Advertisement

Cellular and Molecular Life Sciences

, Volume 72, Issue 9, pp 1741–1757 | Cite as

Molecular basis of embryonic stem cell self-renewal: from signaling pathways to pluripotency network

  • Guanyi Huang
  • Shoudong Ye
  • Xingliang Zhou
  • Dahai Liu
  • Qi-Long Ying
Review

Abstract

Embryonic stem cells (ESCs) can be maintained in culture indefinitely while retaining the capacity to generate any type of cell in the body, and therefore not only hold great promise for tissue repair and regeneration, but also provide a powerful tool for modeling human disease and understanding biological development. In order to fulfill the full potential of ESCs, it is critical to understand how ESC fate, whether to self-renew or to differentiate into specialized cells, is regulated. On the molecular level, ESC fate is controlled by the intracellular transcriptional regulatory networks that respond to various extrinsic signaling stimuli. In this review, we discuss and compare important signaling pathways in the self-renewal and differentiation of mouse, rat, and human ESCs with an emphasis on how these pathways integrate into ESC-specific transcription circuitries. This will be beneficial for understanding the common and conserved mechanisms that govern self-renewal, and for developing novel culture conditions that support ESC derivation and maintenance.

Keywords

Embryonic stem cells Stem cell self-renewal Pluripotency LIF/Stat3 signaling pathway Wnt/β-catenin signaling pathway 

Notes

Acknowledgments

We thank Dr. Chang Tong for his advice and critical reading of this manuscript. This review was supported by funding from NIH/NCRR grant (R01 RR025881) and California Institute for Regenerative Medicine (CIRM) grant (RN2-00938-1), and in part, by the 211 Project of Anhui University (10117700027, 02303203, J10117700060, Y0520374). The authors have no conflicts of interest to declare.

References

  1. 1.
    Smith AG (2001) Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol 17:435–462PubMedGoogle Scholar
  2. 2.
    Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156PubMedGoogle Scholar
  3. 3.
    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 78:7634–7638PubMedCentralPubMedGoogle Scholar
  4. 4.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedGoogle Scholar
  5. 5.
    Buehr M, Meek S, Blair K, Yang J, Ure J, Silva J et al (2008) Capture of authentic embryonic stem cells from rat blastocysts. Cell 135:1287–1298PubMedGoogle Scholar
  6. 6.
    Li P, Tong C, Mehrian-Shai R, Jia L, Wu N, Yan Y et al (2008) Germline competent embryonic stem cells derived from rat blastocysts. Cell 135:1299–1310PubMedCentralPubMedGoogle Scholar
  7. 7.
    Saiz N, Plusa B (2013) Early cell fate decisions in the mouse embryo. Reproduction 145:R65–R80PubMedGoogle Scholar
  8. 8.
    Nichols J, Smith A (2012) Pluripotency in the embryo and in culture. Cold Spring Harb Perspect Biol 4:a008128PubMedCentralPubMedGoogle Scholar
  9. 9.
    Rossant J (2009) Tam PP. Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136:701–713PubMedGoogle Scholar
  10. 10.
    Brons IG, Smithers LE, Trotter MW, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes SM et al (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448:191–195Google Scholar
  11. 11.
    Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP, Mack DL et al (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448:196–199PubMedGoogle Scholar
  12. 12.
    Nichols J, Smith A (2009) Naive and primed pluripotent states. Cell Stem Cell 4:487–492PubMedGoogle Scholar
  13. 13.
    Hanna J, Cheng AW, Saha K, Kim J, Lengner CJ, Soldner F et al (2010) Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc Natl Acad Sci USA 107:9222–9227PubMedCentralPubMedGoogle Scholar
  14. 14.
    Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J et al (2008) The ground state of embryonic stem cell self-renewal. Nature 453:519–523PubMedGoogle Scholar
  15. 15.
    Kim H, Wu J, Ye S, Tai CI, Zhou X, Yan H et al (2013) Modulation of beta-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal. Nat Commun 4:2403PubMedCentralPubMedGoogle Scholar
  16. 16.
    Martello G, Sugimoto T, Diamanti E, Joshi A, Hannah R, Ohtsuka S et al (2012) Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal. Cell Stem Cell 11:491–504PubMedCentralPubMedGoogle Scholar
  17. 17.
    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
  18. 18.
    Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M et al (1988) Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336:688–690PubMedGoogle Scholar
  19. 19.
    Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP et al (1988) Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336:684–687PubMedGoogle Scholar
  20. 20.
    Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956PubMedCentralPubMedGoogle Scholar
  21. 21.
    Kehler J, Tolkunova E, Koschorz B, Pesce M, Gentile L, Boiani M et al (2004) Oct4 is required for primordial germ cell survival. EMBO Rep 5:1078–1083PubMedCentralPubMedGoogle Scholar
  22. 22.
    Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I et al (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379–391PubMedGoogle Scholar
  23. 23.
    Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X et al (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38:431–440PubMedGoogle Scholar
  24. 24.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedGoogle Scholar
  25. 25.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920PubMedGoogle Scholar
  26. 26.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedGoogle Scholar
  27. 27.
    Hamanaka S, Yamaguchi T, Kobayashi T, Kato-Itoh M, Yamazaki S, Sato H et al (2011) Generation of germline-competent rat induced pluripotent stem cells. PLoS One 6:e22008PubMedCentralPubMedGoogle Scholar
  28. 28.
    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
  29. 29.
    Karwacki-Neisius V, Goke J, Osorno R, Halbritter F, Ng JH, Weisse AY 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 12:531–545PubMedCentralPubMedGoogle Scholar
  30. 30.
    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 17:126–140PubMedCentralPubMedGoogle Scholar
  31. 31.
    Wood HB, Episkopou V (1999) Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stages. Mech Dev 86:197–201PubMedGoogle Scholar
  32. 32.
    Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K et al (2007) Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 9:625–635PubMedGoogle Scholar
  33. 33.
    Ivanova N, Dobrin R, Lu R, Kotenko I, Levorse J, DeCoste C et al (2006) Dissecting self-renewal in stem cells with RNA interference. Nature 442:533–538PubMedGoogle Scholar
  34. 34.
    Yuan H, Corbi N, Basilico C, Dailey L (1995) Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev 9:2635–2645PubMedGoogle Scholar
  35. 35.
    Kuroda T, Tada M, Kubota H, Kimura H, Hatano SY, Suemori H et al (2005) Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Mol Cell Biol 25:2475–2485PubMedCentralPubMedGoogle Scholar
  36. 36.
    Nakatake Y, Fukui N, Iwamatsu Y, Masui S, Takahashi K, Yagi R et al (2006) Klf4 cooperates with Oct3/4 and Sox2 to activate the Lefty1 core promoter in embryonic stem cells. Mol Cell Biol 26:7772–7782PubMedCentralPubMedGoogle Scholar
  37. 37.
    Tomioka M, Nishimoto M, Miyagi S, Katayanagi T, Fukui N, Niwa H et al (2002) Identification of Sox-2 regulatory region which is under the control of Oct-3/4-Sox-2 complex. Nucleic Acids Res 30:3202–3213PubMedCentralPubMedGoogle Scholar
  38. 38.
    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
  39. 39.
    MacArthur BD, Sevilla A, Lenz M, Muller FJ, Schuldt BM, Schuppert AA et al (2012) Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity. Nat Cell Biol 14:1139–1147PubMedCentralPubMedGoogle Scholar
  40. 40.
    Kalmar T, Lim C, Hayward P, Munoz-Descalzo S, Nichols J, Garcia-Ojalvo J et al (2009) Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol 7:e1000149PubMedCentralPubMedGoogle Scholar
  41. 41.
    Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S et al (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643–655PubMedGoogle Scholar
  42. 42.
    Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K et al (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642PubMedGoogle Scholar
  43. 43.
    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
  44. 44.
    Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, Robertson M et al (2007) Nanog safeguards pluripotency and mediates germline development. Nature 450:1230–1234PubMedGoogle Scholar
  45. 45.
    Hyslop L, Stojkovic M, Armstrong L, Walter T, Stojkovic P, Przyborski S et al (2005) Downregulation of NANOG induces differentiation of human embryonic stem cells to extraembryonic lineages. Stem Cells 23:1035–1043PubMedGoogle Scholar
  46. 46.
    Festuccia N, Osorno R, Halbritter F, Karwacki-Neisius V, Navarro P, Colby D et al (2012) Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells. Cell Stem Cell 11:477–490PubMedCentralPubMedGoogle Scholar
  47. 47.
    Carter AC, Davis-Dusenbery BN, Koszka K, Ichida JK, Eggan K (2014) Nanog-Independent Reprogramming to iPSCs with Canonical Factors. Stem Cell Rep 2:119–126Google Scholar
  48. 48.
    Schwarz BA, Bar-Nur O, Silva JC, Hochedlinger K (2014) Nanog is dispensable for the generation of induced pluripotent stem cells. Curr Biol 24:347–350PubMedCentralPubMedGoogle Scholar
  49. 49.
    Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW et al (2006) A protein interaction network for pluripotency of embryonic stem cells. Nature 444:364–368PubMedGoogle Scholar
  50. 50.
    Wu Q, Chen X, Zhang J, Loh YH, Low TY, Zhang W et al (2006) Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. J Biol Chem 281:24090–24094PubMedGoogle Scholar
  51. 51.
    Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB et al (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133:1106–1117PubMedGoogle Scholar
  52. 52.
    Tai CI, Ying QL (2013) Gbx2, a LIF/Stat3 target, promotes reprogramming to and retention of the pluripotent ground state. J Cell Sci 126:1093–1098PubMedGoogle Scholar
  53. 53.
    Aksoy I, Sakabedoyan C, Bourillot PY, Malashicheva AB, Mancip J, Knoblauch K et al (2007) Self-renewal of murine embryonic stem cells is supported by the serine/threonine kinases Pim-1 and Pim-3. Stem Cells 25:2996–3004PubMedGoogle Scholar
  54. 54.
    Hall J, Guo G, Wray J, Eyres I, Nichols J, Grotewold L et al (2009) Oct4 and LIF/Stat3 additively induce Kruppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell 5:597–609PubMedGoogle Scholar
  55. 55.
    Zalzman M, Falco G, Sharova LV, Nishiyama A, Thomas M, Lee SL et al (2010) Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature 464:858–863PubMedCentralPubMedGoogle Scholar
  56. 56.
    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
  57. 57.
    Kaji K, Caballero IM, MacLeod R, Nichols J, Wilson VA, Hendrich B (2006) The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol 8:285–292PubMedGoogle Scholar
  58. 58.
    Niwa H, Ogawa K, Shimosato D, Adachi K (2009) A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 460:118–122PubMedGoogle Scholar
  59. 59.
    Wray J, Kalkan T, Gomez-Lopez S, Eckardt D, Cook A, Kemler R 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 13:838–845PubMedCentralPubMedGoogle Scholar
  60. 60.
    Acampora D, Di Giovannantonio LG, Simeone A (2013) Otx2 is an intrinsic determinant of the embryonic stem cell state and is required for transition to a stable epiblast stem cell condition. Development 140:43–55PubMedGoogle Scholar
  61. 61.
    Martello G, Bertone P, Smith A (2013) Identification of the missing pluripotency mediator downstream of leukaemia inhibitory factor. EMBO J 32:2561–2574PubMedCentralPubMedGoogle Scholar
  62. 62.
    Ye S, Li P, Tong C, Ying QL (2013) Embryonic stem cell self-renewal pathways converge on the transcription factor Tfcp2l1. EMBO J 32:2548–2560PubMedCentralPubMedGoogle Scholar
  63. 63.
    Niwa H, Toyooka Y, Shimosato D, Strumpf D, Takahashi K, Yagi R et al (2005) Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123:917–929PubMedGoogle Scholar
  64. 64.
    Grabole N, Tischler J, Hackett JA, Kim S, Tang F, Leitch HG et al (2013) Prdm14 promotes germline fate and naive pluripotency by repressing FGF signalling and DNA methylation. EMBO Rep 14:629–637PubMedCentralPubMedGoogle Scholar
  65. 65.
    Fujikura J, Yamato E, Yonemura S, Hosoda K, Masui S, Nakao K et al (2002) Differentiation of embryonic stem cells is induced by GATA factors. Genes Dev 16:784–789PubMedCentralPubMedGoogle Scholar
  66. 66.
    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 153:335–347PubMedCentralPubMedGoogle Scholar
  67. 67.
    Tamm C, Bower N, Anneren C (2011) Regulation of mouse embryonic stem cell self-renewal by a Yes-YAP-TEAD2 signaling pathway downstream of LIF. J Cell Sci 124:1136–1144PubMedGoogle Scholar
  68. 68.
    Lian I, Kim J, Okazawa H, Zhao J, Zhao B, Yu J et al (2010) The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev 24:1106–1118PubMedCentralPubMedGoogle Scholar
  69. 69.
    Adachi K, Nikaido I, Ohta H, Ohtsuka S, Ura H, Kadota M et al (2013) Context-dependent wiring of Sox2 regulatory networks for self-renewal of embryonic and trophoblast stem cells. Mol Cel 52:380–392Google Scholar
  70. 70.
    O’Loghlen A, Munoz-Cabello AM, Gaspar-Maia A, Wu HA, Banito A, Kunowska N et al (2012) MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation. Cell Stem Cell 10:33–46PubMedCentralPubMedGoogle Scholar
  71. 71.
    Niakan KK, Ji H, Maehr R, Vokes SA, Rodolfa KT, Sherwood RI et al (2010) Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic gene expression and indirectly antagonizing self-renewal. Genes Dev 24:312–326PubMedCentralPubMedGoogle Scholar
  72. 72.
    Zhang J, Tam WL, Tong GQ, Wu Q, Chan HY, Soh BS et al (2006) Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 8:1114–1123PubMedGoogle Scholar
  73. 73.
    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 121:1–9PubMedGoogle Scholar
  74. 74.
    Niwa H, Burdon T, Chambers I, Smith A (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev 12:2048–2060PubMedCentralPubMedGoogle Scholar
  75. 75.
    Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20PubMedCentralPubMedGoogle Scholar
  76. 76.
    Wang X, Crowe PJ, Goldstein D, Yang JL (2012) STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (review). Int J Oncol 41:1181–1191PubMedGoogle Scholar
  77. 77.
    Sasse J, Hemmann U, Schwartz C, Schniertshauer U, Heesel B, Landgraf C et al (1997) Mutational analysis of acute-phase response factor/Stat3 activation and dimerization. Mol Cell Biol 17:4677–4686PubMedCentralPubMedGoogle Scholar
  78. 78.
    Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662PubMedGoogle Scholar
  79. 79.
    Burdon T, Chambers I, Stracey C, Niwa H, Smith A (1999) Signaling mechanisms regulating self-renewal and differentiation of pluripotent embryonic stem cells. Cells Tissues Organs 165:131–143PubMedGoogle Scholar
  80. 80.
    Hirai H, Karian P, Kikyo N (2011) Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor. Biochem J 438:11–23PubMedCentralPubMedGoogle Scholar
  81. 81.
    Migone TS, Rodig S, Cacalano NA, Berg M, Schreiber RD, Leonard WJ (1998) Functional cooperation of the interleukin-2 receptor beta chain and Jak1 in phosphatidylinositol 3-kinase recruitment and phosphorylation. Mol Cell Biol 18:6416–6422PubMedCentralPubMedGoogle Scholar
  82. 82.
    Paling NR, Wheadon H, Bone HK, Welham MJ (2004) Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling. J Biol Chem 279:48063–48070PubMedGoogle Scholar
  83. 83.
    Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T et al (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5:449–460PubMedGoogle Scholar
  84. 84.
    Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T et al (1999) STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J 18:4261–4269PubMedCentralPubMedGoogle Scholar
  85. 85.
    Burdon T, Stracey C, Chambers I, Nichols J, Smith A (1999) Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Dev Biol 210:30–43PubMedGoogle Scholar
  86. 86.
    Huang G, Yan H, Ye S, Tong C, Ying QL (2013) STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ES cell fates. Stem Cells 32:1149–1160Google Scholar
  87. 87.
    Tai CI, Schulze EN, Ying QL (2014) Stat3 signaling regulates embryonic stem cell fate in a dose-dependent manner. Biol Open 3:958–965PubMedCentralPubMedGoogle Scholar
  88. 88.
    Snyder M, Huang XY, Zhang JJ (2008) Identification of novel direct Stat3 target genes for control of growth and differentiation. J Biol Chem 283:3791–3798PubMedGoogle Scholar
  89. 89.
    Sekkai D, Gruel G, Herry M, Moucadel V, Constantinescu SN, Albagli O et al (2005) Microarray analysis of LIF/Stat3 transcriptional targets in embryonic stem cells. Stem Cells 23:1634–1642PubMedGoogle Scholar
  90. 90.
    Bourillot PY, Aksoy I, Schreiber V, Wianny F, Schulz H, Hummel O et al (2009) Novel STAT3 target genes exert distinct roles in the inhibition of mesoderm and endoderm differentiation in cooperation with Nanog. Stem Cells 27:1760–1771PubMedGoogle Scholar
  91. 91.
    Cinelli P, Casanova EA, Uhlig S, Lochmatter P, Matsuda T, Yokota T et al (2008) Expression profiling in transgenic FVB/N embryonic stem cells overexpressing STAT3. BMC Dev Biol 8:57PubMedCentralPubMedGoogle Scholar
  92. 92.
    Xie X, Chan KS, Cao F, Huang M, Li Z, Lee A et al (2009) Imaging of STAT3 signaling pathway during mouse embryonic stem cell differentiation. Stem Cells Dev 18:205–214PubMedCentralPubMedGoogle Scholar
  93. 93.
    Kidder BL, Yang J, Palmer S (2008) Stat3 and c-Myc genome-wide promoter occupancy in embryonic stem cells. PLoS One 3:e3932PubMedCentralPubMedGoogle Scholar
  94. 94.
    Casanova EA, Shakhova O, Patel SS, Asner IN, Pelczar P, Weber FA et al (2011) Pramel7 mediates LIF/STAT3-dependent self-renewal in embryonic stem cells. Stem Cells 29:474–485PubMedGoogle Scholar
  95. 95.
    Sar A, Ponjevic D, Nguyen M, Box AH, Demetrick DJ (2009) Identification and characterization of demethylase JMJD1A as a gene upregulated in the human cellular response to hypoxia. Cell Tissue Res 337:223–234PubMedGoogle Scholar
  96. 96.
    Li Y, McClintick J, Zhong L, Edenberg HJ, Yoder MC, Chan RJ (2005) Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4. Blood 105:635–637PubMedGoogle Scholar
  97. 97.
    Guo G, Yang J, Nichols J, Hall JS, Eyres I, Mansfield W et al (2009) Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136:1063–1069PubMedCentralPubMedGoogle Scholar
  98. 98.
    Daheron L, Opitz SL, Zaehres H, Lensch MW, Andrews PW, Itskovitz-Eldor J et al (2004) LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells 22:770–778PubMedGoogle Scholar
  99. 99.
    van Oosten AL, Costa Y, Smith A, Silva JC (2012) JAK/STAT3 signalling is sufficient and dominant over antagonistic cues for the establishment of naive pluripotency. Nat Commun 3:817PubMedGoogle Scholar
  100. 100.
    Yang J, van Oosten AL, Theunissen TW, Guo G, Silva JC, Smith A (2010) Stat3 activation is limiting for reprogramming to ground state pluripotency. Cell Stem Cell 7:319–328PubMedCentralPubMedGoogle Scholar
  101. 101.
    Gafni O, Weinberger L, Mansour AA, Manor YS, Chomsky E, Ben-Yosef D et al (2013) Derivation of novel human ground state naive pluripotent stem cells. Nature 504:282–286PubMedGoogle Scholar
  102. 102.
    Ware CB, Nelson AM, Mecham B, Hesson J, Zhou W, Jonlin EC et al (2014) Derivation of naive human embryonic stem cells. In: Proceedings of the National Academy of Sciences of the United States of America 2014Google Scholar
  103. 103.
    O’Leary T, Heindryckx B, Lierman S, van Bruggen D, Goeman JJ, Vandewoestyne M et al (2012) Tracking the progression of the human inner cell mass during embryonic stem cell derivation. Nat Biotechnol 30:278–282PubMedGoogle Scholar
  104. 104.
    Takashima Y, Guo G, Loos R, Nichols J, Ficz G, Krueger F et al (2014) Resetting transcription factor control circuitry toward ground-state pluripotency in human. Cell 158:1254–1269PubMedCentralPubMedGoogle Scholar
  105. 105.
    Renfree MB, Shaw G (2000) Diapause. Annu Rev Physiol 62:353–375PubMedGoogle Scholar
  106. 106.
    Nichols J, Chambers I, Taga T, Smith A (2001) Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines. Development 128:2333–2339PubMedGoogle Scholar
  107. 107.
    Brook FA, Gardner RL (1997) The origin and efficient derivation of embryonic stem cells in the mouse. Proc Natl Acad Sci USA 94:5709–5712PubMedCentralPubMedGoogle Scholar
  108. 108.
    Ying QL, Smith AG (2003) Defined conditions for neural commitment and differentiation. Methods Enzymol 365:327–341PubMedGoogle Scholar
  109. 109.
    Wray J, Kalkan T, Smith AG (2010) The ground state of pluripotency. Biochem Soc Trans 38:1027–1032PubMedGoogle Scholar
  110. 110.
    Nichols J, Jones K, Phillips JM, Newland SA, Roode M, Mansfield W et al (2009) Validated germline-competent embryonic stem cell lines from nonobese diabetic mice. Nat Med 15:814–818PubMedGoogle Scholar
  111. 111.
    Ye S, Tan L, Yang R, Fang B, Qu S, Schulze EN et al (2012) Pleiotropy of glycogen synthase kinase-3 inhibition by CHIR99021 promotes self-renewal of embryonic stem cells from refractory mouse strains. PLoS One 7:e35892PubMedCentralPubMedGoogle Scholar
  112. 112.
    van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J et al (1997) Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88:789–799PubMedGoogle Scholar
  113. 113.
    Valenta T, Hausmann G, Basler K (2012) The many faces and functions of beta-catenin. EMBO J 31:2714–2736PubMedCentralPubMedGoogle Scholar
  114. 114.
    Lyashenko N, Winter M, Migliorini D, Biechele T, Moon RT, Hartmann C (2011) Differential requirement for the dual functions of beta-catenin in embryonic stem cell self-renewal and germ layer formation. Nat Cell Biol 13:753–761PubMedCentralPubMedGoogle Scholar
  115. 115.
    Meek S, Wei J, Sutherland L, Nilges B, Buehr M, Tomlinson SR et al (2013) Tuning of beta-catenin activity is required to stabilize self-renewal of rat embryonic stem cells. Stem Cells 31:2104–2115PubMedGoogle Scholar
  116. 116.
    Atlasi Y, Noori R, Gaspar C, Franken P, Sacchetti A, Rafati H et al (2013) Wnt signaling regulates the lineage differentiation potential of mouse embryonic stem cells through Tcf3 down-regulation. PLoS Genet 9:e1003424PubMedCentralPubMedGoogle Scholar
  117. 117.
    Shy BR, Wu CI, Khramtsova GF, Zhang JY, Olopade OI, Goss KH et al (2013) Regulation of Tcf7l1 DNA binding and protein stability as principal mechanisms of Wnt/beta-catenin signaling. Cell Rep 4:1–9PubMedCentralPubMedGoogle Scholar
  118. 118.
    Hikasa H, Ezan J, Itoh K, Li X, Klymkowsky MW, Sokol SY (2010) Regulation of TCF3 by Wnt-dependent phosphorylation during vertebrate axis specification. Dev Cell 19:521–532PubMedCentralPubMedGoogle Scholar
  119. 119.
    Cole MF, Johnstone SE, Newman JJ, Kagey MH, Young RA (2008) Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev 22:746–755PubMedCentralPubMedGoogle Scholar
  120. 120.
    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 26:1951–1960PubMedCentralPubMedGoogle Scholar
  121. 121.
    Yi F, Pereira L, Hoffman JA, Shy BR, Yuen CM, Liu DR et al (2011) Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal. Nat Cell Biol 13:762–770PubMedCentralPubMedGoogle Scholar
  122. 122.
    Pereira L, Yi F, Merrill BJ (2006) Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Mol Cell Biol 26:7479–7491PubMedCentralPubMedGoogle Scholar
  123. 123.
    Wagner RT, Xu X, Yi F, Merrill BJ, Cooney AJ (2010) Canonical Wnt/beta-catenin regulation of liver receptor homolog-1 mediates pluripotency gene expression. Stem Cells 28:1794–1804PubMedCentralPubMedGoogle Scholar
  124. 124.
    Tanaka SS, Kojima Y, Yamaguchi YL, Nishinakamura R (2011) Tam PP. Impact of WNT signaling on tissue lineage differentiation in the early mouse embryo. Dev Growth Differ 53:843–856PubMedGoogle Scholar
  125. 125.
    Heng JC, Feng B, Han J, Jiang J, Kraus P, Ng JH et al (2010) The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell Stem Cell 6:167–174PubMedGoogle Scholar
  126. 126.
    Guo G, Smith A (2010) A genome-wide screen in EpiSCs identifies Nr5a nuclear receptors as potent inducers of ground state pluripotency. Development 137:3185–3192PubMedCentralPubMedGoogle Scholar
  127. 127.
    Fuhrmann G, Chung AC, Jackson KJ, Hummelke G, Baniahmad A, Sutter J et al (2001) Mouse germline restriction of Oct4 expression by germ cell nuclear factor. Dev Cell 1:377–387PubMedGoogle Scholar
  128. 128.
    Gu P, LeMenuet D, Chung AC, Mancini M, Wheeler DA, Cooney AJ (2005) Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during retinoic acid-induced embryonic stem cell differentiation. Mol Cell Biol 25:8507–8519PubMedCentralPubMedGoogle Scholar
  129. 129.
    Chen Y, Blair K, Smith A (2013) Robust Self-Renewal of Rat Embryonic Stem Cells Requires Fine-Tuning of Glycogen Synthase Kinase-3 Inhibition. Stem Cell Reports 1:209–217PubMedCentralPubMedGoogle Scholar
  130. 130.
    Ullmann U, Gilles C, De Rycke M, Van de Velde H, Sermon K, Liebaers I (2008) GSK-3-specific inhibitor-supplemented hESC medium prevents the epithelial-mesenchymal transition process and the up-regulation of matrix metalloproteinases in hESCs cultured in feeder-free conditions. Mol Hum Reprod 14:169–179PubMedGoogle Scholar
  131. 131.
    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 10:55–63PubMedGoogle Scholar
  132. 132.
    Cai L, Ye Z, Zhou BY, Mali P, Zhou C, Cheng L (2007) Promoting human embryonic stem cell renewal or differentiation by modulating Wnt signal and culture conditions. Cell Res 17:62–72PubMedGoogle Scholar
  133. 133.
    Dravid G, Ye Z, Hammond H, Chen G, Pyle A, Donovan P et al (2005) Defining the role of Wnt/beta-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells 23:1489–1501PubMedGoogle Scholar
  134. 134.
    Nakanishi M, Kurisaki A, Hayashi Y, Warashina M, Ishiura S, Kusuda-Furue M et al (2009) Directed induction of anterior and posterior primitive streak by Wnt from embryonic stem cells cultured in a chemically defined serum-free medium. FASEB J 23:114–122PubMedGoogle Scholar
  135. 135.
    Davidson KC, Adams AM, Goodson JM, McDonald CE, Potter JC, Berndt JD et al (2012) Wnt/beta-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4. Proc Natl Acad Sci USA 109:4485–4490PubMedCentralPubMedGoogle Scholar
  136. 136.
    Sumi T, Tsuneyoshi N, Nakatsuji N, Suemori H (2008) Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/beta-catenin. Activin/Nodal and BMP signaling. Development 135:2969–2979PubMedGoogle Scholar
  137. 137.
    ten Berge D, Kurek D, Blauwkamp T, Koole W, Maas A, Eroglu E et al (2011) Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nat Cell Biol 13:1070–1075PubMedCentralPubMedGoogle Scholar
  138. 138.
    Rappolee DA, Basilico C, Patel Y, Werb Z (1994) Expression and function of FGF-4 in peri-implantation development in mouse embryos. Development 120:2259–2269PubMedGoogle Scholar
  139. 139.
    Niswander L, Martin GR (1992) Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development 114:755–768PubMedGoogle Scholar
  140. 140.
    Feldman B, Poueymirou W, Papaioannou VE, DeChiara TM, Goldfarb M (1995) Requirement of FGF-4 for postimplantation mouse development. Science 267:246–249PubMedGoogle Scholar
  141. 141.
    Tanaka S, Kunath T, Hadjantonakis AK, Nagy A, Rossant J (1998) Promotion of trophoblast stem cell proliferation by FGF4. Science 282:2072–2075PubMedGoogle Scholar
  142. 142.
    Kunath T, Arnaud D, Uy GD, Okamoto I, Chureau C, Yamanaka Y et al (2005) Imprinted X-inactivation in extra-embryonic endoderm cell lines from mouse blastocysts. Development 132:1649–1661PubMedGoogle Scholar
  143. 143.
    Yoshida-Koide U, Matsuda T, Saikawa K, Nakanuma Y, Yokota T, Asashima M et al (2004) Involvement of Ras in extraembryonic endoderm differentiation of embryonic stem cells. Biochem Biophys Res Commun 313:475–481PubMedGoogle Scholar
  144. 144.
    Cheng AM, Saxton TM, Sakai R, Kulkarni S, Mbamalu G, Vogel W et al (1998) Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell 95:793–803PubMedGoogle Scholar
  145. 145.
    Lanner F, Rossant J (2010) The role of FGF/Erk signaling in pluripotent cells. Development 137:3351–3360PubMedGoogle Scholar
  146. 146.
    Coutu DL, Galipeau J (2011) Roles of FGF signaling in stem cell self-renewal, senescence and aging. Aging 3:920–933PubMedCentralPubMedGoogle Scholar
  147. 147.
    Wilder PJ, Kelly D, Brigman K, Peterson CL, Nowling T, Gao QS 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 192:614–629PubMedGoogle Scholar
  148. 148.
    Kunath T, Saba-El-Leil MK, Almousailleakh M, Wray J, Meloche S, Smith A (2007) FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development 134:2895–2902PubMedGoogle Scholar
  149. 149.
    Batlle-Morera L, Smith A, Nichols J (2008) Parameters influencing derivation of embryonic stem cells from murine embryos. Genesis 46:758–767PubMedGoogle Scholar
  150. 150.
    Yang SH, 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:e1003112PubMedCentralPubMedGoogle Scholar
  151. 151.
    Nichols J, Silva J, Roode M, Smith A (2009) Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 136:3215–3222PubMedCentralPubMedGoogle Scholar
  152. 152.
    Silva J, Nichols J, Theunissen TW, Guo G, van Oosten AL, Barrandon O et al (2009) Nanog is the gateway to the pluripotent ground state. Cell 138:722–737PubMedCentralPubMedGoogle Scholar
  153. 153.
    Kim MO, Kim SH, Cho YY, Nadas J, Jeong CH, Yao K et al (2012) ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4. Nat Struct Mol Biol 19:283–290PubMedGoogle Scholar
  154. 154.
    Vallier L, Alexander M, Pedersen RA (2005) Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci 118:4495–4509PubMedGoogle Scholar
  155. 155.
    Greber B, Lehrach H, Adjaye J (2007) Fibroblast growth factor 2 modulates transforming growth factor beta signaling in mouse embryonic fibroblasts and human ESCs (hESCs) to support hESC self-renewal. Stem Cells 25:455–464PubMedGoogle Scholar
  156. 156.
    Greber B, Wu G, Bernemann C, Joo JY, Han DW, Ko K et al (2010) Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cells. Cell Stem Cell 6:215–226PubMedGoogle Scholar
  157. 157.
    Li J, Wang G, Wang C, Zhao Y, Zhang H, Tan Z et al (2007) MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal. Differentiation 75:299–307PubMedGoogle Scholar
  158. 158.
    Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, Werbowetski-Ogilvie T et al (2007) IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448:1015–1021PubMedGoogle Scholar
  159. 159.
    Singh AM, Reynolds D, Cliff T, Ohtsuka S, Mattheyses AL, Sun Y et al (2012) Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 10:312–326PubMedCentralPubMedGoogle Scholar
  160. 160.
    Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700PubMedGoogle Scholar
  161. 161.
    Wilson PA, Hemmati-Brivanlou A (1995) Induction of epidermis and inhibition of neural fate by Bmp-4. Nature 376:331–333PubMedGoogle Scholar
  162. 162.
    Fei T, Xia K, Li Z, Zhou B, Zhu S, Chen H et al (2010) Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination. Genome Res 20:36–44PubMedCentralPubMedGoogle Scholar
  163. 163.
    Qi X, Li TG, Hao J, Hu J, Wang J, Simmons H et al (2004) BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proc Natl Acad Sci USA 101:6027–6032PubMedCentralPubMedGoogle Scholar
  164. 164.
    Li Z, Fei T, Zhang J, Zhu G, Wang L, Lu D et al (2012) BMP4 Signaling Acts via dual-specificity phosphatase 9 to control ERK activity in mouse embryonic stem cells. Cell Stem Cell 10:171–182PubMedGoogle Scholar
  165. 165.
    Zhang P, Li J, Tan Z, Wang C, Liu T, Chen L et al (2008) Short-term BMP-4 treatment initiates mesoderm induction in human embryonic stem cells. Blood 111:1933–1941PubMedGoogle Scholar
  166. 166.
    Xu RH, Chen X, Li DS, Li R, Addicks GC, Glennon C et al (2002) BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol 20:1261–1264PubMedGoogle Scholar
  167. 167.
    Xu RH, Peck RM, Li DS, Feng X, Ludwig T, Thomson JA (2005) Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nat Methods 2:185–190PubMedGoogle Scholar
  168. 168.
    Vallier L, Mendjan S, Brown S, Chng Z, Teo A, Smithers LE et al (2009) Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development 136:1339–1349PubMedCentralPubMedGoogle Scholar
  169. 169.
    Xiao L, Yuan X, Sharkis SJ (2006) Activin A maintains self-renewal and regulates fibroblast growth factor, Wnt, and bone morphogenic protein pathways in human embryonic stem cells. Stem Cells 24:1476–1486PubMedGoogle Scholar
  170. 170.
    Xu RH, Sampsell-Barron TL, Gu F, Root S, Peck RM, Pan G et al (2008) NANOG is a direct target of TGFbeta/activin-mediated SMAD signaling in human ESCs. Cell Stem Cell 3:196–206PubMedCentralPubMedGoogle Scholar
  171. 171.
    Brown S, Teo A, Pauklin S, Hannan N, Cho CH, Lim B et al (2011) Activin/Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors. Stem Cells 29:1176–1185PubMedGoogle Scholar
  172. 172.
    Mullen AC, Orlando DA, Newman JJ, Loven J, Kumar RM, Bilodeau S et al (2011) Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell 147:565–576PubMedCentralPubMedGoogle Scholar
  173. 173.
    Breitkreutz D, Braiman-Wiksman L, Daum N, Denning MF, Tennenbaum T (2007) Protein kinase C family: on the crossroads of cell signaling in skin and tumor epithelium. J Cancer Res Clin Oncol 133:793–808PubMedGoogle Scholar
  174. 174.
    Heo JS, Han HJ (2006) ATP stimulates mouse embryonic stem cell proliferation via protein kinase C, phosphatidylinositol 3-kinase/Akt, and mitogen-activated protein kinase signaling pathways. Stem Cells 24:2637–2648PubMedGoogle Scholar
  175. 175.
    Quinlan LR, Faherty S, Kane MT (2003) Phospholipase C and protein kinase C involvement in mouse embryonic stem-cell proliferation and apoptosis. Reproduction 126:121–131PubMedGoogle Scholar
  176. 176.
    Garavello NM, Pena DA, Bonatto JM, Duarte ML, Costa-Junior HM, Schumacher RI et al (2013) Activation of protein kinase C delta by psideltaRACK peptide promotes embryonic stem cell proliferation through ERK 1/2. J Proteomics 94:497–512PubMedGoogle Scholar
  177. 177.
    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 29:618–628PubMedCentralPubMedGoogle Scholar
  178. 178.
    Rajendran G, Dutta D, Hong J, Paul A, Saha B, Mahato B et al (2013) Inhibition of protein kinase C signaling maintains rat embryonic stem cell pluripotency. J Biol Chem 288:24351–24362PubMedCentralPubMedGoogle Scholar
  179. 179.
    Feng X, Zhang J, Smuga-Otto K, Tian S, Yu J, Stewart R et al (2012) Protein kinase C mediated extraembryonic endoderm differentiation of human embryonic stem cells. Stem Cells 30:461–470PubMedCentralPubMedGoogle Scholar
  180. 180.
    Kinehara M, Kawamura S, Tateyama D, Suga M, Matsumura H, Mimura S et al (2013) Protein kinase C regulates human pluripotent stem cell self-renewal. PLoS One 8:e54122PubMedCentralPubMedGoogle Scholar
  181. 181.
    Theunissen TW, Powell BE, Wang H, Mitalipova M, Faddah DA, Reddy J et al (2014) Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell 15:471–487PubMedCentralPubMedGoogle Scholar
  182. 182.
    Surface LE, Thornton SR, Boyer LA (2010) Polycomb group proteins set the stage for early lineage commitment. Cell Stem Cell 7:288–298PubMedGoogle Scholar
  183. 183.
    Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S et al (2008) Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134:521–533PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Guanyi Huang
    • 1
    • 2
  • Shoudong Ye
    • 1
    • 2
  • Xingliang Zhou
    • 2
  • Dahai Liu
    • 1
  • Qi-Long Ying
    • 2
  1. 1.Center for Stem Cell and Translational Medicine, School of Life SciencesAnhui UniversityHefeiPR China
  2. 2.Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

Personalised recommendations