Stem Cells pp 21-51 | Cite as

Embryonic Stem Cell-Derived Embryoid Bodies: An In Vitro Model of Eutherian Pregastrulation Development and Early Gastrulation

  • G. Weitzer
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 174)


In this review, I describe the dawn of embryoid body research and the influence of stem cell properties on embryoid body development. I will focus on the in vitro differentiation of embryonic stem cells in embryoid bodies. I summarize and combine published data for embryo-like development of embryoid bodies, and based on these findings, I will discuss open questions, concerns, and possible future directions of this still emerging field of research. I hope to provide new perspectives and experimental approaches that go beyond the current state of the art to foster an understanding of eutherian embryogenesis and provide clues for the efficient production of somatic cells for cell therapy.


Embryoid body Gastrulation Morphogenesis Embryogenesis 


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  1. Abe K, Niwa H, Iwase K, Takiguchi M, Mori M, Abe SI, Yamamura KI (1996) Endoderm-specific gene expression in embryonic stem cells differentiated to embryoid bodies. Exp Cell Res 229:27–34PubMedGoogle Scholar
  2. Adamson ED, Strickland S, Tu M, Kahan B (1985) A teratocarcinoma-derived endoderm stem cell line (1H5) that can differentiate into extra-embryonic endoderm cell types. Differentiation 29:68–76PubMedGoogle Scholar
  3. Allen ND, Barton SC, Hilton K, Norris ML, Surani MA (1994) A functional analysis of imprinting in parthenogenetic embryonic stem cells. Development 120:1473–1482PubMedGoogle Scholar
  4. Aumailley M, Pesch M, Tunggal L, Gaill F, Fässler R (2000) Altered synthesis of laminin 1 and absence of basement membrane component deposition in (beta)1 integrin-deficient embryoid bodies. J Cell Sci 113:259–268PubMedGoogle Scholar
  5. Bader A, Al-Dubai H, Weitzer G (2000) Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite fashions. Circ Res 86:787–794PubMedGoogle Scholar
  6. Bader A, Gruss A, HÖllrigl A, Al Dubai H, Capetanaki Y, Weitzer G (2001) Paracrine promotion of cardiomyogenesis in embryoid bodies by LIF modulated endoderm. Differentiation 68:31–43CrossRefPubMedGoogle Scholar
  7. Bagutti C, Wobus AM, Fässler R, Watt FM (1996) Differentiation of embryonal stem cells into keratinocytes: comparison of wild-type and beta 1 integrin-deficient cells. Dev Biol 179:184–196CrossRefPubMedGoogle Scholar
  8. Becker S, Wang ZJ, Massey H, Arauz A, Labosky P, Hammerschmidt M, St-Jacques B, Bumcrot D, McMahon A, Grabel L (1997) A role for Indian hedgehog in extraembryonic endoderm differentiation in F9 cells and the early mouse embryo. Dev Biol 187:298–310CrossRefPubMedGoogle Scholar
  9. Bhattacharya B, Miura T, Brandenberger R, Mejido J, Luo Y, Yang AX, Joshi BH, Ginis I, Thies RS, Amit M, Lyons I, Condie BG, Itskovitz-Eldor J, Rao MS, Puri RK (2004) Gene expression in human embryonic stem cell lines: unique molecular signature. Blood 103:2956–2964CrossRefPubMedGoogle Scholar
  10. Blewitt ME, Chong S, Whitelaw E (2004) How the mouse got its spots. Trends Genet 20:550–554CrossRefPubMedGoogle Scholar
  11. Boheler KR, Czyz J, Tweedie D, Yang HT, Anisimov SV, Wobus AM (2002) Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res 91:189–201CrossRefPubMedGoogle Scholar
  12. Bradley A, Evans M, Kaufman MH, Robertson E (1984) Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature 309:255–256CrossRefPubMedGoogle Scholar
  13. Bradley A, Zheng B, Liu P (1998) Thirteen years of manipulating the mouse genome: a personal history. Int J Dev Biol 42:943–950PubMedGoogle Scholar
  14. Brand T (2003) Heart development: molecular insights into cardiac specification and early morphogenesis. Dev Biol 258:1–19CrossRefPubMedGoogle Scholar
  15. Buehr M, Smith A (2003) Genesis of embryonic stem cells. Philos Trans R Soc Lond B Biol Sci 358:1397–1402PubMedGoogle Scholar
  16. Buehr M, Nichols J, Stenhouse F, Mountford P, Greenhalgh CJ, Kantachuvesiri S, Brooker G, Mullins J, Smith AG (2003) Rapid loss of Oct-4 and pluripotency in cultured rodent blastocysts and derivative cell lines. Biol Reprod 68:222–229PubMedGoogle Scholar
  17. Burdon T, Smith A, Savatier P (2002) Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol 12:432–438CrossRefPubMedGoogle Scholar
  18. Carpenter MK, Rosler E, Rao MS (2003) Characterization and differentiation of human embryonic stem cells. Cloning Stem Cells 5:79–88CrossRefPubMedGoogle Scholar
  19. Carpenter MK, Rosler ES, Fisk GJ, Brandenberger R, Ares X, Miura T, Lucero M, Rao MS (2004) Properties of four human embryonic stem cell lines maintained in a feeder-free culture system. Dev Dyn 229:243–258CrossRefPubMedGoogle Scholar
  20. Casanova JE, Grabel LB (1988) The role of cell interactions in the differentiation of teratocarcinoma-derived parietal and visceral endoderm. Dev Biol 129:124–139CrossRefPubMedGoogle Scholar
  21. Chambers I, Smith A (2004) Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene 23:7150–7160CrossRefPubMedGoogle Scholar
  22. Chang IK, Jeong DK, Hong YH, Park TS, Moon YK, Ohno T, Han JY (1997) Production of germline chimeric chickens by transfer of cultured primordial germ cells. Cell Biol Int 21:495–499CrossRefPubMedGoogle Scholar
  23. Chen L, Li H (2004) [Progress in the studies of parthenogenetic embryonic stem cells]. Zhonghua Nan Ke Xue 10:55–58PubMedGoogle Scholar
  24. Chen Y, Li X, Eswarakumar VP, Seger R, Lonai P (2000) Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt/PKB is required for embryoid body differentiation. Oncogene 19:3750–3756CrossRefPubMedGoogle Scholar
  25. Cheng L, Grabel LB (1997) The involvement of tissue-type plasminogen activator in parietal endoderm outgrowth. Exp Cell Res 230:187–196CrossRefPubMedGoogle Scholar
  26. Chong S, Whitelaw E (2004) Epigenetic germline inheritance. Curr Opin Genet Dev 14:692–696CrossRefPubMedGoogle Scholar
  27. Conley BJ, Trounson AO, Mollard R (2004a) Human embryonic stem cells form embryoid bodies containing visceral endoderm-like derivatives. Fetal Diagn Ther 19:218–223CrossRefPubMedGoogle Scholar
  28. Conley BJ, Young JC, Trounson AO, Mollard R (2004b) Derivation, propagation and differentiation of human embryonic stem cells. Int J Biochem Cell Biol 36:555–567CrossRefPubMedGoogle Scholar
  29. Coucouvanis E, Martin GR (1999) BMP signaling plays a role in visceral endoderm differentiation and cavitation in the early mouse embryo. Development 126:535–546PubMedGoogle Scholar
  30. Czyz J, Wobus A (2001) Embryonic stem cell differentiation: the role of extracellular factors. Differentiation 68:167–174CrossRefPubMedGoogle Scholar
  31. Czyz J, Wiese C, Rolletschek A, Blyszczuk P, Cross M, Wobus AM (2003) Potential of embryonic and adult stem cells in vitro. Biol Chem 384:1391–1409CrossRefPubMedGoogle Scholar
  32. Daley GQ (2003) From embryos to embryoid bodies: generating blood from embryonic stem cells. Ann N Y Acad Sci 996:122–131PubMedGoogle Scholar
  33. Dang SM, Zandstra PW (2004) Scalable production of embryonic stem cell-derived cells. Methods Mol Biol 290:353–364Google Scholar
  34. Dang SM, Kyba M, Perlingeiro R, Daley GQ, Zandstra PW (2002) Efficiency of embryoid body formation and hematopoietic development from embryonic stem cells in different culture systems. Biotechnol Bioeng 78:442–453CrossRefPubMedGoogle Scholar
  35. Dang SM, Gerecht-Nir S, Chen J, Itskovitz-Eldor J, Zandstra PW (2004) Controlled, scalable embryonic stem cell differentiation culture. Stem Cells 22:275–282CrossRefPubMedGoogle Scholar
  36. Dean W, Santos F, Reik W (2003) Epigenetic reprogramming in early mammalian development and following somatic nuclear transfer. Semin Cell Dev Biol 14:93–100CrossRefPubMedGoogle Scholar
  37. Desbaillets I, Ziegler U, Groscurth P, Gassmann M (2000) Embryoid bodies: an in vitro model of mouse embryogenesis. Exp Physiol 85:645–651CrossRefPubMedGoogle Scholar
  38. Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP (1998) Pten is essential for embryonic development and tumour suppression. Nat Genet 19:348–355PubMedGoogle Scholar
  39. 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
  40. Doetschman T, Williams P, Maeda N (1988) Establishment of hamster blastocyst-derived embryonic stem (ES) cells. Dev Biol 127:224–227CrossRefPubMedGoogle Scholar
  41. Dyban PA (1984) [Characteristics of the growth and differentiation of teratocarcinoma OC15S1 in syngeneic and allogeneic mice]. Biull Eksp Biol Med 97:71–72PubMedGoogle Scholar
  42. Edwards RG (2004) Stem cells today: A. Origin and potential of embryo stem cells. Reprod Biomed Online 8:275–306PubMedGoogle Scholar
  43. Esner M, Pachernik J, Hampl A, Dvorak P (2002) Targeted disruption of fibroblast growth factor receptor-1 blocks maturation of visceral endoderm and cavitation in mouse embryoid bodies. Int J Dev Biol 46:817–825PubMedGoogle Scholar
  44. Evans MJ (1972) The isolation and properties of a clonal tissue culture strain of pluripotent mouse teratoma cells. J Embryol Exp Morphol 28:163–176PubMedGoogle Scholar
  45. Evans M (1981) Origin of mouse embryonal carcinoma cells and the possibility of their direct isolation into tissue culture. J Reprod Fertil 62:625–631PubMedGoogle Scholar
  46. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156PubMedGoogle Scholar
  47. Fässler R, Pfaff M, Murphy J, Noegel AA, Johansson S, Timpl R, Albrecht R (1995) Lack of beta 1 integringene in embryonic stem cells affects morphology, adhesion, and migration but not integration into the inner cell mass of blastocysts. J Cell Biol 128:979–988PubMedGoogle Scholar
  48. Fässler R, Rohwedel J, Maltsev V, Bloch W, Lentini S, Guan K, Gullberg D, Hescheler J, Addicks K, Wobus AM (1996) Differentiation and integrity of cardiac muscle cells are impaired in the absence of beta 1 integrin. J Cell Sci 109:2989–2999PubMedGoogle Scholar
  49. Fortunel NO, Otu HH, Ng HH, Chen J, Mu X, Chevassut T, Li X, Joseph M, Bailey C, Hatzfeld JA, Hatzfeld A, Usta F, Vega VB, Long PM, Libermann TA, Lim B (2003) Comment on “’stemness’: transcriptional profiling of embryonic and adult stem cells” and “a stem cell molecular signature”. Science 302:393bCrossRefPubMedGoogle Scholar
  50. Fujikura J, Yamato E, Yonemura S, Hosoda K, Masui S, Nakao K, Miyazaki Ji J, Niwa H (2002) Differentiation of embryonic stem cells is induced by GATA factors. Genes Dev 16:784–789CrossRefPubMedGoogle Scholar
  51. Gao F, Shi HY, Daughty C, Cella N, Zhang M (2004) Maspin plays an essential role in early embryonic development. Development 131:1479–1489CrossRefPubMedGoogle Scholar
  52. Gardner RL (1985) Regeneration of endoderm from primitive ectoderm in the mouse embryo: fact or artifact? J Embryol Exp Morphol 88:303–326PubMedGoogle Scholar
  53. Geijsen N, Horoschak M, Kim K, Gribnau J, Eggan K, Daley GQ (2004) Derivation of embryonic germ cells and male gametes from embryonic stemcells. Nature 427:148–154CrossRefPubMedGoogle Scholar
  54. Gerecht-Nir S, Cohen S, Itskovitz-Eldor J (2004) Bioreactor cultivation enhances the efficiency of human embryoid body (hEB) formation and differentiation. Biotechnol Bioeng 86:493–502CrossRefPubMedGoogle Scholar
  55. Ginis I, Luo Y, Miura T, Thies S, Brandenberger R, Gerecht-Nir S, Amit M, Hoke A, Carpenter MK, Itskovitz-Eldor J, Rao MS (2004) Differences between human and mouse embryonic stem cells. Dev Biol 269:360–380CrossRefPubMedGoogle Scholar
  56. Grabel LB, Casanova JE (1986) The outgrowth of parietal endoderm from mouse teratocarcinoma stem-cell embryoid bodies. Differentiation 32:67–73PubMedGoogle Scholar
  57. Grabel LB, Watts TD (1987) The role of extracellular matrix in the migration and differentiation of parietal endoderm from teratocarcinoma embryoid bodies. J Cell Biol 105:441–448CrossRefPubMedGoogle Scholar
  58. Graves KH, Moreadith RW (1993) Derivation and characterization of putative pluripotential embryonic stemcells from preimplantation rabbit embryos. Mol Reprod Dev 36:424–433CrossRefPubMedGoogle Scholar
  59. Grover A, Oshima RG, Adamson ED (1983) Epithelial layer formation in differentiating aggregates of F9 embryonal carcinoma cells. J Cell Biol 96:1690–1696CrossRefPubMedGoogle Scholar
  60. Hamazaki T, Oka M, Yamanaka S, Terada N (2004) Aggregation of embryonic stem cells induces Nanog repression and primitive endoderm differentiation. J Cell Sci 117:5681–5686CrossRefPubMedGoogle Scholar
  61. Harland R, Gerhart J (1997) Formation and function of Spemann’s organizer. Annu Rev Cell Dev Biol 13:611–667CrossRefPubMedGoogle Scholar
  62. Hescheler J, Fleischmann BK, Lentini S, Maltsev VA, Rohwedel J, Wobus AM, Addicks K (1997) Embryonic stem cells: a model to study structural and functional properties in cardiomyogenesis. Cardiovasc Res 36:149–162CrossRefPubMedGoogle Scholar
  63. Hochepied T, Schoonjans L, Staelens J, Kreemers V, Danloy S, Puimege L, Collen D, Van Roy F, Libert C (2004) Breaking the species barrier: derivation of germline-competent embryonic stem cells from Mus spretus x C57BL/6 hybrids. Stem Cells 22:441–447CrossRefPubMedGoogle Scholar
  64. Hong Y, Winkler C, Schartl M (1998a) Efficiency of cell culture derivation from blastula embryos and of chimera formation in the medaka (Oryzias latipes) depends on donor genotype and passage number. Dev Genes Evol 208:595–602CrossRefPubMedGoogle Scholar
  65. Hong Y, Winkler C, Schartl M (1998b) Production of medakafish chimeras from a stable embryonic stem cell line. Proc Natl Acad Sci U S A 95:3679–3684CrossRefPubMedGoogle Scholar
  66. Hubner K, Fuhrmann G, Christenson LK, Kehler J, Reinbold R, De La Fuente R, Wood J, Strauss JF 3rd, Boiani M, Scholer HR (2003) Derivation of oocytes from mouse embryonic stem cells. Science 300:1251–1256CrossRefPubMedGoogle Scholar
  67. 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 22:522–530CrossRefPubMedGoogle Scholar
  68. Humpherys D, Eggan K, Akutsu H, Hochedlinger K, Rideout WM 3rd, Biniszkiewicz D, Yanagimachi R, Jaenisch R (2001) Epigenetic instability in ES cells and cloned mice. Science 293:95–97CrossRefPubMedGoogle Scholar
  69. Hwang WS, Ryu YJ, Park JH, Park ES, Lee EG, Koo JM, Jeon HY, Lee BC, Kang SK, Kim SJ, Ahn C, Hwang JH, Park KY, Cibelli JB, Moon SY (2004) Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science 303:1669–1674CrossRefPubMedGoogle Scholar
  70. Iannaccone PM, Taborn GU, Garton RL, Caplice MD, Brenin DR (1994) Pluripotent embryonic stem cells from the rat are capable of producing chimeras. Dev Biol 163:288–292CrossRefPubMedGoogle Scholar
  71. Ikeda W, Nakanishi H, Miyoshi J, Mandai K, Ishizaki H, Tanaka M, Togawa A, Takahashi K, Nishioka H, Yoshida H, Mizoguchi A, Nishikawa S, Takai Y (1999) Afadin: a key molecule essential for structural organization of cell-cell junctions of polarized epithelia during embryogenesis. J Cell Biol 146:1117–1131CrossRefPubMedGoogle Scholar
  72. Itskovitz Eldor J, Schuldiner M, Karsenti D, Eden A, Yanuka O, Amit M, Soreq H, Benvenisty N (2000) Differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers. Mol Med 6:88–95PubMedGoogle Scholar
  73. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR (2002) A stemcell molecular signature. Science 298:601–604CrossRefPubMedGoogle Scholar
  74. Jiang R, Grabel LB (1995) Function and differential regulation of the alpha 6 integrin isoforms during parietal endoderm differentiation. Exp Cell Res 217:195–204CrossRefPubMedGoogle Scholar
  75. Jiang R, Kato M, Bernfield M, Grabel LB (1995) Expression of syndecan-1 changes during the differentiation of visceral and parietal endoderm from murine F9 teratocarcinoma cells. Differentiation 59:225–233CrossRefPubMedGoogle Scholar
  76. Kaufman MH, Robertson EJ, Handyside AH, Evans MJ (1983) Establishment of pluripotential cell lines from haploid mouse embryos. J Embryol Exp Morphol 73:249–261PubMedGoogle Scholar
  77. Keller G, Kennedy M, Papayannopoulou T, Wiles MV (1993) Hematopoietic commitment during embryonic stem cell differentiation in culture. Mol Cell Biol 13:473–486PubMedGoogle Scholar
  78. Keller R, Davidson LA, Shook DR (2003) How we are shaped: the biomechanics of gastrulation. Differentiation 71:171–205CrossRefPubMedGoogle Scholar
  79. Kleinsmith LJ, Pierce GB Jr (1964) Multipotentiality of single embryonal carcinoma cells. Cancer Res 24:1544–1551PubMedGoogle Scholar
  80. 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 131:1651–1662CrossRefPubMedGoogle Scholar
  81. Kuo HC, Pau KY, Yeoman RR, Mitalipov SM, Okano H, Wolf DP (2003) Differentiation of monkey embryonic stem cells into neural lineages. Biol Reprod 68:1727–1735PubMedGoogle Scholar
  82. Lacham-Kaplan O (2004) In vivo and in vitro differentiation of male germ cells in the mouse. Reproduction 128:147–152CrossRefPubMedGoogle Scholar
  83. Lake J, Rathjen J, Remiszewski J, Rathjen PD (2000) Reversible programming of pluripotent cell differentiation. J Cell Sci 113:555–566PubMedGoogle Scholar
  84. Lang KJ, Rathjen J, Vassilieva S, Rathjen PD (2004) Differentiation of embryonic stem cells to a neural fate: a route to re-building the nervous system? J Neurosci Res 76:184–192CrossRefPubMedGoogle Scholar
  85. Lanza R (2004a) Handbook of stem cells. Elsevier, Academic Press, AmsterdamGoogle Scholar
  86. Lanza R (2004b) Handbook of stem cells. Elsevier, Academic Press, AmsterdamGoogle Scholar
  87. Lauss M, Stary M, Tischler J, Egger G, Puz S, Bader-Allmer A, Seiser C, Weitzer G (2005) Single inner cell masses yield embryonic stem cell lines differing in life expression and their developmental potential. Biochem Biophys Res Commun 331:1577–1586CrossRefPubMedGoogle Scholar
  88. Lavon N, Benvenisty N (2003) Differentiation and genetic manipulation of human embryonic stem cells and the analysis of the cardiovascular system. Trends Cardiovasc Med 13:47–52CrossRefPubMedGoogle Scholar
  89. Leahy A, Xiong JW, Kuhnert F, Stuhlmann H (1999) Use of developmental marker genes to define temporal and spatial patterns of differentiation during embryoid body formation. J Exp Zool 284:67–81CrossRefPubMedGoogle Scholar
  90. Levine AJ, Torosian M, Sarokhan AJ, Teresky AK (1974) Biochemical criteria for the in vitro differentiation of embryoid bodies produced by a transplantable teratoma of mice. The production of acetylcholine esterase and creatine phosphokinase by teratomacells. J Cell Physiol 84:311–317PubMedGoogle Scholar
  91. Li L, Arman E, Ekblom P, Edgar D, Murray P, Lonai P (2004) Distinct GATA6-and laminin-dependent mechanisms regulate endodermal and ectodermal embryonic stemcell fates. Development 131:5277–5286PubMedGoogle Scholar
  92. Li M, Pevny L, Lovell Badge R, Smith A (1998) Generation of purified neural precursors from embryonic stem cells by lineage selection. Curr Biol 8:971–974CrossRefPubMedGoogle Scholar
  93. Li S, Harrison D, Carbonetto S, Fassler R, Smyth N, Edgar D, Yurchenco PD (2002) Matrix assembly, regulation, and survival functions of laminin and its receptors in embryonic stem cell differentiation. J Cell Biol 157:1279–1290PubMedGoogle Scholar
  94. Li M, Zhang D, Hou Y, Jiao L, Zheng X, Wang WH (2003a) Isolation and culture of embryonic stem cells from porcine blastocysts. Mol Reprod Dev 65:429–434CrossRefPubMedGoogle Scholar
  95. Li S, Edgar D, Fassler R, Wadsworth W, Yurchenco PD (2003b) The role of laminin in embryonic cell polarization and tissue organization. Dev Cell 4:613–624PubMedGoogle Scholar
  96. Li X, Chen Y, Scheele S, Arman E, Haffner Krausz R, Ekblom P, Lonai P (2001) Fibroblast growth factor signaling and basement membrane assembly are connected during epithelial morphogenesis of the embryoid body. J Cell Biol 153:811–822CrossRefPubMedGoogle Scholar
  97. Maltsev VA, Rohwedel J, Hescheler J, Wobus AM (1993) Embryonic stem cells differentiate in vitro into cardiomyocytes representing sinusnodal, atrial and ventricular cell types. Mech Dev 44:41–50CrossRefPubMedGoogle Scholar
  98. Mann JR, Gadi I, Harbison ML, Abbondanzo SJ, Stewart CL (1990) Androgenetic mouse embryonic stem cells are pluripotent and cause skeletal defects in chimeras: implications for genetic imprinting. Cell 62:251–260CrossRefPubMedGoogle Scholar
  99. Martin GR (1980) Teratocarcinomas and mammalian embryogenesis. Science 209:768–776PubMedGoogle Scholar
  100. 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 U S A 78:7634–7638PubMedGoogle Scholar
  101. Martin GR, Evans MJ (1975) Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. Proc Natl Acad Sci U S A 72:1441–1445PubMedGoogle Scholar
  102. Martin GR, Wiley LM, Damjanov I (1977) The development of cystic embryoid bodies in vitro from clonal teratocarcinoma stem cells. Dev Biol 61:230–244CrossRefPubMedGoogle Scholar
  103. Masson P (1970) Human tumors, histology, diagnosis and technique, edn. Wayne State University PressGoogle Scholar
  104. Matsui Y, Zsebo K, Hogan BL (1992) Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70:841–847CrossRefPubMedGoogle Scholar
  105. McBurney MW, Strutt BJ (1980) Genetic activity of X chromosomes in pluripotent female teratocarcinoma cells and their differentiated progeny. Cell 21:357–364CrossRefPubMedGoogle Scholar
  106. Miki K (1999) Volume of liquid below the epithelium of an F9 cell as a signal for differentiation into visceral endoderm. J Cell Sci 112:3071–3080PubMedGoogle Scholar
  107. Milner DJ, Weitzer G, Tran D, Bradley A, Capetanaki Y (1996) Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J Cell Biol 134:1255–1270CrossRefPubMedGoogle Scholar
  108. Mitalipova M, Beyhan Z, First NL (2001) Pluripotency of bovine embryonic cell line derived from precompacting embryos. Cloning 3:59–67CrossRefPubMedGoogle Scholar
  109. Moens A, Flechon B, Degrouard J, Vignon X, Ding J, Flechon JE, Betteridge KJ, Renard JP (1997) Ultrastructural and immunocytochemical analysis of diploid germ cells isolated from fetal rabbit gonads. Zygote 5:47–60PubMedGoogle Scholar
  110. Mummery CL, van den Eijnden-van Raaij AJ, Feijen A, Freund E, Hulskotte E, Schoorlemmer J, Kruijer W (1990) Expression of growth factors during the differentiation of embryonic stem cells in monolayer. Dev Biol 142:406–413PubMedGoogle Scholar
  111. Mummery CL, van Achterberg TA, van den Eijnden-van Raaij AJ, van Haaster L, Willemse A, de Laat SW, Piersma AH (1991) Visceral-endoderm-like cell lines induce differentiation of murine P19 embryonal carcinoma cells. Differentiation 46:51–60PubMedGoogle Scholar
  112. Murray P, Edgar D (2001a) The regulation of embryonic stem cell differentiation by leukaemia inhibitory factor (LIF). Differentiation 68:227–234CrossRefPubMedGoogle Scholar
  113. Murray P, Edgar D (2001b) Regulation of the differentiation and behaviour of extraembryonic endodermal cells by basement membranes. J Cell Sci 114:931–939PubMedGoogle Scholar
  114. Murray P, Edgar D (2004) The topographical regulation of embryonic stem cell differentiation. Philos Trans R Soc Lond B Biol Sci 359:1009–1020PubMedGoogle Scholar
  115. Nakatsuji N, Suemori H (2002) Embryonic stem cell lines of nonhuman primates. Sci World J 2:1762–1773Google Scholar
  116. Nicolas JF, Dubois P, Jakob H, Gaillard J, Jacob F (1975) [Mouse teratocarcinoma: differentiation in cultures of a multipotential primitive cell line (author’s transl)]. Ann Microbiol (Paris) 126:3–22Google Scholar
  117. Niwa H, Miyazaki J, Smith AG (2000) Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24:372–376CrossRefPubMedGoogle Scholar
  118. Notarianni E, Galli C, Laurie S, Moor RM, Evans MJ (1991) Derivation of pluripotent, embryonic cell lines from the pig and sheep. J Reprod Fertil Suppl 43:255–260Google Scholar
  119. Nusslein-Volhard CN (2004) Von Genen und Embryonen. Reclam Verlag, LeipzigGoogle Scholar
  120. O’shea KS(2004) Self-renewal vs. differentiation of mouse embryonic stem cells. Biol Reprod 71:1755–1765Google Scholar
  121. Pain B, Clark ME, Shen M, Nakazawa H, Sakurai M, Samarut J, Etches RJ (1996) Long-term in vitro culture and characterisation of avian embryonic stem cells with multiple morphogenetic potentialities. Development 122:2339–2348PubMedGoogle Scholar
  122. Pandur P, Lasche M, Eisenberg LM, Kuhl M (2002) Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 418:636–641CrossRefPubMedGoogle Scholar
  123. Park JH, Kim SJ, Lee JB, Song JM, Kim CG, Roh S 2nd, Yoon HS (2004) Establishment of a human embryonic germ cell line and comparison with mouse and human embryonic stem cells. Mol Cells 17:309–315PubMedGoogle Scholar
  124. Pau KY, Wolf DP (2004) Derivation and characterization of monkey embryonic stem cells. Reprod Biol Endocrinol 2:41CrossRefPubMedGoogle Scholar
  125. Pelton TA, Bettess MD, Lake J, Rathjen J, Rathjen PD (1998) Developmental complexity of early mammalian pluripotent cell populations in vivo and in vitro. Reprod Fertil Dev 10:535–549CrossRefPubMedGoogle Scholar
  126. Pesce M, Scholer HR (2001) Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 19:271–278CrossRefPubMedGoogle Scholar
  127. Petitte JN, Liu G, Yang Z (2004) Avian pluripotent stem cells. Mech Dev 121:1159–1168CrossRefPubMedGoogle Scholar
  128. Peyron A (1939) Faits nouveaux relatifs à l’origine et à l’histogénèse des embryomes. Bull Assoc Franc étude cancer 28:658–681Google Scholar
  129. Piedrahita JA, Moore K, Oetama B, Lee CK, Scales N, Ramsoondar J, Bazer FW, Ott T (1998) Generation of transgenic porcine chimeras using primordial germ cell-derived colonies. Biol Reprod 58:1321–1329CrossRefPubMedGoogle Scholar
  130. Pierce GB Jr, Dixon FJ Jr, Verney EL (1960) Teratocarcinogenic and tissue-forming potentials of the cell types comprising neoplastic embryoid bodies. Lab Invest 9:583–602PubMedGoogle Scholar
  131. Prelle K, Zink N, Wolf E (2002) Pluripotent stem cells—model of embryonic development, tool for gene targeting, and basis of cell therapy. Anat Histol Embryol 31:169–186PubMedGoogle Scholar
  132. Rakyan VK, Preis J, Morgan HD, Whitelaw E (2001) The marks, mechanisms and memory of epigenetic states in mammals. Biochem J 356:1–10CrossRefPubMedGoogle Scholar
  133. Ramalho Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA (2002) “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298:597–600PubMedGoogle Scholar
  134. Rathjen J, Rathjen PD (2003) Lineage specific differentiation of mouse ES cells: formation and differentiation of early primitive ectoderm-like (EPL) cells. Methods Enzymol 365:3–25PubMedGoogle Scholar
  135. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293:1089–1093CrossRefPubMedGoogle Scholar
  136. Resnick JL, Bixler LS, Cheng L, Donovan PJ (1992) Long-term proliferation of mouse primordial germ cells in culture. Nature 359:550–551CrossRefPubMedGoogle Scholar
  137. Robertson EJ, Evans MJ, Kaufman MH (1983) X-chromosome instability in pluripotential stem cell lines derived from parthenogenetic embryos. J Embryol Exp Morphol 74:297–309PubMedGoogle Scholar
  138. Robertson E, Bradley A, Kuehn M, Evans M (1986) Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature 323:445–448CrossRefPubMedGoogle Scholar
  139. Robertson EJ, Conlon FL, Barth KS, Costantini F, Lee JJ (1992) Use of embryonic stem cells to study mutations affecting postimplantation development in the mouse. Ciba Found Symp 165:237–250; discussion 250–255PubMedGoogle Scholar
  140. Rohwedel J, Guan K, Zuschratter W, Jin S, Ahnert-Hilger G, Furst D, Fassler R, Wobus AM (1998) Loss of beta1 integrin function results in a retardation of myogenic, but an acceleration of neuronal, differentiation of embryonic stem cells in vitro. Dev Biol 201:167–184CrossRefPubMedGoogle Scholar
  141. Rossant J (2001) Stem cells from the mammalian blastocyst. Stem Cells 19:477–482CrossRefPubMedGoogle Scholar
  142. Rossant J, Tam PPL (2002) Mouse development. Academic Press, LondonGoogle Scholar
  143. Sachinidis A, Fleischmann BK, Kolossov E, Wartenberg M, Sauer H, Hescheler J (2003) Cardiac specific differentiation of mouse embryonic stem cells. Cardiovasc Res 58:278–291CrossRefPubMedGoogle Scholar
  144. Saito S, Ugai H, Sawai K, Yamamoto Y, Minamihashi A, Kurosaka K, Kobayashi Y, Murata T, Obata Y, Yokoyama K (2002) Isolation of embryonic stem-like cells from equine blastocysts and their differentiation in vitro. FEBS Lett 531:389–396CrossRefPubMedGoogle Scholar
  145. Sato N, Sanjuan IM, Heke M, Uchida M, Naef F, Brivanlou AH (2003)Molecular signature of human embryonic stem cells and its comparison with the mouse. Dev Biol 260:404–413CrossRefPubMedGoogle Scholar
  146. Schoonjans L, Albright GM, Li JL, Collen D, Moreadith RW (1996) Pluripotential rabbit embryonic stem (ES) cells are capable of forming overt coat color chimeras following injection into blastocysts. Mol Reprod Dev 45:439–443CrossRefPubMedGoogle Scholar
  147. Schuldiner M, Yanuka O, Itskovitz-Eldor J, Melton DA, Benvenisty N (2000) Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 97:11307–11312CrossRefPubMedGoogle Scholar
  148. Schultheiss TM, Burch JB, Lassar AB (1997) A role for bone morphogenetic proteins in the induction of cardiac myogenesis. Genes Dev 11:451–462PubMedGoogle Scholar
  149. Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield JW, Donovan PJ, Blumenthal PD, Huggins GR, Gearhart JD (1998) Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci U S A 95:13726–13731CrossRefPubMedGoogle Scholar
  150. Shim H, Gutierrez-Adan A, Chen LR, BonDurant RH, Behboodi E, Anderson GB (1997) Isolation of pluripotent stem cells from cultured porcine primordial germ cells. Biol Reprod 57:1089–1095CrossRefPubMedGoogle Scholar
  151. Smith A (2001a) Embryonic stem cells. Cold Spring Harbor Laboratory Press, New YorkGoogle Scholar
  152. Smith AG (2001b) Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol 17:435–462CrossRefPubMedGoogle Scholar
  153. Smith ER, Smedberg JL, Rula ME, Xu XX (2004) Regulation of Ras-MAPK pathway mitogenic activity by restricting nuclear entry of activated MAPK in endoderm differentiation of embryonic carcinoma and stem cells. J Cell Biol 164:689–699CrossRefPubMedGoogle Scholar
  154. Smith JC, Gurdon JB (2004) Many ways to make a gradient. Bioessays 26:705–706PubMedGoogle Scholar
  155. Smyth N, Vatansever HS, Murray P, Meyer M, Frie C, Paulsson M, Edgar D (1999) Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation. J Cell Biol 144:151–160CrossRefPubMedGoogle Scholar
  156. Soriano P, Montgomery C, Geske R, Bradley A (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64:693–702CrossRefPubMedGoogle Scholar
  157. Soudais C, Bielinska M, Heikinheimo M, MacArthur CA, Narita N, Saffitz JE, Simon MC, Leiden JM, Wilson DB (1995) Targeted mutagenesis of the transcription factor GATA-4 gene in mouse embryonic stem cells disrupts visceral endoderm differentiation in vitro. Development 121:3877–3888PubMedGoogle Scholar
  158. Stern CD, Canning DR (1990) Origin of cells giving rise to mesoderm and endoderm in chick embryo. Nature 343:273–275CrossRefPubMedGoogle Scholar
  159. Stevens LC (1958) Studies on transplantable testicular teratomas of strain 129 mice. J Natl Cancer Inst 20:1257–1275PubMedGoogle Scholar
  160. Stevens LC (1959) Embryology of testicular teratomas in strain 129 mice. J Natl Cancer Inst 23:1249–1295PubMedGoogle Scholar
  161. Stevens LC (1960) Embryonic potency of embryoid bodies derived from a transplantable testicular teratoma of the mouse. Dev Biol 2:285–297CrossRefPubMedGoogle Scholar
  162. Stice SL, Strelchenko NS, Keefer CL, Matthews L (1996) Pluripotent bovine embryonic cell lines direct embryonic development following nuclear transfer. Biol Reprod 54:100–110CrossRefPubMedGoogle Scholar
  163. Suemori H, Nakatsuji N (2003) Growth and differentiation of cynomolgus monkey ES cells. Methods Enzymol 365:419–429PubMedGoogle Scholar
  164. Sukoyan MA, Golubitsa AN, Zhelezova AI, Shilov AG, Vatolin SY, Maximovsky LP, Andreeva LE, McWhir J, Pack SD, Bayborodin SI (1992) Isolation and cultivation of blastocyst-derived stem cell lines from American mink (Mustela vison). Mol Reprod Dev 33:418–431CrossRefPubMedGoogle Scholar
  165. Sukoyan MA, Vatolin SY, Golubitsa AN, Zhelezova AI, Semenova LA, Serov OL (1993) Embryonic stem cells derived from morulae, inner cell mass, and blastocysts of mink: comparisons of their pluripotencies. Mol Reprod Dev 36:148–158CrossRefPubMedGoogle Scholar
  166. Tanaka S, Kunath T, Hadjantonakis AK, Nagy A, Rossant J (1998) Promotion of trophoblast stem cell proliferation by FGF4. Science 282:2072–2075CrossRefPubMedGoogle Scholar
  167. Thomson JA, Marshall VS (1998) Primate embryonic stem cells. Curr Top Dev Biol 38:133–165PubMedGoogle Scholar
  168. Thompson JR, Gudas LJ (2002) Retinoic acid induces parietal endoderm but not primitive endoderm and visceral endoderm differentiation in F9 teratocarcinoma stem cells with a targeted deletion of the Rex-1 (Zfp-42) gene. Mol Cell Endocrinol 195:119–133CrossRefPubMedGoogle Scholar
  169. Thomson JA, Kalishman J, Golos TG, Durning M, Harris CP, Becker RA, Hearn JP (1995) Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci U S A 92:7844–7848PubMedGoogle Scholar
  170. Thomson JA, Kalishman J, Golos TG, Durning M, Harris CP, Hearn JP (1996) Pluripotent cell lines derived from common marmoset (Callithrix jacchus) blastocysts. Biol Reprod 55:254–259CrossRefPubMedGoogle Scholar
  171. 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 282:1145–1147CrossRefPubMedGoogle Scholar
  172. Vallier L, Reynolds D, Pedersen RA (2004) Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Dev Biol 275:403–421CrossRefPubMedGoogle Scholar
  173. Veltmaat JM, Orelio CC, Ward Van Oostwaard D, Van Rooijen MA, Mummery CL, Defize LH (2000) Snail is an immediate early target gene of parathyroid hormone related peptide signaling in parietal endoderm formation. Int J Dev Biol 44:297–307PubMedGoogle Scholar
  174. Verheijen MH, Defize LH (1999) Signals governing extraembryonic endoderm formation in the mouse: involvement of the type 1 parathyroid hormone-related peptide (PTHrP) receptor, p21Ras and cell adhesion molecules. Int J Dev Biol 43:711–721PubMedGoogle Scholar
  175. Wang QT, Piotrowska K, Ciemerych MA, Milenkovic L, Scott MP, Davis RW, Zernicka-Goetz M (2004) A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo. Dev Cell 6:133–144CrossRefPubMedGoogle Scholar
  176. Watson AJ, Barcroft LC (2001) Regulation of blastocyst formation. Front Biosci 6: D708–D730PubMedGoogle Scholar
  177. Weitzer G, Milner DJ, Kim JU, Bradley A, Capetanaki Y (1995) Cytoskeletal control of myogenesis: a desmin null mutation blocks the myogenic pathway during embryonic stem cell differentiation. Dev Biol 172:422–439CrossRefPubMedGoogle Scholar
  178. Wells DN, Misica PM, Day TA, Tervit HR (1997) Production of cloned lambs from an established embryonic cell line: a comparison between in vivo-and in vitro-matured cytoplasts. Biol Reprod 57:385–393CrossRefPubMedGoogle Scholar
  179. Wheeler MB (1994) Development and validation of swine embryonic stem cells: a review. Reprod Fertil Dev 6:563–568CrossRefPubMedGoogle Scholar
  180. Wobus AM, Boheler KR (2005) Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol Rev 85:635–678CrossRefPubMedGoogle Scholar
  181. Wobus AM, Rohwedel J, Strübing C, Jin S, Adler K, Maltsev V, Hescheler J (1997) In vitro differentiation of embryonic stem cells. Blackwell, Berlin, pp 1–17Google Scholar
  182. Xiong JW, Battaglino R, Leahy A, Stuhlmann H (1998) Large-scale screening for developmental genes in embryonic stem cells and embryoid bodies using retroviral entrapment vectors. Dev Dyn 212:181–197CrossRefPubMedGoogle Scholar
  183. 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 20:1261–1264CrossRefPubMedGoogle Scholar
  184. Yoshida-Koide U, Matsuda T, Saikawa K, Nakanuma Y, Yokota T, Asashima M, Koide H (2004) Involvement of Ras in extraembryonic endoderm differentiation of embryonic stem cells. Biochem Biophys Res Commun 313:475–481CrossRefPubMedGoogle Scholar
  185. Young RH (2004) A brief history of the pathology of the gonads. Mod Pathol doi:10.1038/modpathol.3800305:1–15Google Scholar
  186. Yu L, Sangster N, Perez A, McCormick PJ (2004) The bHLH protein MyoR inhibits the differentiation of early embryonic endoderm. Differentiation 72:341–347CrossRefPubMedGoogle Scholar
  187. Zeng X, Miura T, Luo Y, Bhattacharya B, Condie B, Chen J, Ginis I, Lyons I, Mejido J, Puri RK, Rao MS, Freed WJ (2004) Properties of pluripotent human embryonic stem cells BG01 and BG02. Stem Cells 22:292–312PubMedGoogle Scholar
  188. Zeuthen J, Norgaard JO, Avner P, Fellous M, Wartiovaara J, Vaheri A, Rosen A, Giovanella BC (1980) Characterization of a human ovarian teratocarcinoma-derived cell line. Int J Cancer 25:19–32PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • G. Weitzer
    • 1
  1. 1.Max F. Perutz Laboratories, Department of Medical Biochemistry, Division of Molecular Cell Biology, University Institutes at the Vienna BiocenterMedical University of ViennaViennaAustria

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