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Extrinsic regulation of pluripotent stem cells

Abstract

During early mammalian development, as the pluripotent cells that give rise to all of the tissues of the body proliferate and expand in number, they pass through transition states marked by a stepwise restriction in developmental potential and by changes in the expression of key regulatory genes. Recent findings show that cultured stem-cell lines derived from different stages of mouse development can mimic these transition states. They further reveal that there is a high degree of heterogeneity and plasticity in pluripotent populations in vitro and that these properties are modulated by extrinsic signalling. Understanding the extrinsic control of plasticity will guide efforts to use human pluripotent stem cells in research and therapy.

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Figure 1: Stem-cell types derived from mouse embryos around the time of implantation.
Figure 2: Extrinsic signals that affect self-renewal, differentiation and viability of human ES cells.
Figure 3: Interconversion of mouse embryo-derived stem-cell types.

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References

  1. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    ADS  CAS  PubMed  Google Scholar 

  2. Reubinoff, B. E., Pera, M. F., Fong, C. Y., Trounson, A. & Bongso, A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro . Nature Biotechnol. 18, 399–404 (2000).

    Article  CAS  Google Scholar 

  3. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Bibikova, M., Laurent, L. C., Ren, B., Loring, J. F. & Fan, J. B. Unraveling epigenetic regulation in embryonic stem cells. Cell Stem Cell 2, 123–134 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Chambers, I. & Tomlinson, S. R. The transcriptional foundation of pluripotency. Development 136, 2311–2322 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nishikawa, S., Jakt, L. M. & Era, T. Embryonic stem-cell culture as a tool for developmental cell biology. Nature Rev. Mol. Cell Biol. 8, 502–507 (2007).

    Article  CAS  Google Scholar 

  9. Tam, P. P. & Loebel, D. A. Gene function in mouse embryogenesis: get set for gastrulation. Nature Rev. Genet. 8, 368–381 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Assou, S. et al. A meta-analysis of human embryonic stem cells transcriptome integrated into a web-based expression atlas. Stem Cells 25, 961–973 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Adewumi, O. et al. Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nature Biotechnol. 25, 803–816 (2007).

    Article  CAS  Google Scholar 

  12. Henderson, J. K. et al. Preimplantation human embryos and embryonic stem cells show comparable expression of stage-specific embryonic antigens. Stem Cells 20, 329–337 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Cauffman, G., Van de Velde, H., Liebaers, I. & Van Steirteghem, A. Oct-4 mRNA and protein expression during human preimplantation development. Mol. Hum. Reprod. 11, 173–181 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Huntriss, J. et al. Expression of mRNAs for DNA methyltransferases and methyl-CpG-binding proteins in the human female germ line, preimplantation embryos, and embryonic stem cells. Mol. Reprod. Dev. 67, 323–336 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Adjaye, J. et al. Primary differentiation in the human blastocyst: comparative molecular portraits of inner cell mass and trophectoderm cells. Stem Cells 23, 1514–1525 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Rathjen, J. et al. Formation of a primitive ectoderm like cell population, EPL cells, from ES cells in response to biologically derived factors. J. Cell Sci. 112, 601–612 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Brons, I. G. et al. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448, 191–195 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Tesar, P. J. et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448, 196–199 (2007). References 17 and 18 describe the derivation of pluripotent stem-cell lines with novel properties from the post-implantation epiblast in mice.

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Nichols, J., Silva, J., Roode, M. & Smith, A. Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 136, 3215–3222 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bao, S. et al. Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells. Nature 461, 1292–1295 (2009). This study shows the conversion of EpiSCs to ES cells.

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Chou, Y. F. et al. The growth factor environment defines distinct pluripotent ground states in novel blastocyst-derived stem cells. Cell 135, 449–461 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nichols, J. & Smith, A. Naive and primed pluripotent states. Cell Stem Cell 4, 487–492 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Vallier, L. et al. Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development 136, 1339–1349 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Clark, A. T. et al. Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma. Stem Cells 22, 169–179 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Chan, K. K. et al. KLF4 and PBX1 directly regulate NANOG expression in human embryonic stem cells. Stem Cells 27, 2114–2125 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Hayashi, K., Lopes, S. M., Tang, F. & Surani, M. A. Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. Cell Stem Cell 3, 391–401 (2008). This paper provides evidence for the interconversion of stem-cell states in mouse ES-cell cultures.

    Article  CAS  PubMed  Google Scholar 

  27. Guo, G. et al. Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136, 1063–1069 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Babaie, Y. et al. Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells. Stem Cells 25, 500–510 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Greber, B. et al. Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cells. Cell Stem Cell 6, 215–226 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Ogawa, K. et al. Activin–Nodal signaling is involved in propagation of mouse embryonic stem cells. J. Cell Sci. 120, 55–65 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. James, D., Levine, A. J., Besser, D. & Hemmati-Brivanlou, A. TGFβ/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 132, 1273–1282 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Pera, M. F. & Trounson, A. O. Human embryonic stem cells: prospects for development. Development 131, 5515–5525 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Eakin, G. S. & Behringer, R. R. Diversity of germ layer and axis formation among mammals. Semin. Cell Dev. Biol. 15, 619–629 (2004).

    Article  PubMed  Google Scholar 

  34. Murry, C. E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Pera, M. F., Cooper, S., Mills, J. & Parrington, J. M. Isolation and characterization of a multipotent clone of human embryonal carcinoma cells. Differentiation 42, 10–23 (1989).

    Article  CAS  PubMed  Google Scholar 

  36. Pera, M. F., Reubinoff, B. & Trounson, A. Human embryonic stem cells. J. Cell Sci. 113, 5–10 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Vallier, L., Alexander, M. & Pedersen, R. A. Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J. Cell Sci. 118, 4495–4509 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Vallier, L., Reynolds, D. & Pedersen, R. A. Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Dev. Biol. 275, 403–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Xiao, L., Yuan, X. & Sharkis, S. J. Activin A maintains self-renewal and regulates fibroblast growth factor, Wnt, and bone morphogenic protein pathways in human embryonic stem cells. Stem Cells 24, 1476–1486 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Greber, B., Lehrach, H. & Adjaye, J. Fibroblast growth factor 2 modulates transforming growth factor β signaling in mouse embryonic fibroblasts and human ESCs (hESCs) to support hESC self-renewal. Stem Cells 25, 455–464 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Xu, R. H. et al. NANOG is a direct target of TGFβ/activin-mediated SMAD signaling in human ESCs. Cell Stem Cell 3, 196–206 (2008). This study reveals how TGF- β -mediated signalling affects the transcriptional regulation of pluripotency.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dvash, T., Sharon, N., Yanuka, O. & Benvenisty, N. Molecular analysis of LEFTY-expressing cells in early human embryoid bodies. Stem Cells 25, 465–472 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Takaoka, K. et al. The mouse embryo autonomously acquires anterior–posterior polarity at implantation. Dev. Cell 10, 451–459 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Chazaud, C., Yamanaka, Y., Pawson, T. & Rossant, J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2–MAPK pathway. Dev. Cell 10, 615–624 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Shen, M. M. Nodal signaling: developmental roles and regulation. Development 134, 1023–1034 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Levine, A. J. & Brivanlou, A. H. GDF3 at the crossroads of TGF-β signaling. Cell Cycle 5, 1069–1073 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Chen, C. et al. The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo. Development 133, 319–329 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Levine, A. J. & Brivanlou, A. H. GDF3, a BMP inhibitor, regulates cell fate in stem cells and early embryos. Development 133, 209–216 (2006). References 47 and 48 elucidate the functions of GDF3, a putative autocrine maintenance factor for ES cells.

    Article  CAS  PubMed  Google Scholar 

  49. Levine, A. J., Levine, Z. J. & Brivanlou, A. H. GDF3 is a BMP inhibitor that can activate Nodal signaling only at very high doses. Dev. Biol. 325, 43–48 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Hannan, N. R., Jamshidi, P., Pera, M. F. & Wolvetang, E. J. BMP-11 and myostatin support undifferentiated growth of human embryonic stem cells in feeder-free cultures. Cloning Stem Cells 11, 427–435 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Itsykson, P. et al. Derivation of neural precursors from human embryonic stem cells in the presence of noggin. Mol. Cell. Neurosci. 30, 24–36 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Pera, M. F. et al. Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin. J. Cell Sci. 117, 1269–1280 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Xu, R. H. et al. Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nature Methods 2, 185–190 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Ying, Q. L., Nichols, J., Chambers, I. & Smith, A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115, 281–292 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Sirard, C. et al. Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor β-related signaling. J. Biol. Chem. 275, 2063–2070 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Mishina, Y., Suzuki, A., Ueno, N. & Behringer, R. R. Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev. 9, 3027–3037 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Winnier, G., Blessing, M., Labosky, P. A. & Hogan, B. L. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 9, 2105–2116 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Peerani, R. et al. Niche-mediated control of human embryonic stem cell self-renewal and differentiation. EMBO J. 26, 4744–4755 (2007). This paper uncovers autocrine and paracrine factors involved in human ES-cell regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Amit, M. et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev. Biol. 227, 271–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Chase, L. G. & Firpo, M. T. Development of serum-free culture systems for human embryonic stem cells. Curr. Opin. Chem. Biol. 11, 367–372 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Dvorak, P. et al. Expression and potential role of fibroblast growth factor 2 and its receptors in human embryonic stem cells. Stem Cells 23, 1200–1211 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Li, J. et al. MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal. Differentiation 75, 299–307 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Kang, H. B. et al. Basic fibroblast growth factor activates ERK and induces c-fos in human embryonic stem cell line MizhES1. Stem Cells Dev. 14, 395–401 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Burdon, T., Stracey, C., Chambers, I., Nichols, J. & Smith, A. Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Dev. Biol. 210, 30–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Wilder, P. J. et al. 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, 614–629 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Tanaka, S., Kunath, T., Hadjantonakis, A. K., Nagy, A. & Rossant, J. Promotion of trophoblast stem cell proliferation by FGF4. Science 282, 2072–2075 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  67. Hamazaki, T., Kehoe, S. M., Nakano, T. & Terada, N. The Grb2/Mek pathway represses Nanog in murine embryonic stem cells. Mol. Cell. Biol. 26, 7539–7549 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kunath, T. et al. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development 134, 2895–2902 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Bendall, S. C. et al. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro . Nature 448, 1015–1021 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  70. Stojkovic, P. et al. An autogeneic feeder cell system that efficiently supports growth of undifferentiated human embryonic stem cells. Stem Cells 23, 306–314 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. McLean, A. B. et al. Activin A efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed. Stem Cells 25, 29–38 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Pebay, A. et al. Essential roles of sphingosine-1-phosphate and platelet-derived growth factor in the maintenance of human embryonic stem cells. Stem Cells 23, 1541–1548 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Brill, L. M. et al. Phosphoproteomic analysis of human embryonic stem cells. Cell Stem Cell 5, 204–213 (2009). This study takes a proteomics approach to investigating signal transduction in human ES cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Nishikawa, S. I., Nishikawa, S., Hirashima, M., Matsuyoshi, N. & Kodama, H. Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development 125, 1747–1757 (1998).

  75. Wang, L. et al. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling. Blood 110, 4111–4119 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang, X., Lin, G., Martins-Taylor, K., Zeng, H. & Xu, R. H. Inhibition of caspase-mediated anoikis is critical for basic fibroblast growth factor-sustained culture of human pluripotent stem cells. J. Biol. Chem. 284, 34054–34064 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wong, R. C., Tellis, I., Jamshidi, P., Pera, M. & Pebay, A. Anti-apoptotic effect of sphingosine-1-phosphate and platelet-derived growth factor in human embryonic stem cells. Stem Cells Dev. 16, 989–1001 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A. H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Med. 10, 55–63 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Dravid, G. et al. Defining the role of Wnt/β-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells 23, 1489–1501 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Lu, J., Hou, R., Booth, C. J., Yang, S. H. & Snyder, M. Defined culture conditions of human embryonic stem cells. Proc. Natl Acad. Sci. USA 103, 5688–5693 (2006).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  81. Miyabayashi, T. et al. Wnt/β-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc. Natl Acad. Sci. USA 104, 5668–5673 (2007).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu, P. et al. Requirement for Wnt3 in vertebrate axis formation. Nature Genet. 22, 361–365 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Kemp, C., Willems, E., Abdo, S., Lambiv, L. & Leyns, L. Expression of all Wnt genes and their secreted antagonists during mouse blastocyst and postimplantation development. Dev. Dyn. 233, 1064–1075 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Niwa, H., Ogawa, K., Shimosato, D. & Adachi, K. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 460, 118–122 (2009).

    Article  ADS  CAS  PubMed  Google Scholar 

  85. Silva, J. & Smith, A. Capturing pluripotency. Cell 132, 532–536 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ying, Q. L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008). This study shows that mouse ES cells default to the state of self-renewal when the signalling pathways that activate their differentiation are suppressed.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. Enver, T. et al. Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum. Mol. Genet. 14, 3129–3140 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Hough, S. R., Laslett, A. L., Grimmond, S. B., Kolle, G. & Pera, M. F. A continuum of cell states spans pluripotency and lineage commitment in human embryonic stem cells. PLoS ONE 4, e7708 (2009).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  89. Laslett, A. L. et al. Transcriptional analysis of early lineage commitment in human embryonic stem cells. BMC Dev. Biol. 7, 12 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Kolle, G. et al. Identification of human embryonic stem cell surface markers by combined membrane-polysome translation state array analysis and immunotranscriptional profiling. Stem Cells 27, 2446–2456 (2009).

    Article  ADS  CAS  PubMed  Google Scholar 

  91. Hanna, J. et al. Metastable pluripotent states in NOD-mouse-derived ESCs. Cell Stem Cell 4, 513–524 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lander, A. D. The 'stem cell' concept: is it holding us back? J. Biol. 8, 70 (2009). An overview of emerging concepts of stemness in cell lineages.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Rossant, J. & Tam, P. P. Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136, 701–713 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).

    Article  ADS  CAS  PubMed  Google Scholar 

  95. Martin, G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634–7638 (1981).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  96. Nichols, J., Evans, E. P. & Smith, A. G. Establishment of germ-line-competent embryonic stem (ES) cells using differentiation inhibiting activity. Development 110, 1341–1348 (1990).

    Article  CAS  PubMed  Google Scholar 

  97. Kunath, T. et al. Imprinted X-inactivation in extra-embryonic endoderm cell lines from mouse blastocysts. Development 132, 1649–1661 (2005).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Martin F. Pera or Patrick P. L. Tam.

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Pera, M., Tam, P. Extrinsic regulation of pluripotent stem cells. Nature 465, 713–720 (2010). https://doi.org/10.1038/nature09228

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