedGoogle Scholar
  71. Mantel C, Guo Y, Lee MR, Kim MK, Han MK, Shibayama H, Fukuda S, Yoder MC, Pelus LM, Kim KS, Broxmeyer HE (2007) Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability. Blood 109:4518–4527PubMedGoogle Scholar
  72. Marchetti S, Gimond C, Iljin K, Bourcier C, Alitalo K, Pouyssegur J, Pages G (2002) Endothelial cells genetically selected from differentiating mouse embryonic stem cells incorporate at sites of neovascularization in vivo. J Cell Sci 115:2075–2085PubMedGoogle Scholar
  73. Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78:7634–7638PubMedGoogle Scholar
  74. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642PubMedGoogle Scholar
  75. Miyazaki S, Yamato E, Miyazaki J (2004) Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Diabetes 53:1030–1037PubMedGoogle Scholar
  76. Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K (2002) Two major Smad pathways in TGF-beta superfamily signalling. Genes Cells 7:1191–1204PubMedGoogle Scholar
  77. Mizuseki K, Sakamoto T, Watanabe K, Muguruma K, Ikeya M, Nishiyama A, Arakawa A, Suemori H, Nakatsuji N, Kawasaki H, Murakami F, Sasai Y (2003) Generation of neural crest-derived peripheral neurons and floor plate cells from mouse and primate embryonic stem cells. Proc Natl Acad Sci USA 100:5828–5833PubMedGoogle Scholar
  78. Motohashi T, Aoki H, Yoshimura N, Kunisada T (2006) Induction of melanocytes from embryonic stem cells and their therapeutic potential. Pigment Cell Res 19:284–289PubMedGoogle Scholar
  79. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Schoeler H, Smith A (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379–391PubMedGoogle Scholar
  80. Nishikawa SI, Nishikawa S, Hirashima M, Matsuyoshi N, Kodama H (1998) Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development 125:1747–1757PubMedGoogle Scholar
  81. Niwa H, Miyazaki J, Smith AG (2000) Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24:372–376PubMedGoogle Scholar
  82. Niwa H, Toyooka Y, Shimosato D, Strumpf D, Takahashi K, Yagi R, Rossant J (2005) Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123:917–929PubMedGoogle Scholar
  83. Ogawa K, Nishinakamura R, Iwamatsu Y, Shimosato D, Niwa H (2006) Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. Biochem Biophys Res Commun 343:159–166PubMedGoogle Scholar
  84. Ogawa K, Saito A, Matsui H, Suzuki H, Ohtsuka S, Shimosato D, Morishita Y, Watabe T, Niwa H, Miyazono K (2007) Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells. J Cell Sci 120:55–65PubMedGoogle Scholar
  85. Okamoto K, Okazawa H, Okuda A, Sakai M, Muramatsu M, Hamada H (1990) A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 60:461–472PubMedGoogle Scholar
  86. Okuda A, Fukushima A, Nishimoto M, Orimo A, Yamagishi T, Nabeshima Y, Kuro-o M, Boon K, Keaveney M, Stunnenberg HG, Muramatsu M (1998) UTF1, a novel transcriptional coactivator expressed in pluripotent embryonic stem cells and extra-embryonic cells. EMBO J 17:2019–2032PubMedGoogle Scholar
  87. Okumura-Nakanishi S, Saito M, Niwa H, Ishikawa F (2005) Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. J Biol Chem 280:5307–5317PubMedGoogle Scholar
  88. Park CH, Minn YK, Lee JY, Choi DH, Chang MY, Shim JW, Ko JY, Koh HC, Kang MJ, Kang JS, Rhie DJ, Lee YS, Son H, Moon SY, Kim KS, Lee SH (2005) In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J Neurochem 92:1265–1276PubMedGoogle Scholar
  89. Pfendler KC, Catuar CS, Meneses JJ, Pedersen RA (2005) Overexpression of Nodal promotes differentiation of mouse embryonic stem cells into mesoderm and endoderm at the expense of neuroectoderm formation. Stem Cells Dev 14:162–172PubMedGoogle Scholar
  90. Pomp O, Brokhman I, Ben-Dor I, Reubinoff B, Goldstein RS (2005) Generation of peripheral sensory and sympathetic neurons and neural crest cells from human embryonic stem cells. Stem Cells 23:923–930PubMedGoogle Scholar
  91. Quinn G, Ochiya T, Terada M, Yoshida T (2000) Mouse flt-1 promoter directs endothelial-specific expression in the embyroid body model of embryogenesis. Biochem Biophys Res Commun 276:1089–1099PubMedGoogle Scholar
  92. Rajagopal J, Anderson WJ, Kume S, Martinez OI, Melton DA (2003) Insulin staining of ES cell progeny from insulin uptake. Science 299:363PubMedGoogle Scholar
  93. Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850PubMedGoogle Scholar
  94. Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P (2005) Transcriptional regulation of Nanog by OCT4 and SOX2. J Biol Chem 280:24731–24737PubMedGoogle Scholar
  95. Rohwedel J, Maltsev V, Bober E, Arnold HH, Hescheler J, Wobus AM (1994) Muscle cell differentiation of embryonic stem cells reflects myogenesis in vivo: developmentally regulated expression of myogenic determination genes and functional expression of ionic currents. Dev Biol 164:87–101PubMedGoogle Scholar
  96. Rolletschek A, Kania G, Wobus AM (2006) Generation of pancreatic insulin-producing cells from embryonic stem cells—“proof of principle”, but questions still unanswered. Diabetologia 49:2541–2545PubMedGoogle Scholar
  97. Savatier P, Lapillonne H, van Grunsven LA, Rudkin BB, Samarut J (1996) Withdrawal of differentiation inhibitory activity/leukemia inhibitory factor up-regulates D-type cyclins and cyclin-dependent kinase inhibitors in mouse embryonic stem cells. Oncogene 12:309–322PubMedGoogle Scholar
  98. Schoeler HR, Balling R, Hatzopoulos AK, Suzuki N, Gruss P (1989) Octamer binding proteins confer transcriptional activity in early mouse embryogenesis. EMBO J 8:2551–2557Google Scholar
  99. Schoeler HR, Ruppert S, Suzuki N, Chowdhury K, Gruss P (1990) New type of POU domain in germ line-specific protein Oct-4. Nature 344:435–439Google Scholar
  100. Schroeder IS, Rolletschek A, Blyszczuk P, Kania G, Wobus AM (2006) Differentiation of mouse embryonic stem cells to insulin-producing cells. Nat Protoc 1:495–507PubMedGoogle Scholar
  101. Schwartz RE, Linehan JL, Painschab MS, Hu WS, Verfaillie CM, Kaufman DS (2005) Defined conditions for development of functional hepatic cells from human embryonic stem cells. Stem Cells Dev 14:643–655PubMedGoogle Scholar
  102. Shalaby F, Ho J, Stanford WL, Fischer KD, Schuh AC, Schwartz L, Bernstein A, Rossant J (1997) A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 89:981–990PubMedGoogle Scholar
  103. 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 23:656–662PubMedGoogle Scholar
  104. Shiroi A, Yoshikawa M, Yokota H, Fukui H, Ishizaka S, Tatsumi K, Takahashi Y (2002) Identification of insulin-producing cells derived from embryonic stem cells by zinc-chelating dithizone. Stem Cells 20:284–292PubMedGoogle Scholar
  105. Singla DK, Schneider DJ, LeWinter MM, Sobel BE (2006) wnt3a but not wnt11 supports self-renewal of embryonic stem cells. Biochem Biophys Res Commun 345:789–795PubMedGoogle Scholar
  106. Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D (1988) Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336:688–690PubMedGoogle Scholar
  107. Snow MH, Bennett D (1978) Gastrulation in the mouse: assessment of cell populations in the epiblast of tw18/tw18 embryos. J Embryol Exp Morphol 47:39–52PubMedGoogle Scholar
  108. Soria B (2001) In-vitro differentiation of pancreatic beta-cells. Differentiation 68:205–219PubMedGoogle Scholar
  109. Soto-Gutierrez A, Navarro-Alvarez N, Zhao D, Rivas-Carrillo JD, Lebkowski J, Tanaka N, Fox IJ, Kobayashi N (2007) Differentiation of mouse embryonic stem cells to hepatocyte-like cells by co-culture with human liver nonparenchymal cell lines. Nat Protoc 2:347–356PubMedGoogle Scholar
  110. Sutton J, Costa R, Klug M, Field L, Xu D, Largaespada DA, Fletcher CF, Jenkins NA, Copeland NG, Klemsz M, Hromas R (1996) Genesis, a winged helix transcriptional repressor with expression restricted to embryonic stem cells. J Biol Chem 271:23126–23133PubMedGoogle Scholar
  111. Tada S, Era T, Furusawa C, Sakurai H, Nishikawa S, Kinoshita M, Nakao K, Chiba T (2005) Characterization of mesendoderm: a diverging point of the definitive endoderm and mesoderm in embryonic stem cell differentiation culture. Development 132:4363–4374PubMedGoogle Scholar
  112. Takahashi T, Lord B, Schulze PC, Fryer RM, Sarang SS, Gullans SR, Lee RT (2003) Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 107:1912–1916PubMedGoogle Scholar
  113. Tanaka Y, Patestos NP, Maekawa T, Ishii S (1999) B-myb is required for inner cell mass formation at an early stage of development. J Biol Chem 274:28067–28070PubMedGoogle Scholar
  114. Teratani T, Yamamoto H, Aoyagi K, Sasaki H, Asari A, Quinn G, Terada M, Ochiya T (2005) Direct hepatic fate specification from mouse embryonic stem cells. Hepatology 41:836–846PubMedGoogle Scholar
  115. 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 282:1145–1147PubMedGoogle Scholar
  116. Troy TC, Turksen K (2005) Commitment of embryonic stem cells to an epidermal cell fate and differentiation in vitro. Dev Dyn 232:293–300PubMedGoogle Scholar
  117. Vaca P, Martin F, Vegara-Meseguer JM, Rovira JM, Berna G, Soria B (2006) Induction of differentiation of embryonic stem cells into insulin-secreting cells by fetal soluble factors. Stem Cells 24:258–265PubMedGoogle Scholar
  118. Wang ZZ, Au P, Chen T, Shao Y, Daheron LM, Bai H, Arzigian M, Fukumura D, Jain RK, Scadden DT (2007) Endothelial cells derived from human embryonic stem cells form durable blood vessels in vivo. Nat Biotechnol 25:317–318PubMedGoogle Scholar
  119. Weitzer G (2005) Embryonic stem cell-derived embryoid bodies: an in vitro model of eutherian pregastrulation development and early gastrulation. Handb Exp Pharmacol 174:21–51CrossRefGoogle Scholar
  120. Wiles MV, Johansson BM (1997) Analysis of factors controlling primary germ layer formation and early hematopoiesis using embryonic stem cell in vitro differentiation. Leukemia 11 (Suppl 3):454–456PubMedGoogle Scholar
  121. Wiles MV, Keller G (1991) Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture. Development 111:259–267PubMedGoogle Scholar
  122. Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM (1988) Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336:684–687PubMedGoogle Scholar
  123. Wobus AM, Boheler KR (2005) Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol Rev 85:635–678PubMedGoogle Scholar
  124. Wobus AM, Guan K, Yang H-T, Boheler KR (2002) Embryonic stem cells as a model to study cardiac, skeletal muscle and vascular smooth muscle cell differentiation. In: Turksen K (ed) Methods in molecular biology, vol 185. Humana, Totowa, N.J., pp 127–156Google Scholar
  125. Wu SM, Fujiwara Y, Cibulsky SM, Clapham DE, Lien CL, Schultheiss TM, Orkin SH (2006) Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell 127:1137–1150PubMedGoogle Scholar
  126. Xu RH, Chen X, Li DS, Li R, Addicks GC, Glennon C, Zwaka TP, Thomson JA (2002) BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol 20:1261–1264PubMedGoogle Scholar
  127. Yamamoto H, Quinn G, Asari A, Yamanokuchi H, Teratani T, Terada M, Ochiya T (2003) Differentiation of embryonic stem cells into hepatocytes: biological functions and therapeutic application. Hepatology 37:983–993PubMedGoogle Scholar
  128. Yamamoto Y, Teratani T, Yamamoto H, Quinn G, Murata S, Ikeda R, Kinoshita K, Matsubara K, Kato T, Ochiya T (2005) Recapitulation of in vivo gene expression during hepatic differentiation from murine embryonic stem cells. Hepatology 42:558–567PubMedGoogle Scholar
  129. Yasunaga M, Tada S, Torikai-Nishikawa S, Nakano Y, Okada M, Jakt LM, Nishikawa S, Chiba T, Era T (2005) Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol 23:1542–1550PubMedGoogle Scholar
  130. Ying QL, Nichols J, Chambers I, Smith A (2003) BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115:281–292PubMedGoogle Scholar
  131. Yu L, Sangster N, Perez A, McCormick PJ (2004) The bHLH protein MyoR inhibits the differentiation of early embryonic endoderm. Differentiation 72:341–347PubMedGoogle Scholar
  132. Yuasa S, Itabashi Y, Koshimizu U, Tanaka T, Sugimura K, Kinoshita M, Hattori F, Fukami S, Shimazaki T, Ogawa S, Okano H, Fukuda K (2005) Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells. Nat Biotechnol 23:607–611PubMedGoogle Scholar
  133. Zeng X, Cai J, Chen J, Luo Y, You ZB, Fotter E, Wang Y, Harvey B, Miura T, Backman C, Chen GJ, Rao MS, Freed WJ (2004) Dopaminergic differentiation of human embryonic stem cells. Stem Cells 22:925–940PubMedGoogle Scholar
  134. Zhang J, Tam WL, Tong GQ, Wu Q, Chan HY, Soh BS, Lou Y, Yang J, Ma Y, Chai L, Ng HH, Lufkin T, Robson P, Lim B (2006) Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 8:1114–1123PubMedGoogle Scholar
  135. Zhou QJ, Xiang LX, Shao JZ, Hu RZ, Lu YL, Yao H, Dai LC (2007) In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate. J Cell Biochem 100:29–42PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Satoshi Yamanaka
    • 1
  • Jinliang Li
    • 1
  • Gabriela Kania
    • 2
  • Steve Elliott
    • 3
  • Robert P. Wersto
    • 1
  • Jennifer Van Eyk
    • 3
  • Anna M. Wobus
    • 2
  • Kenneth R. Boheler
    • 1
    Email author
  1. 1.Laboratory of Cardiovascular Sciences, Gerontology Research CenterNational Institute on AgingBaltimoreUSA
  2. 2.In Vitro Differentiation GroupLeibniz Institute (IPK) GaterslebenGaterslebenGermany
  3. 3.Department of MedicineJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations