Mouse embryonic stem (ES) cells perpetuate in vitro the broad developmental potential of naïve founder cells in the preimplantation embryo. ES cells self-renew relentlessly in culture but can reenter embryonic development seamlessly, differentiating on schedule to form all elements of the fetus. Here we review the properties of these remarkable cells. Arising from the stability, homogeneity, and equipotency of ES cells, we consider the concept of a pluripotent ground state. We evaluate the authenticity of ES cells in relation to cells in the embryo and examine their utility for dissecting mechanisms that confer pluripotency and that execute fate choice. We summarize current knowledge of the transcription factor circuitry that governs the ES cell state and discuss the opportunity to expose molecular logic further through iterative computational modeling and experimentation. Finally, we present a perspective on unresolved questions, including the challenge of deriving ground state pluripotent stem cells from non-rodent species.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Adachi K, Nikaido I, Ohta H, Ohtsuka S, Ura H. et al. 2013. Context-dependent wiring of Sox2 regulatory networks for self-renewal of embryonic and trophoblast stem cells. Mol. Cell 52:380–92 [Google Scholar]
  2. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S. et al. 1994. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77:163–71 [Google Scholar]
  3. 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. 17:116321–29 [Google Scholar]
  4. Berge DT, Kurek D, Blauwkamp T, Koole W, Maas A. et al. 2011. Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nat. Cell Biol. 13:91070–75 [Google Scholar]
  5. Betschinger J, Nichols J, Dietmann S, Corrin PD, Paddison PJ, Smith A. 2013. Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell 153:2335–47 [Google Scholar]
  6. Boeuf H, Hauss C, Graeve FD, Baran N, Kedinger C. 1997. Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells. J. Cell Biol. 138:61207–17 [Google Scholar]
  7. Boroviak T, Loos R, Bertone P, Smith A, Nichols J. 2014. The ability of inner cell mass cells to self-renew as embryonic stem cells is acquired upon epiblast specification. Nat. Cell Biol. 16:6516–28 [Google Scholar]
  8. Bourillot P-Y, Aksoy I, Schreiber V, Wianny F, Schulz H. et al. 2009. Novel STAT3 target genes exert distinct roles in the inhibition of mesoderm and endoderm differentiation in cooperation with Nanog. Stem Cells 27:81760–71 [Google Scholar]
  9. Bradley A, Evans M, Kaufman MH, Robertson E. 1984. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature 309:5965255–56 [Google Scholar]
  10. Brons IG, Smithers LE, Trotter MW, Rugg-Gunn P, Sun B. et al. 2007. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448:191–95 [Google Scholar]
  11. Buecker C, Srinivasan R, Wu Z, Calo E, Acampora D. et al. 2014. Reorganization of enhancer patterns in transition from naive to primed pluripotency. Cell Stem Cell 14:838–53 [Google Scholar]
  12. Buehr M, Meek S, Blair K, Yang J, Ure J. et al. 2008. Capture of authentic embryonic stem cells from rat blastocysts. Cell 135:71287–98 [Google Scholar]
  13. Buehr M, Smith A. 2003. Genesis of embryonic stem cells. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358:14361397–402 discussion 1402 [Google Scholar]
  14. Buganim Y, Faddah DA, Cheng AW, Itskovich E, Markoulaki S. et al. 2012. Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell 150:61209–22 [Google Scholar]
  15. Burdon T, Stracey C, Chambers I, Nichols J, Smith AG. 1999. Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Dev. Biol. 210:130–43 [Google Scholar]
  16. Capecchi MR. 2005. Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century. Nat. Rev. Genet. 6:6507–12 [Google Scholar]
  17. Chambers I, Colby D, Robertson M, Nichols J, Lee S. et al. 2003. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:5643–55 [Google Scholar]
  18. Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B. et al. 2007. Nanog safeguards pluripotency and mediates germline development. Nature 450:71731230–34 [Google Scholar]
  19. Chambers I, Tomlinson SR. 2009. The transcriptional foundation of pluripotency. Development 136:2311–22 [Google Scholar]
  20. Chazaud C, Yamanaka Y, Pawson T, Rossant J. 2006. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev. Cell 10:615–24 [Google Scholar]
  21. Chen X, Xu H, Yuan P, Fang F, Huss M. et al. 2008. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133:61106–17 [Google Scholar]
  22. Clevers H. 2006. Wnt/β-catenin signaling in development and disease. Cell 127:3469–80 [Google Scholar]
  23. Dani C, Chambers I, Johnstone S, Robertson M, Ebrahimi B. et al. 1998. Paracrine induction of stem cell renewal by LIF-deficient cells: a new ES cell regulatory pathway. Dev. Biol. 203:1149–62 [Google Scholar]
  24. Davies OR, Lin C-Y, Radzisheuskaya A, Zhou X, Taube J. et al. 2013. Tcf15 primes pluripotent cells for differentiation. Cell Rep. 3:2472–84 [Google Scholar]
  25. DeVeale B, Brokhman I, Mohseni P, Babak T, Yoon C. et al. 2013. Oct4 is required ∼E7.5 for proliferation in the primitive streak. PLOS Genet. 9:11e1003957 [Google Scholar]
  26. Dick JE. 2008. Stem cell concepts renew cancer research. Blood 112:134793–807 [Google Scholar]
  27. Ding L, Paszkowski-Rogacz M, Nitzsche A, Slabicki MM, Heninger AK. et al. 2009. A genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell identity. Cell Stem Cell 4:403–15 [Google Scholar]
  28. Diwan SB, Stevens LC. 1976. Development of teratomas from the ectoderm of mouse egg cylinders. J. Natl. Cancer Inst. 57:4937–42 [Google Scholar]
  29. Doble BW, Patel S, Wood GA, Kockeritz LK, Woodgett JR. 2007. Functional redundancy of GSK-3α and GSK-3β in Wnt/β-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev. Cell 12:6957–71 [Google Scholar]
  30. Doble BW, Woodgett JR. 2003. GSK-3: tricks of the trade for a multi-tasking kinase. J. Cell Sci. 116:Pt. 71175–86 [Google Scholar]
  31. Dunn S-J, Martello G, Yordanov B, Emmott S, Smith AG. 2014. Defining an essential transcription factor program for naïve pluripotency. Science 344:61881156–60 [Google Scholar]
  32. Dutta D, Ray S, Home P, Larson M, Wolfe MW, Paul S. 2011. Self-renewal versus lineage commitment of embryonic stem cells: protein kinase C signaling shifts the balance. Stem Cells 29:618–28 [Google Scholar]
  33. Eakin GS, Hadjantonakis A-K, Papaioannou VE, Behringer RR. 2005. Developmental potential and behavior of tetraploid cells in the mouse embryo. Dev. Biol. 288:1150–59 [Google Scholar]
  34. Evans MJ, Kaufman MH. 1981. Establishment in culture of pluripotential cells from mouse embryos. Nature 292:5819154–56 [Google Scholar]
  35. Faddah DA, Wang H, Cheng AW, Katz Y, Buganim Y, Jaenisch R. 2013. Single-cell analysis reveals that expression of Nanog is biallelic and equally variable as that of other pluripotency factors in mouse ESCs. Cell Stem Cell 13:123–29 [Google Scholar]
  36. Feng B, Jiang J, Kraus P, Ng J-H, Heng J-CD. et al. 2009. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat. Cell Biol. 11:2197–203 [Google Scholar]
  37. Festuccia N, Osorno R, Halbritter F, Karwacki-Neisius V, Navarro P. et al. 2012. Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells. Cell Stem Cell 11:4477–90 [Google Scholar]
  38. Ficz G, Hore TA, Santos F, Lee HJ, Dean W. et al. 2013. FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell 13:3351–59 [Google Scholar]
  39. Filipczyk A, Gkatzis K, Fu J, Hoppe PS, Lickert H. et al. 2013. Biallelic expression of Nanog protein in mouse embryonic stem cells. Cell Stem Cell 13:12–13 [Google Scholar]
  40. Gardner RL. 1998. Contributions of blastocyst micromanipulation to the study of mammalian development. BioEssays 20:168–80 [Google Scholar]
  41. Gardner RL, Brook FA. 1997. Reflections on the biology of embryonic stem (ES) cells. Int. J. Dev. Biol. 41:2235–43 [Google Scholar]
  42. Guo G, Huang Y, Humphreys P, Wang X, Smith A. 2011. A PiggyBac-based recessive screening method to identify pluripotency regulators. PLOS ONE 6:4e18189 [Google Scholar]
  43. Guo G, Huss M, Tong GQ, Wang C, Sun LL. et al. 2010. Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst. Dev. Cell 18:4675–85 [Google Scholar]
  44. Guo G, Yang J, Nichols J, Hall JS, Eyres I. et al. 2009. Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136:71063–69 [Google Scholar]
  45. Habibi E, Brinkman AB, Arand J, Kroeze LI, Kerstens HHD. et al. 2013. Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell 13:3360–69 [Google Scholar]
  46. Hall J, Guo G, Wray J, Eyres I, Nichols J. et al. 2009. Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell 5:6597–609 [Google Scholar]
  47. Han J, Yuan P, Yang H, Zhang J, Soh BS. et al. 2010. Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature 463:1096–100 [Google Scholar]
  48. Hayashi K, Chuva de Sousa Lopes SM, Tang F, Surani MA. 2008. Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. Cell Stem Cell 3:391–401 [Google Scholar]
  49. Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M. 2011. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell 146:519–32 [Google Scholar]
  50. Herberg M, Kalkan T, Glauche I, Smith A, Roeder I. 2014. A model-based analysis of culture-dependent phenotypes of mESCs. PLOS ONE 9:e92496 [Google Scholar]
  51. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V. et al. 2013. Super-enhancers in the control of cell identity and disease. Cell 155:4934–47 [Google Scholar]
  52. Houston DW, Kofron M, Resnik E, Langland R, Destree O. et al. 2002. Repression of organizer genes in dorsal and ventral Xenopus cells mediated by maternal XTcf3. Development 129:174015–25 [Google Scholar]
  53. Hu G, Kim J, Xu Q, Leng Y, Orkin SH, Elledge SJ. 2009. A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. Genes Dev. 23:837–48 [Google Scholar]
  54. Ivanova N, Dobrin R, Lu R, Kotenko I, Levorse J. et al. 2006. Dissecting self-renewal in stem cells with RNA interference. Nat. Cell Biol. 442:7102533–38 [Google Scholar]
  55. Kahan BW, Ephrussi B. 1970. Developmental potentialities of clonal in vitro cultures of mouse testicular teratoma. J. Natl. Cancer Inst. 44:51015–36 [Google Scholar]
  56. Kalkan T, Smith A. 2014. Mapping the route from naive pluripotency to lineage specification. Philos. Trans. R. Soc. Lond. B Biol. Sci. In press [Google Scholar]
  57. Kalmar T, Lim C, Hayward P, Muñoz-Descalzo S, Nichols J. et al. 2009. Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells. PLOS Biol. 7:e1000149 [Google Scholar]
  58. Karwacki-Neisius V, Göke J, Osorno R, Halbritter F, Ng J-H. et al. 2013. Reduced Oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by Oct4 and Nanog. Cell Stem Cell 12:5531–45 [Google Scholar]
  59. Keramari M, Razavi J, Ingman KA, Patsch C, Edenhofer F. et al. 2010. Sox2 is essential for formation of trophectoderm in the preimplantation embryo. PLOS ONE 5:11e13952 [Google Scholar]
  60. Kiyonari H, Kaneko M, Abe S-I, Aizawa S. 2010. Three inhibitors of FGF receptor, ERK, and GSK3 establishes germline-competent embryonic stem cells of C57BL/6N mouse strain with high efficiency and stability. Genesis 48:5317–27 [Google Scholar]
  61. Kleinsmith LJ, Pierce GB. 1964. Multipotentiality of single embryonal carcinoma cells. Cancer Res. 24:1544–51 [Google Scholar]
  62. Kojima Y, Kaufman-Francis K, Studdert JB, Steiner KA, Power MD. et al. 2014. The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell 14:1107–20 [Google Scholar]
  63. Koopman P, Cotton RG. 1984. A factor produced by feeder cells which inhibits embryonal carcinoma cell differentiation. Characterization and partial purification. Exp. Cell Res. 154:1233–42 [Google Scholar]
  64. Kopp JL, Ormsbee BD, Desler M, Rizzino A. 2008. Small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells. Stem Cells 26:4903–11 [Google Scholar]
  65. Kunath T, Saba-El-Leil MK, Almousailleakh M, Wray J, Meloche S, Smith AG. 2007. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development 134:162895–902 [Google Scholar]
  66. Lanner F, Lee KL, Sohl M, Holmborn K, Yang H. et al. 2010. Heparan sulfation-dependent fibroblast growth factor signaling maintains embryonic stem cells primed for differentiation in a heterogeneous state. Stem Cells 28:2191–200 [Google Scholar]
  67. Le Bin GC, Muñoz-Descalzo S, Kurowski A, Leitch H, Lou X. et al. 2014. Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst. Development 141:51001–10 [Google Scholar]
  68. Leeb M, Dietmann S, Paramor M, Niwa H, Smith A. 2014. Genetic exploration of the exit from self-renewal using haploid embryonic stem cells. Cell Stem Cell 14:3385–93 [Google Scholar]
  69. Leitch HG, Blair K, Mansfield W, Ayetey H, Humphreys P. et al. 2010. Embryonic germ cells from mice and rats exhibit properties consistent with a generic pluripotent ground state. Development 137:142279–87 [Google Scholar]
  70. Leitch HG, McEwen KR, Turp A, Encheva V, Carroll T. et al. 2013a. Naive pluripotency is associated with global DNA hypomethylation. Nat. Struct. Mol. Biol. 20:3311–16 [Google Scholar]
  71. Leitch HG, Nichols J, Humphreys P, Mulas C, Martello G. et al. 2013b. Rebuilding pluripotency from primordial germ cells. Stem Cell Rep. 1:166–78 [Google Scholar]
  72. Leitch HG, Smith A. 2013. The mammalian germline as a pluripotency cycle. Development 140:122495–501 [Google Scholar]
  73. Li P, Tong C, Mehrian-Shai R, Jia L, Wu N. et al. 2008. Germline competent embryonic stem cells derived from rat blastocysts. Cell 135:71299–310 [Google Scholar]
  74. Liu Z, Scannell DR, Eisen MB, Tjian R. 2011. Control of embryonic stem cell lineage commitment by core promoter factor, TAF3. Cell 146:720–31 [Google Scholar]
  75. Loh KM, Lim B. 2011. A precarious balance: pluripotency factors as lineage specifiers. Cell Stem Cell 8:4363–69 [Google Scholar]
  76. Loh Y-H, Wu Q, Chew J-L, Vega VB, Zhang W. et al. 2006. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat. Genet. 38:4431–40 [Google Scholar]
  77. Luo Y, Lim CL, Nichols J, Martinez-Arias A, Wernisch L. 2012. Cell signalling regulates dynamics of Nanog distribution in embryonic stem cell populations. J. R. Soc. Interface 10:20120525 [Google Scholar]
  78. Lu R, Markowetz F, Unwin RD, Leek JT, Airoldi EM. et al. 2009. Systems-level dynamic analyses of fate change in murine embryonic stem cells. Nature 462:7271358–62 [Google Scholar]
  79. Lyashenko N, Winter M, Migliorini D, Biechele T, Moon RT, Hartmann C. 2011. Differential requirement for the dual functions of β-catenin in embryonic stem cell self-renewal and germ layer formation. Nat. Cell Biol. 13:7753–61 [Google Scholar]
  80. MacArthur BD, Lemischka IR. 2013. Statistical mechanics of pluripotency. Cell 154:3484–89 [Google Scholar]
  81. MacArthur BD, Sevilla A, Lenz M, Müller FJ, Schuldt BM. et al. 2012. Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity. Nat. Cell Biol. 14:1139–47 [Google Scholar]
  82. Malaguti M, Nistor PA, Blin G, Pegg A, Zhou X, Lowell S. 2013. Bone morphogenic protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin. eLife 2:e01197 [Google Scholar]
  83. Marks H, Kalkan T, Menafra R, Denissov S, Jones K. et al. 2012. The transcriptional and epigenomic foundations of ground state pluripotency. Cell 149:3590–604 [Google Scholar]
  84. Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T. et al. 2008. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134:3521–33 [Google Scholar]
  85. Martello G, Bertone P, Smith A. 2013. Identification of the missing pluripotency mediator downstream of leukaemia inhibitory factor. EMBO J. 32:2531–56 [Google Scholar]
  86. Martello G, Sugimoto T, Diamanti E, Joshi A, Hannah R. et al. 2012. Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal. Cell Stem Cell 11:4491–504 [Google Scholar]
  87. Martin GR. 1975. Teratocarcinomas as a model system for the study of embryogenesis and neoplasia. Cell 5:3229–43 [Google Scholar]
  88. Martin GR. 1980. Teratocarcinomas and mammalian embryogenesis. Science 209:4458768–76 [Google Scholar]
  89. 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 78:127634–38 [Google Scholar]
  90. Martin GR, Evans MJ. 1975. Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. Proc. Natl. Acad. Sci. USA 72:41441–45 [Google Scholar]
  91. Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R. et al. 2007. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat. Cell Biol. 9:6625–35 [Google Scholar]
  92. Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M. et al. 1999. STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J. 18:154261–69 [Google Scholar]
  93. Matsui Y, Zsebo K, Hogan BL. 1992. Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70:5841–47 [Google Scholar]
  94. Merrill BJ, Gat U, Dasgupta R, Fuchs E. 2001. Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev. 15:131688–705 [Google Scholar]
  95. Merrill BJ, Pasolli HA, Polak L, Rendl M, García-García MJ. et al. 2004. Tcf3: a transcriptional regulator of axis induction in the early embryo. Development 131:2263–74 [Google Scholar]
  96. Meshorer E, Yellajoshula D, George E, Scambler PJ, Brown DT, Misteli T. 2006. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev. Cell 10:105–16 [Google Scholar]
  97. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M. et al. 2003. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:5631–42 [Google Scholar]
  98. Nagy A, Gócza E, Merentes Diaz E, Prideaux VR, Iványi E. et al. 1991. Embryonic stem cells alone are able to support fetal development in the mouse. Development 110:815–21 [Google Scholar]
  99. Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder JC. 1993. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. USA 90:8424–28 [Google Scholar]
  100. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T. et al. 2007. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. 26:1101–6 [Google Scholar]
  101. Nakatake Y, Fujii S, Masui S, Sugimoto T, Torikai-Nishikawa S. et al. 2013. Kinetics of drug selection systems in mouse embryonic stem cells. BMC Biotechnol. 13:64 [Google Scholar]
  102. Navarro P, Festuccia N, Colby D, Gagliardi A, Mullin NP. et al. 2012. OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells. EMBO J. 31:4547–62 [Google Scholar]
  103. Nichols J, Chambers I, Taga T, Smith A. 2001. Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines. Development 128:122333–39 [Google Scholar]
  104. Nichols J, Jones K, Phillips JM, Newland SA, Roode M. et al. 2009a. Validated germline-competent embryonic stem cell lines from nonobese diabetic mice. Nat. Med. 15:7814–18 [Google Scholar]
  105. Nichols J, Silva J, Roode M, Smith A. 2009b. Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 136:193215–22 [Google Scholar]
  106. Nichols J, Smith A. 2011. The origin and identity of embryonic stem cells. Development 138:13–8 [Google Scholar]
  107. Nichols J, Smith A. 2012. Pluripotency in the embryo and in culture. Cold Spring Harb. Perspect. Biol. 4:8a008128 [Google Scholar]
  108. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D. et al. 1998. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:3379–91 [Google Scholar]
  109. Nishiyama A, Sharov AA, Piao Y, Amano M, Amano T. et al. 2013. Systematic repression of transcription factors reveals limited patterns of gene expression changes in ES cells. Sci. Rep. 3:1390 [Google Scholar]
  110. Niwa H. 2007. Open conformation chromatin and pluripotency. Genes Dev. 21:212671–76 [Google Scholar]
  111. Niwa H, Burdon T, Chambers I, Smith AG. 1998. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 12:132048–60 [Google Scholar]
  112. Niwa H, Miyazaki J, Smith AG. 2000. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat. Genet. 24:4372–76 [Google Scholar]
  113. Niwa H, Ogawa K, Shimosato D, Adachi K. 2009. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 460:7251118–22 [Google Scholar]
  114. O'Leary T, Heindryckx B, Lierman S, van Bruggen D, Goeman JJ. et al. 2012. Tracking the progression of the human inner cell mass during embryonic stem cell derivation. Nat. Biotechnol. 30:3278–82 [Google Scholar]
  115. 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. 343:1159–66 [Google Scholar]
  116. 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 60:3461–72 [Google Scholar]
  117. Okita K, Ichisaka T, Yamanaka S. 2007. Generation of germline-competent induced pluripotent stem cells. Nature 448:7151313–17 [Google Scholar]
  118. Onishi K, Tonge PD, Nagy A, Zandstra PW. 2014. Local BMP-SMAD1 signaling increases LIF receptor-dependent STAT3 responsiveness and primed-to-naive mouse pluripotent stem cell conversion frequency. Stem Cell Rep. 3:156–68 [Google Scholar]
  119. Osorno R, Tsakiridis A, Wong F, Cambray N, Economou C. et al. 2012. The developmental dismantling of pluripotency is reversed by ectopic Oct4 expression. Development 139:2288–98 [Google Scholar]
  120. Pardo M, Lang B, Yu L, Prosser H, Bradley A. et al. 2010. An expanded Oct4 interaction network: implications for stem cell biology, development, and disease. Cell Stem Cell 6:4382–95 [Google Scholar]
  121. Papaioannou VE, Rossant J. 1992. Effects of the embryonic environment on proliferation and differentiation of embryonal carcinoma cells. Cancer Surv. 2:165–83 [Google Scholar]
  122. Pelton TA, Sharma S, Schulz TC, Rathjen J, Rathjen PD. 2002. Transient pluripotent cell populations during primitive ectoderm formation: correlation of in vivo and in vitro pluripotent cell development. J. Cell Sci. 115:Pt. 2329–39 [Google Scholar]
  123. Pereira L, Yi F, Merrill BJ. 2006. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Mol. Cell. Biol. 26:207479–91 [Google Scholar]
  124. Radzisheuskaya A, Le Bin Chia G, dos Santos RL, Theunissen TW, Castro LFC. et al. 2013. A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. Nat. Cell Biol. 15:6579–90 [Google Scholar]
  125. Rastan S, Robertson EJ. 1985. X-chromosome deletions in embryo-derived (EK) cell lines associated with lack of X-chromosome inactivation. J. Embryol. Exp. Morphol. 90:379–88 [Google Scholar]
  126. Rathjen PD, Nichols J, Toth S, Edwards DR, Heath JK, Smith AG. 1990. Developmentally programmed induction of differentiation inhibiting activity and the control of stem cell populations. Genes Dev. 4:12B2308–18 [Google Scholar]
  127. Resnick JL, Bixler LS, Cheng L, Donovan PJ. 1992. Long-term proliferation of mouse primordial germ cells in culture. Nature 359:6395550–51 [Google Scholar]
  128. Robertson E, Bradley A, Kuehn M, Evans M. 1986. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature 323:445–48 [Google Scholar]
  129. Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. 2004. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat. Med. 10:155–63 [Google Scholar]
  130. Schöler HR, Dressler GR, Balling R, Rohdewohld H, Gruss P. 1990. Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. EMBO J. 9:72185–95 [Google Scholar]
  131. Shy BR, Wu C-I, Khramtsova GF, Zhang JY, Olopade OI. et al. 2013. Regulation of Tcf7l1 DNA binding and protein stability as principal mechanisms of Wnt/β-catenin signaling. Cell Rep. 4:11–9 [Google Scholar]
  132. Silva J, Barrandon O, Nichols J, Kawaguchi J, Theunissen TW, Smith AG. 2008. Promotion of reprogramming to ground state pluripotency by signal inhibition. PLOS Biol. 6:10e253 [Google Scholar]
  133. Silva J, Chambers I, Pollard S, Smith AG. 2006. Nanog promotes transfer of pluripotency after cell fusion. Nature 441:7096997–1001 [Google Scholar]
  134. Silva J, Nichols J, Theunissen TW, Guo G, van Oosten AL. et al. 2009. Nanog is the gateway to the pluripotent ground state. Cell 138:4722–37 [Google Scholar]
  135. Silva J, Smith AG. 2008. Capturing pluripotency. Cell 132:4532–36 [Google Scholar]
  136. Simons BD, Clevers H. 2011. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145:851–62 [Google Scholar]
  137. Smith A. 2013. Nanog heterogeneity: Tilting at windmills?. Cell Stem Cell 13:6–7 [Google Scholar]
  138. Smith A. 2001a. Embryonic stem cells. Stem Cell Biology DR Marshak, RL Gardner, D Gottlieb 205–30 New York: Cold Spring Harb. Lab. Press [Google Scholar]
  139. Smith AG. 2001b. Embryo-derived stem cells: of mice and men. Annu. Rev. Cell Dev. Biol. 17:435–62 [Google Scholar]
  140. Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J. et al. 1988. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336:6200688–90 [Google Scholar]
  141. Smith TA, Hooper ML. 1983. Medium conditioned by feeder cells inhibits the differentiation of embryonal carcinoma cultures. Exp. Cell Res. 145:2458–62 [Google Scholar]
  142. Smith AG, Hooper ML. 1987. Buffalo rat liver cells produce a diffusible activity which inhibits the differentiation of murine embryonal carcinoma and embryonic stem cells. Dev. Biol. 121:1–9 [Google Scholar]
  143. Smith ZD, Chan MM, Mikkelsen TS, Gu H, Gnirke A. et al. 2012. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature 484:7394339–44 [Google Scholar]
  144. Solter D, Skreb N, Damjanov I. 1970. Extrauterine growth of mouse egg-cylinders results in malignant teratoma. Nature 227:5257503–4 [Google Scholar]
  145. Som A, Harder C, Greber B, Siatkowski M, Paudel Y. et al. 2010. The PluriNetWork: an electronic representation of the network underlying pluripotency in mouse, and its applications. PLOS ONE 5:12e15165 [Google Scholar]
  146. Sridharan R, Tchieu J, Mason MJ, Yachechko R, Kuoy E. et al. 2009. Role of the murine reprogramming factors in the induction of pluripotency. Cell 136:364–77 [Google Scholar]
  147. Stavridis MP, Lunn JS, Collins BJ, Storey KG. 2007. A discrete period of FGF-induced Erk1/2 signalling is required for vertebrate neural specification. Development 134:162889–94 [Google Scholar]
  148. Stead E, White J, Faast R, Conn S, Goldstone S. et al. 2002. Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities. Oncogene 21:8320–33 [Google Scholar]
  149. Stevens LC. 1968. The development of teratomas from intratesticular grafts of tubal mouse eggs. J. Embryol. Exp. Morphol. 20:3329–41 [Google Scholar]
  150. Stevens LC. 1983. The origin and development of testicular, ovarian and embryo-derived teratomas. Teratocarcinoma Stem Cells (Cold Spring Harbor Conferences on Cell Proliferation) 10 LM Silver, GM Martin S Strickland, pp. 666–70. New York: Cold Spring Harb. Lab. Press [Google Scholar]
  151. Stevens LC, Little CC. 1954. Spontaneous testicular teratomas in an inbred strain of mice. Proc. Natl. Acad. Sci. USA 40:111080–87 [Google Scholar]
  152. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I. et al. 1992. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 359:76–79 [Google Scholar]
  153. Tai C-I, Ying Q-L. 2013. Gbx2, a LIF/Stat3 target, promotes reprogramming to and retention of the pluripotent ground state. J. Cell Sci. 126:1093–98 [Google Scholar]
  154. Takahashi K, Yamanaka S. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:4663–76 [Google Scholar]
  155. Tam PPL, Rossant J. 2003. Mouse embryonic chimeras: tools for studying mammalian development. Development 130:256155–63 [Google Scholar]
  156. Tang F, Barbacioru C, Bao S, Lee C, Nordman E. et al. 2010. Tracing the derivation of embryonic stem cells from the inner cell mass by single-cell RNA-Seq analysis. Cell Stem Cell 6:5468–78 [Google Scholar]
  157. Tang Y, Luo Y, Jiang Z, Ma Y, Lin C-J. et al. 2012. Jak/Stat3 signaling promotes somatic cell reprogramming by epigenetic regulation. Stem Cells 30:122645–56 [Google Scholar]
  158. Tesar PJ. 2005. Derivation of germ-line-competent embryonic stem cell lines from preblastocyst mouse embryos. Proc. Natl. Acad. Sci. USA 102:8239–44 [Google Scholar]
  159. Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP. et al. 2007. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448:196–99 [Google Scholar]
  160. Theunissen TW, van Oosten AL, Castelo-Branco G, Hall J, Smith A, Silva JCR. 2011. Nanog overcomes reprogramming barriers and induces pluripotency in minimal conditions. Curr. Biol. 21:165–71 [Google Scholar]
  161. Thompson S, Clarke AR, Pow AM, Hooper ML, Melton DW. 1989. Germ line transmission and expression of a corrected HPRT gene produced by gene targeting in embryonic stem cells. Cell 56:2313–21 [Google Scholar]
  162. Thomson M, Liu SJ, Zou L-N, Smith Z, Meissner A, Ramanathan S. 2011. Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. Cell 145:6875–89 [Google Scholar]
  163. Toyooka Y, Shimosato D, Murakami K, Takahashi K, Niwa H. 2008. Identification and characterization of subpopulations in undifferentiated ES cell culture. Development 135:5909–18 [Google Scholar]
  164. Trott J, Martinez Arias A. 2013. Single cell lineage analysis of mouse embryonic stem cells at the exit from pluripotency. Biol. Open 2:101049–56 [Google Scholar]
  165. Tsakiridis A, Huang Y, Blin G, Skylaki S, Wymeersch F. et al. 2014. Distinct Wnt-driven primitive streak-like populations reflect in vivo lineage precursors. Development 141:1209–21 [Google Scholar]
  166. Tsubooka N, Ichisaka T, Okita K, Takahashi K, Nakagawa M, Yamanaka S. 2009. Roles of Sall4 in the generation of pluripotent stem cells from blastocysts and fibroblasts. Genes Cells 14:6683–94 [Google Scholar]
  167. van den Berg DLC, Snoek T, Mullin NP, Yates A, Bezstarosti K. et al. 2010. An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell 6:4369–81 [Google Scholar]
  168. Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW. et al. 2013. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153:4910–18 [Google Scholar]
  169. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M. et al. 2007. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448:7151318–24 [Google Scholar]
  170. Wilder PJ, Kelly D, Brigman K, Peterson CL, Nowling T. et al. 1997. Inactivation of the FGF-4 gene in embryonic stem cells alters the growth and/or the survival of their early differentiated progeny. Dev. Biol. 192:2614–29 [Google Scholar]
  171. Wiles MV, Johansson BM. 1999. Embryonic stem cell development in a chemically defined medium. Exp. Cell Res. 247:1241–48 [Google Scholar]
  172. Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL. et al. 1988. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336:6200684–87 [Google Scholar]
  173. Wong CC, Gaspar-Maia A, Ramalho-Santos M, Reijo Pera RA. 2008. High-efficiency stem cell fusion-mediated assay reveals Sall4 as an enhancer of reprogramming. PLOS ONE 3:4e1955 [Google Scholar]
  174. Wray J, Kalkan T, Gomez-Lopez S, Eckardt D, Cook A. et al. 2011. Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Nat. Cell Biol. 13:838–45 [Google Scholar]
  175. Wray J, Kalkan T, Smith AG. 2010. The ground state of pluripotency. Biochem. Soc. Trans. 38:41027–32 [Google Scholar]
  176. Wu C-I, Hoffman JA, Shy BR, Ford EM, Fuchs E. et al. 2012. Function of Wnt/β-catenin in counteracting Tcf3 repression through the Tcf3-β-catenin interaction. Development 139:122118–29 [Google Scholar]
  177. Yamanaka Y, Lanner F, Rossant J. 2010. FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development 137:5715–24 [Google Scholar]
  178. Yan L, Yang M, Guo H, Yang L, Wu J. et al. 2013. Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells. Nat. Struct. Mol. Biol. 20:1131–39 [Google Scholar]
  179. Yang J, van Oosten AL, Theunissen TW, Guo G, Silva JCR, Smith A. 2010. Stat3 activation is limiting for reprogramming to ground state pluripotency. Cell Stem Cell 7:3319–28 [Google Scholar]
  180. Yang S-H, Kalkan T, Morrisroe C, Smith A, Sharrocks AD. 2012. A genome-wide RNAi screen reveals MAP kinase phosphatases as key ERK pathway regulators during embryonic stem cell differentiation. PLOS Genet. 8:12e1003112 [Google Scholar]
  181. Yang S-H, Kalkan T, Morissroe C, Marks H, Stunnenberg H. et al. 2014. Otx2 and Oct4 drive early enhancer activation during embryonic stem cell transition from naive pluripotency. Cell Rep. 7:1–14 [Google Scholar]
  182. Ye S, Li P, Tong C, Ying QL. 2013. Embryonic stem cell self-renewal pathways converge on the transcription factor Tfcp2l1. EMBO J. 32:192548–60 [Google Scholar]
  183. Yi F, Pereira L, Merrill BJ. 2008. Tcf3 functions as a steady-state limiter of transcriptional programs of mouse embryonic stem cell self-renewal. Stem Cells 26:81951–60 [Google Scholar]
  184. Ying QL, Nichols J, Chambers I, Smith A. 2003a. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115:3281–92 [Google Scholar]
  185. Ying QL, Stavridis M, Griffiths D, Li M, Smith AG. 2003b. Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat. Biotechnol. 21:181–86 [Google Scholar]
  186. Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B. et al. 2008. The ground state of embryonic stem cell self-renewal. Nature 453:7194519–23 [Google Scholar]
  187. Young RA. 2011. Control of the embryonic stem cell state. Cell 144:6940–54 [Google Scholar]
  188. Zalzman M, Falco G, Sharova LV, Nishiyama A, Thomas M. et al. 2010. Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature 464:858–63 [Google Scholar]
  189. Zhang K, Li L, Huang C, Shen C, Tan F. et al. 2010. Distinct functions of BMP4 during different stages of mouse ES cell neural commitment. Development 137:132095–105 [Google Scholar]
  190. Zhao S, Nichols J, Smith AG, Li M. 2004. SoxB transcription factors specify neuroectodermal lineage choice in ES cells. Mol. Cell. Neurosci. 27:3332–42 [Google Scholar]
  191. Zhong Z, Wen Z, Darnell JE. 1994. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264:515595–98 [Google Scholar]
  192. Zhou W, Choi M, Margineantu D, Margaretha L, Hesson J. et al. 2012. HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. EMBO J. 31:2103–16 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error