The pluripotent cell lineage of the embryo comprises a series of temporally and functionally distinct intermediary cell states, the epiblast precursor cell of the newly formed blastocyst, the epiblast population of the inner cell mass, and the early and late epiblast of the postimplantation embryo, referred to here as early and late primitive ectoderm. Pluripotent cell populations representative of the embryonic populations can be formed in culture. Although multiple pluripotent cell states are now recognised, little is known about the signals and pathways that progress cells from the epiblast precursor cell to the late primitive ectoderm in the embryo or in culture. The characterisation of cell states is most advanced in mouse where conditions for culturing distinct pluripotent cell states are well established and embryonic material is accessible. This review will focus on the pluripotent cell states present during embryonic development in the mouse and what is known of the mechanisms that regulate the progression of the lineage from the epiblast precursor cell and the ground state of pluripotency to the late primitive ectoderm present immediately prior to cell differentiation. 1. Introduction Establishment and development of the pluripotent cell lineage in the mouse embryo are a progressive process characterised by the sequential formation of a series of temporally and functionally distinct intermediary cell states. Cells fated to form the pluripotent lineage can be identified in the interior of the compacted morula of the mouse embryo by day 3, encapsulated within cells destined to establish the trophectoderm. These cells establish the inner cell mass (ICM) of the blastocyst, which on day 3.5 comprises genetically discrete populations of epiblast precursor cells and primitive endoderm precursor cells. By 4.5 days post coitum (d.p.c.) these populations have segregated into spatially distinct regions of the ICM and cell identity has been fixed, forming the pluripotent epiblast and the extraembryonic primitive endoderm lineage (also known as the hypoblast). The epiblast proliferates rapidly and forms a psuedostratified epithelium of epiblast that has been designated primitive ectoderm. Primitive ectoderm can be distinguished from the preceding epiblast by morphology, gene expression, and differentiation potential. Analysis of the mouse embryo has revealed at least four identifiable pluripotent cell populations, or states, that comprise the pluripotent lineage—the epiblast precursor cell, the epiblast of the ICM, and the early and late epiblasts of the
References
[1]
S. J. Kelly, “Studies of the developmental potential of 4- and 8-cell stage mouse blastomeres,” Journal of Experimental Zoology, vol. 200, no. 3, pp. 365–376, 1977.
[2]
W. Garner and A. McLaren, “Cell distribution in chimaeric mouse embryos before implantation,” Journal of Embryology and Experimental Morphology, vol. 32, no. 2, pp. 495–503, 1974.
[3]
H. Balakier and R. A. Pedersen, “Allocation of cells to inner cell mass and trophectoderm lineages in preimplantation mouse embryos,” Developmental Biology, vol. 90, no. 2, pp. 352–362, 1982.
[4]
G. Guo, M. Huss, G. Q. Tong et al., “Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst,” Developmental Cell, vol. 18, no. 4, pp. 675–685, 2010.
[5]
J. B. Levy, M. H. Johnson, H. Goodall, and B. Maro, “The timing of compaction: control of a major developmental transition in mouse early embryogenesis,” Journal of Embryology and Experimental Morphology, vol. 95, pp. 213–237, 1986.
[6]
T. Ducibella, T. Ukena, M. Karnovsky, and E. Anderson, “Changes in cell surface and cortical cytoplasmic organization during early embryogenesis in the preimplantation mouse embryo,” Journal of Cell Biology, vol. 74, no. 1, pp. 153–167, 1977.
[7]
W. J. Reeve and C. A. Ziomek, “Distribution of microvilli on dissociated blastomeres from mouse embryos: evidence for surface polarization at compaction,” Journal of Embryology and Experimental Morphology, vol. 62, pp. 339–350, 1981.
[8]
E. Lehtonen and R. A. Badley, “Localization of cytoskeletal proteins in preimplantation mouse embryos,” Journal of Embryology and Experimental Morphology, vol. 55, pp. 211–225, 1980.
[9]
A. H. Handyside, “Distribution of antibody and lectin-binding sites on dissociated blastomeres from mouse morulae: evidence for polarization at compaction,” Journal of Embryology and Experimental Morphology, vol. 60, pp. 99–116, 1980.
[10]
J. R. McLachlin, S. Caveney, and G. M. Kidder, “Control of gap junction formation in early mouse embryos,” Developmental Biology, vol. 98, no. 1, pp. 155–164, 1983.
[11]
F. D. Houghton, K. J. Barr, G. Walter et al., “Functional significance of Gap junctional coupling in preimplantation development,” Biology of Reproduction, vol. 66, no. 5, pp. 1403–1412, 2002.
[12]
D. Riethmacher, V. Brinkmanni, and C. Birchmeier, “A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 3, pp. 855–859, 1995.
[13]
L. Larue, M. Ohsugi, J. Hirchenhain, and R. Kemler, “E-cadherin null mutant embryos fail to form a trophectoderm epithelium,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 17, pp. 8263–8267, 1994.
[14]
N. G. Kan, M. P. Stemmler, D. Junghans et al., “Gene replacement reveals a specific role for E-cadherin in the formation of a functional trophectoderm,” Development, vol. 134, no. 1, pp. 31–41, 2007.
[15]
V. Hyenne, S. Louvet-Vallée, A. El-Amraoui, C. Petit, B. Maro, and M. Simmler, “Vezatin, a protein associated to adherens junctions, is required for mouse blastocyst morphogenesis,” Developmental Biology, vol. 287, no. 1, pp. 180–191, 2005.
[16]
I. Khang, S. Sonn, J. Park, K. Rhee, D. Park, and K. Kim, “Expression of epithin in mouse preimplantation development: its functional role in compaction,” Developmental Biology, vol. 281, no. 1, pp. 134–144, 2005.
[17]
W. N. De Vries, A. V. Evsikov, B. E. Haac et al., “Maternal β-catenin and E-cadherin in mouse development,” Development, vol. 131, no. 18, pp. 4435–4445, 2004.
[18]
L. Chen, D. Wang, Z. Wu, L. Ma, and G. Q. Daley, “Molecular basis of the first cell fate determination in mouse embryogenesis,” Cell Research, vol. 20, no. 9, pp. 982–993, 2010.
[19]
Y. Kurotaki, K. Hatta, K. Nakao, Y. Nabeshima, and T. Fujimori, “Blastocyst axis is specified independently of early cell lineage but aligns with the ZP shape,” Science, vol. 316, no. 5825, pp. 719–723, 2007.
[20]
M. H. Johnson and C. A. Ziomek, “The foundation of two distinct cell lineages within the mouse morula,” Cell, vol. 24, no. 1, pp. 71–80, 1981.
[21]
T. P. Fleming, “A quantitative analysis of cell allocation to trophectoderm and inner cell mass in the mouse blastocyst,” Developmental Biology, vol. 119, no. 2, pp. 520–531, 1987.
[22]
R. A. Pedersen, K. Wu, and H. Balakier, “Origin of the inner cell mass in mouse embryos: cell lineage analysis by microinjection,” Developmental Biology, vol. 117, no. 2, pp. 581–595, 1986.
[23]
R. L. Gardner, “Contributions of blastocyst micromanipulation to the study of mammalian development,” Bioessays, vol. 20, no. 2, pp. 168–180, 1998.
[24]
A. Suwińska, R. Czo？owska, W. Ozdzeński, and A. K. Tarkowski, “Blastomeres of the mouse embryo lose totipotency after the fifth cleavage division: expression of Cdx2 and Oct4 and developmental potential of inner and outer blastomeres of 16- and 32-cell embryos,” Developmental Biology, vol. 322, no. 1, pp. 133–144, 2008.
[25]
S. A. Morris, R. T. Y. Teo, H. Li, P. Robson, D. M. Glover, and M. Zernicka-Goetz, “Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 14, pp. 6364–6369, 2010.
[26]
Y. Yamanaka, F. Lanner, and J. Rossant, “FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst,” Development, vol. 137, no. 5, pp. 715–724, 2010.
[27]
J. Dietrich and T. Hiiragi, “Stochastic patterning in the mouse pre-implantation embryo,” Development, vol. 134, no. 23, pp. 4219–4231, 2007.
[28]
J. Dyce, M. George, H. Goodall, and T. P. Fleming, “Do trophectoderm and inner cell mass cells in the mouse blastocyst maintain discrete lineages,” Development, vol. 100, no. 4, pp. 685–698, 1987.
[29]
N. Nishioka, S. Yamamoto, H. Kiyonari et al., “Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos,” Mechanisms of Development, vol. 125, no. 3-4, pp. 270–283, 2008.
[30]
R. Yagi, M. J. Kohn, I. Karavanova et al., “Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development,” Development, vol. 134, no. 21, pp. 3827–3836, 2007.
[31]
N. Nishioka, K. Inoue, K. Adachi et al., “The hippo signaling pathway components Lats and Yap pattern tead4 activity to distinguish mouse trophectoderm from inner cell mass,” Developmental Cell, vol. 16, no. 3, pp. 398–410, 2009.
[32]
C. Lorthongpanich, T. P. Doris, V. Limviphuvadh, B. B. Knowles, and D. Solter, “Developmental fate and lineage commitment of singled mouse blastomeres,” Development, vol. 139, no. 20, pp. 3722–3731, 2012.
[33]
I. Chambers and S. R. Tomlinson, “The transcriptional foundation of pluripotency,” Development, vol. 136, no. 14, pp. 2311–2322, 2009.
[34]
J. Nichols, B. Zevnik, K. Anastassiadis et al., “Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4,” Cell, vol. 95, no. 3, pp. 379–391, 1998.
[35]
K. Mitsui, Y. Tokuzawa, H. Itoh et al., “The homeoprotein nanog is required for maintenance of pluripotency in mouse epiblast and ES cells,” Cell, vol. 113, no. 5, pp. 631–642, 2003.
[36]
J. Silva, J. Nichols, T. W. Theunissen et al., “Nanog is the gateway to the pluripotent ground state,” Cell, vol. 138, no. 4, pp. 722–737, 2009.
[37]
A. A. Avilion, S. K. Nicolis, L. H. Pevny, L. Perez, N. Vivian, and R. Lovell-Badge, “Multipotent cell lineages in early mouse development depend on SOX2 function,” Genes and Development, vol. 17, no. 1, pp. 126–140, 2003.
[38]
M. Keramari, J. Razavi, K. A. Ingman et al., “Sox2 is essential for formation of trophectoderm in the preimplantation embryo,” PLoS ONE, vol. 5, no. 11, Article ID e13952, 2010.
[39]
A. Ralston and J. Rossant, “Cdx2 acts downstream of cell polarization to cell-autonomously promote trophectoderm fate in the early mouse embryo,” Developmental Biology, vol. 313, no. 2, pp. 614–629, 2008.
[40]
L. Chen, A. Yabuuchi, S. Eminli et al., “Cross-regulation of the nanog and Cdx2 promoters,” Cell Research, vol. 19, no. 9, pp. 1052–1061, 2009.
[41]
H. Niwa, Y. Toyooka, D. Shimosato et al., “Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation,” Cell, vol. 123, no. 5, pp. 917–929, 2005.
[42]
K. Wang, S. Sengupta, L. Magnani, C. A. Wilson, R. W. Henry, and J. G. Knott, “Brg1 is required for Cdx2-mediated repression of Oct4 expression in mouse blastocysts,” PLoS ONE, vol. 5, no. 5, Article ID e10622, 2010.
[43]
A. Nishiyama, L. Xin, A. A. Sharov et al., “Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors,” Cell Stem Cell, vol. 5, no. 4, pp. 420–433, 2009.
[44]
C. Chazaud, Y. Yamanaka, T. Pawson, and J. Rossant, “Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway,” Developmental Cell, vol. 10, no. 5, pp. 615–624, 2006.
[45]
B. Plusa, A. Piliszek, S. Frankenberg, J. Artus, and A. Hadjantonakis, “Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst,” Development, vol. 135, no. 18, pp. 3081–3091, 2008.
[46]
J. Artus, A. Piliszek, and A. Hadjantonakis, “The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17,” Developmental Biology, vol. 350, no. 2, pp. 393–404, 2011.
[47]
P. J. Rugg-Gunn, B. J. Cox, F. Lanner et al., “Cell-surface proteomics identifies lineage-specific markers of embryo-derived stem cells,” Developmental Cell, vol. 22, no. 4, pp. 887–901, 2012.
[48]
A. M. Laeno, D. A. Tamashiro, and V. B. Alarcon, “Rho-associated kinase activity is required for proper morphogenesis of the inner cell mass in the mouse blastocyst,” Biology of Reproduction, vol. 89, no. 5, p. 122, 2013.
[49]
R. L. Gardner, “Regeneration of endoderm from primitive ectoderm in the mouse embryo: fact or artifact?” Journal of Embryology and Experimental Morphology, vol. 88, pp. 303–326, 1985.
[50]
J. Nichols, J. Silva, M. Roode, and A. Smith, “Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo,” Development, vol. 136, no. 19, pp. 3215–3222, 2009.
[51]
S. Frankenberg, F. Gerbe, S. Bessonnard et al., “Primitive endoderm differentiates via a three-step mechanism involving nanog and RTK signaling,” Developmental Cell, vol. 21, no. 6, pp. 1005–1013, 2011.
[52]
A. M. Cheng, T. M. Saxton, R. Sakai et al., “Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation,” Cell, vol. 95, no. 6, pp. 793–803, 1998.
[53]
E. Arman, R. Haffner-Krausz, Y. Chen, J. K. Heath, and P. Lonai, “Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 9, pp. 5082–5087, 1998.
[54]
S. N. Goldin and V. E. Papaioannou, “Paracrine action of FGF4 during periimplantation development maintains trophectoderm and primitive endoderm,” Genesis, vol. 36, no. 1, pp. 40–47, 2003.
[55]
H. Yuan, N. Corbi, C. Basilico, and L. Dailey, “Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3,” Genes and Development, vol. 9, no. 21, pp. 2635–2645, 1995.
[56]
M. H. L. Snow, “Gastrulation in the mouse: growth and regionalization of the epiblast,” Journal of Embryology and Experimental Morphology, vol. 42, pp. 293–303, 1977.
[57]
D. Solter, N. ？kreb, and I. Damjanov, “Cell cycle analysis in the mouse egg-cylinder,” Experimental Cell Research, vol. 64, no. 2, pp. 331–334, 1971.
[58]
E. Stead, J. White, R. Faast et al., “Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities,” Oncogene, vol. 21, no. 54, pp. 8320–8333, 2002.
[59]
E. Coucouvanis and G. R. Martin, “Signals for death and survival: a two-step mechanism for cavitation in the vertebrate embryo,” Cell, vol. 83, no. 2, pp. 279–287, 1995.
[60]
R. L. Gardner and J. Rossant, “Investigation of the fate of 4.5 day post-coitum mouse inner cell mass cells by blastocyst injection,” Journal of Embryology and Experimental Morphology, vol. 52, pp. 141–152, 1979.
[61]
F. A. Brook and R. L. Gardner, “The origin and efficient derivation of embryonic stem cells in the mouse,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 11, pp. 5709–5712, 1997.
[62]
R. S. Beddington, “The origin of foetal tissues during gastrulation in the rodent,” in Development in Mammals, M. H. Johnson, Ed., pp. 1–32, Elesevier, Amsterdam, The Netherlands, 1983.
[63]
J. Rossant, “Cell commitment in early rodent development,” in Development in Mammals, M. H. Johnson, Ed., pp. 119–150, Elesevier, Amsterdam, The Netherlands, 1977.
[64]
R. L. Gardner, “Manipulations on the blastocyst,” Advances in Bioscience, vol. 6, pp. 279–296, 1971.
[65]
T. A. Pelton, S. Sharma, T. C. Schulz, J. Rathjen, and P. D. Rathjen, “Transient pluripotent cell populations during primitive ectoderm formation: correlation of in vivo and in vitro pluripotent cell development,” Journal of Cell Science, vol. 115, no. 2, pp. 329–339, 2002.
[66]
A. H. Hart, L. Hartley, M. Ibrahim, and L. Robb, “Identification, cloning and expression analysis of the pluripotency promoting nanog genes in mouse and human,” Developmental Dynamics, vol. 230, no. 1, pp. 187–198, 2004.
[67]
I. Chambers, D. Colby, M. Robertson et al., “Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells,” Cell, vol. 113, no. 5, pp. 643–655, 2003.
[68]
O. Haub and M. Goldfarb, “Expression of the fibroblast growth factor-5 gene in the mouse embryo,” Development, vol. 112, no. 2, pp. 397–406, 1991.
[69]
P. Gu, B. Goodwin, A. C.-K. Chung et al., “Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development,” Molecular and Cellular Biology, vol. 25, no. 9, pp. 3492–3505, 2005.
[70]
M. Sugimoto, S. Tan, and N. Takagi, “X chromosome inactivation revealed by the X-linked lacZ transgene activity in periimplantation mouse embryos,” International Journal of Developmental Biology, vol. 44, no. 2, pp. 177–182, 2000.
[71]
R. L. Gardner and M. F. Lyon, “Biological sciences: X chromosome inactivation studied by injection of a single cell into the mouse blastocyst,” Nature, vol. 231, no. 5302, pp. 385–386, 1971.
[72]
S. Rastan, “Timing of X-chromosome inactivation in postimplanation mouse embryos,” Journal of Embryology and Experimental Morphology, vol. 71, pp. 11–24, 1982.
[73]
M. Monk and M. I. Harper, “Sequential X chromosome inactivation coupled with cellular differentiation in early mouse embryos,” Nature, vol. 281, no. 5729, pp. 311–313, 1979.
[74]
E. Heard, “Recent advances in X-chromosome inactivation,” Current Opinion in Cell Biology, vol. 16, no. 3, pp. 247–255, 2004.
[75]
J. Borgel, S. Guibert, Y. Li et al., “Targets and dynamics of promoter DNA methylation during early mouse development,” Nature Genetics, vol. 42, no. 12, pp. 1093–1100, 2010.
[76]
M. Williams, C. Burdsal, A. Periasamy, M. Lewandoski, and A. Sutherland, “Mouse primitive streak forms in situ by initiation of epithelial to mesenchymal transition without migration of a cell population,” Developmental Dynamics, vol. 241, no. 2, pp. 270–283, 2012.
[77]
S. S. Tanaka, Y. Kojima, Y. L. Yamaguchi, R. Nishinakamura, and P. P. L. Tam, “Impact of WNT signaling on tissue lineage differentiation in the early mouse embryo,” Development Growth and Differentiation, vol. 53, no. 7, pp. 843–856, 2011.
[78]
P. P. Tam, D. A. Loebel, and S. S. Tanaka, “Building the mouse gastrula: signals, asymmetry and lineages,” Current Opinion in Genetics and Development, vol. 16, no. 4, pp. 419–425, 2006.
[79]
B. Ciruna and J. Rossant, “FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak,” Developmental Cell, vol. 1, no. 1, pp. 37–49, 2001.
[80]
P. P. L. Tam, P. Khoo, S. L. Lewis et al., “Seqeuential allocation and global pattern of movement of the definitive endoderm in the mouse embryo during gastrulation,” Development, vol. 134, no. 2, pp. 251–260, 2007.
[81]
R. Osorno, A. Tsakiridis, F. Wong, et al., “The developmental dismantling of pluripotency is reversed by ectopic Oct4 expression,” Development, vol. 139, no. 13, pp. 2288–2298, 2012.
[82]
Y. Kojima, K. Kaufman-Francis, J. B. Studdert, et al., “The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak,” Cell Stem Cell, 2013.
[83]
K. A. Ewen and P. Koopman, “Mouse germ cell development: from specification to sex determination,” Molecular and Cellular Endocrinology, vol. 323, no. 1, pp. 76–93, 2010.
[84]
W. S. Chen, K. Manova, D. C. Weinstein et al., “Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos,” Genes and Development, vol. 8, no. 20, pp. 2466–2477, 1994.
[85]
D. D. Spyropoulos and M. R. Capecchi, “Targeted disruption of the even-skipped gene, evx1, causes early postimplantation lethality of the mouse conceptus,” Genes and Development, vol. 8, no. 16, pp. 1949–1961, 1994.
[86]
M. Sugimoto, M. Kondo, M. Hirose, et al., “Molecular identification of tw5: Vps52 promotes pluripotential cell differentiation through cell-cell interactions,” Cell Reports, vol. 2, no. 5, pp. 1363–1374, 2012.
[87]
L. C. Stevens, “The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos,” Developmental Biology, vol. 21, no. 3, pp. 364–382, 1970.
[88]
D. Solter, N. ？kreb, and I. Damjanov, “Extrauterine growth of mouse egg-cylinders results in malignant teratoma,” Nature, vol. 227, no. 5257, pp. 503–504, 1970.
[89]
R. L. Gardner, “Mouse chimaeras obtained by the injection of cells into the blastocyst,” Nature, vol. 220, no. 5167, pp. 596–597, 1968.
[90]
M. J. Evans and M. H. Kaufman, “Establishment in culture of pluripotential cells from mouse embryos,” Nature, vol. 292, no. 5819, pp. 154–156, 1981.
[91]
G. R. Martin, “Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 12, pp. 7634–7638, 1981.
[92]
B. Ledermann and K. Burki, “Establishment of a germ-line competent C57BL/6 embryonic stem cell line,” Experimental Cell Research, vol. 197, no. 2, pp. 254–258, 1991.
[93]
E. Kawase, H. Suemori, N. Takahashi, K. Okazaki, K. Hashimoto, and N. Nakatsuji, “Strain difference in establishment of mouse embryonic stem (ES) cell lines,” International Journal of Developmental Biology, vol. 38, no. 2, pp. 385–390, 1994.
[94]
J. McWhir, A. E. Schnieke, R. Ansell et al., “Selective ablation of differentiated cells permits isolation of embryonic stem cell lines from murine embryos with a non-permissive genetic background,” Nature Genetics, vol. 14, no. 2, pp. 223–226, 1996.
[95]
H. R. Eistetter, “Pluripotent embryonal stem cell lines can be established from disaggregated mouse morulae,” Development Growth and Differentiation, vol. 31, no. 3, pp. 275–282, 1989.
[96]
Y. Matsui, K. Zsebo, and B. L. M. Hogan, “Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture,” Cell, vol. 70, no. 5, pp. 841–847, 1992.
[97]
J. L. Resnick, L. S. Bixler, L. Cheng, and P. J. Donovan, “Long-term proliferation of mouse primordial germ cells in culture,” Nature, vol. 359, no. 6395, pp. 550–551, 1992.
[98]
A. G. Smith and M. L. Hooper, “Buffalo rat liver cells produce a diffusible activity which inhibits the differentiation of murine embryonal carcinoma and embryonic stem cells,” Developmental Biology, vol. 121, no. 1, pp. 1–9, 1987.
[99]
A. G. Smith, J. K. Heath, D. D. Donaldson et al., “Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides,” Nature, vol. 336, no. 6200, pp. 688–690, 1988.
[100]
R. L. Williams, D. J. Hilton, S. Pease et al., “Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells,” Nature, vol. 336, no. 6200, pp. 684–687, 1988.
[101]
H. Niwa, T. Burdon, I. Chambers, and A. Smith, “Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3,” Genes and Development, vol. 12, no. 13, pp. 2048–2060, 1998.
[102]
T. Matsuda, T. Nakamura, K. Nakao et al., “STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells,” EMBO Journal, vol. 18, no. 15, pp. 4261–4269, 1999.
[103]
G. Martello, P. Bertone, and A. Smith, “Identification of the missing pluripotency mediator downstream of leukaemia inhibitory factor,” The EMBO Journal, vol. 32, no. 19, pp. 2561–2574, 2013.
[104]
S. Ye, P. Li, C. Tong, and Q.-L. Ying, “Embryonic stem cell self-renewal pathways converge on the transcription factor Tfcp2l1,” The EMBO Journal, vol. 32, no. 19, pp. 2548–2560, 2013.
[105]
Q. Ying, J. Nichols, I. Chambers, and A. Smith, “BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3,” Cell, vol. 115, no. 3, pp. 281–292, 2003.
[106]
D. P. Gearing and A. G. Bruce, “Oncostatin M binds the high-affinity leukemia inhibitory factor receptor,” New Biologist, vol. 4, no. 1, pp. 61–65, 1992.
[107]
J. C. Conover, N. Y. Ip, W. T. Poueymirou et al., “Ciliary neurotrophic factor maintains the pluripotentiality of embryonic stem cells,” Development, vol. 119, no. 3, pp. 559–565, 1993.
[108]
D. Pennica, K. J. Shaw, T. A. Swanson et al., “Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex,” Journal of Biological Chemistry, vol. 270, no. 18, pp. 10915–10922, 1995.
[109]
J. Nichols, I. Chambers, and A. Smith, “Derivation of germline competent embryonic stem cells with a combination of interleukin-6 and soluble interleukin-6 receptor,” Experimental Cell Research, vol. 215, no. 1, pp. 237–239, 1994.
[110]
J. Nichols, D. Davidson, T. Taga, K. Yoshida, I. Chambers, and A. Smith, “Complementary tissue-specific expression of LIF and LIF-receptor mRNAs in early mouse embryogenesis,” Mechanisms of Development, vol. 57, no. 2, pp. 123–131, 1996.
[111]
J.-L. Escary, J. Perreau, D. Dumenil, S. Ezine, and P. Brulet, “Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation,” Nature, vol. 363, no. 6427, pp. 361–364, 1993.
[112]
M. Li, M. Sendtner, and A. Smith, “Essential function of LIF receptor in motor neurons,” Nature, vol. 378, no. 6558, pp. 724–727, 1995.
[113]
K. Yoshida, T. Taga, M. Saito et al., “Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 1, pp. 407–411, 1996.
[114]
K. Kawasaki, Y. Gao, S. Yokose et al., “Osteoclasts are present in gp130-deficient mice,” Endocrinology, vol. 138, no. 11, pp. 4959–4965, 1997.
[115]
K. Takeda, K. Noguchi, W. Shi et al., “Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 8, pp. 3801–3804, 1997.
[116]
J. Nichols, I. Chambers, T. Taga, and A. Smith, “Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines,” Development, vol. 128, no. 12, pp. 2333–2339, 2001.
[117]
G. R. Martin, “Teratocarcinomas and mammalian embryogenesis,” Science, vol. 209, no. 4458, pp. 768–776, 1980.
[118]
K. R. Thomas and M. R. Capecchi, “Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells,” Cell, vol. 51, no. 3, pp. 503–512, 1987.
[119]
E. Robertson, A. Bradley, M. Kuehn, and M. Evans, “Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector,” Nature, vol. 323, no. 6087, pp. 445–448, 1986.
[120]
A. Bradley, M. Evans, M. H. Kaufman, and E. Robertson, “Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines,” Nature, vol. 309, no. 5965, pp. 255–256, 1984.
[121]
C. L. Stewart, “Formation of viable chimaeras by aggregation between teratocarcinomas and preimplantation mouse embryos,” Journal of Embryology and Experimental Morphology, vol. 67, pp. 167–179, 1982.
[122]
M. J. Dewey, D. W. Martin Jr., G. R. Martin, and B. Mintz, “Mosaic mice with teratocarcinoma-derived mutant cells deficient in hypoxanthine phosphoribosyltransferase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 74, no. 12, pp. 5564–5568, 1977.
[123]
G. Chapman, J. L. Remiszewski, G. C. Webb, T. C. Schulz, C. D. K. Bottema, and P. D. Rathjen, “The mouse homeobox gene, Gbx2: genomic organization and expression in pluripotent cells in vitro and in vivo,” Genomics, vol. 46, no. 2, pp. 223–233, 1997.
[124]
H. Niwa, J. Miyazaki, and A. G. Smith, “Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells,” Nature Genetics, vol. 24, no. 4, pp. 372–376, 2000.
[125]
S. Masui, Y. Nakatake, Y. Toyooka et al., “Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells,” Nature Cell Biology, vol. 9, no. 6, pp. 625–635, 2007.
[126]
N. Ivanova, R. Dobrin, R. Lu et al., “Dissecting self-renewal in stem cells with RNA interference,” Nature, vol. 442, no. 7102, pp. 533–538, 2006.
[127]
I. Chambers, J. Silva, D. Colby et al., “Nanog safeguards pluripotency and mediates germline development,” Nature, vol. 450, no. 7173, pp. 1230–1234, 2007.
[128]
Y. Toyooka, D. Shimosato, K. Murakami, K. Takahashi, and H. Niwa, “Identification and characterization of subpopulations in undifferentiated ES cell culture,” Development, vol. 135, no. 5, pp. 909–918, 2008.
[129]
K. Hayashi, S. M. C. D. S. Lopes, F. Tang, and M. A. Surani, “Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states,” Cell Stem Cell, vol. 3, no. 4, pp. 391–401, 2008.
[130]
T. Furusawa, K. Ohkoshi, C. Honda, S. Takahashi, and T. Tokunaga, “Embryonic stem cells expressing both platelet endothelial cell adhesion molecule-1 and stage-specific embryonic antigen-1 differentiate predominantly into epiblast cells in a chimeric embryo,” Biology of Reproduction, vol. 70, no. 5, pp. 1452–1457, 2004.
[131]
D. Acampora, L. G. Di Giovannantonio, and A. Simeone, “Otx2 is an intrinsic determinant of the embryonic stem cell state and is required for transition to a stable epiblast stem cell condition,” Development, vol. 140, no. 1, pp. 43–55, 2013.
[132]
J. Silva and A. Smith, “Capturing pluripotency,” Cell, vol. 132, no. 4, pp. 532–536, 2008.
[133]
B. D. MacArthur, A. Ana, M. Lenz, et al., “Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity,” Nature Cell Biology, vol. 14, no. 11, pp. 1139–1147, 2012.
[134]
A. Smith, “Nanog heterogeneity: tilting at windmills?” Cell Stem Cell, vol. 13, no. 1, pp. 6–7, 2013.
[135]
J. Rathjen, J. M. Washington, M. D. Bettess, and P. D. Rathjen, “Identification of a biological activity that supports maintenance and proliferation of pluripotent cells from the primitive ectoderm of the mouse,” Biology of Reproduction, vol. 69, no. 6, pp. 1863–1871, 2003.
[136]
P. J. Tesar, J. G. Chenoweth, F. A. Brook et al., “New cell lines from mouse epiblast share defining features with human embryonic stem cells,” Nature, vol. 448, no. 7150, pp. 196–199, 2007.
[137]
I. G. M. Brons, L. E. Smithers, M. W. B. Trotter et al., “Derivation of pluripotent epiblast stem cells from mammalian embryos,” Nature, vol. 448, no. 7150, pp. 191–195, 2007.
[138]
F. J. Najm, J. G. Chenoweth, P. D. Anderson et al., “Isolation of epiblast stem cells from preimplantation mouse embryos,” Cell Stem Cell, vol. 8, no. 3, pp. 318–325, 2011.
[139]
G. M. Beattie, A. D. Lopez, N. Bucay et al., “Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers,” Stem Cells, vol. 23, no. 4, pp. 489–495, 2005.
[140]
M. Amit, M. K. Carpenter, M. S. Inokuma et al., “Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture,” Developmental Biology, vol. 227, no. 2, pp. 271–278, 2000.
[141]
T. E. Ludwig, V. Bergendahl, M. E. Levenstein, J. Yu, M. D. Probasco, and J. A. Thomson, “Feeder-independent culture of human embryonic stem cells,” Nature Methods, vol. 3, no. 8, pp. 637–646, 2006.
[142]
M. Sakaki-Yumoto, J. Liu, M. Ramalho-Santos, N. Yoshida, and R. Derynck, “Smad2 is essential for maintenance of the human and mouse primed pluripotent stem cell state,” Journal of Biological Chemistry, vol. 288, no. 25, pp. 18546–18560, 2013.
[143]
J. Rathjen, J. Lake, M. D. Bettess, J. M. Washington, G. Chapman, and P. D. Rathjen, “Formation of a primitive ectoderm like cell population, EPL cells, from ES cells in response to biologically derived factors,” Journal of Cell Science, vol. 112, no. 5, pp. 601–612, 1999.
[144]
R. L. Gardner, M. F. Lyon, E. P. Evans, and M. D. Burtenshaw, “Clonal analysis of X-chromosome inactivation and the origin of the germ line in the mouse embryo,” Journal of Embryology and Experimental Morphology, vol. 88, pp. 349–363, 1985.
[145]
K. A. Lawson, J. J. Meneses, and R. A. Pedersen, “Clonal analysis of epiblast fate during germ layer formation in the mouse embryo,” Development, vol. 113, no. 3, pp. 891–911, 1991.
[146]
E. Tzouanacou, A. Wegener, F. J. Wymeersch, V. Wilson, and J. Nicolas, “Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis,” Developmental Cell, vol. 17, no. 3, pp. 365–376, 2009.
[147]
J. Rathjen, B. P. Haines, K. M. Hudson, A. Nesci, S. Dunn, and P. D. Rathjen, “Directed differentiation of pluripotent cells to neural lineages: homogeneous formation and differentiation of a neurectoderm population,” Development, vol. 129, no. 11, pp. 2649–2661, 2002.
[148]
J. Lake, J. Rathjen, J. Remiszewski, and P. D. Rathjen, “Reversible programming of pluripotent cell differentiation,” Journal of Cell Science, vol. 113, no. 3, pp. 555–566, 2000.
[149]
S. Vassilieva, H. N. Goh, K. X. Lau, et al., “A system to enrich for primitive streak-derivatives, definitive endoderm and mesoderm, from pluripotent cells in culture,” PLoS ONE, vol. 7, no. 6, Article ID e38645, 2012.
[150]
D. W. Han, N. Tapia, J. Y. Joo et al., “Epiblast stem cell subpopulations represent mouse embryos of distinct pregastrulation stages,” Cell, vol. 143, no. 4, pp. 617–627, 2010.
[151]
S. Ohtsuka, S. Nishikawa-Torikai, and H. Niwa, “E-cadherin promotes incorporation of mouse epiblast stem cells into normal development,” PLoS ONE, vol. 7, no. 9, Article ID e45220, 2012.
[152]
Y. Huang, R. Osorno, A. Tsakiridis, and V. Wilson, “In Vivo differentiation potential of epiblast stem cells revealed by chimeric embryo formation,” Cell Reports, vol. 2, no. 6, pp. 1571–1578, 2012.
[153]
J. G. Chenoweth, R. D. G. McKay, and P. J. Tesar, “Epiblast stem cells contribute new insight into pluripotency and gastrulation,” Development Growth and Differentiation, vol. 52, no. 3, pp. 293–301, 2010.
[154]
J. Nichols and A. Smith, “Naive and primed pluripotent states,” Cell Stem Cell, vol. 4, no. 6, pp. 487–492, 2009.
[155]
G. Guo, J. Yang, J. Nichols et al., “Klf4 reverts developmentally programmed restriction of ground state pluripotency,” Development, vol. 136, no. 7, pp. 1063–1069, 2009.
[156]
I. Hiratani, T. Ryba, M. Itoh et al., “Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis,” Genome Research, vol. 20, no. 2, pp. 155–169, 2010.
[157]
W. Zhou, M. Choi, D. Margineantu et al., “HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition,” EMBO Journal, vol. 31, no. 9, pp. 2103–2116, 2012.
[158]
S. Bao, F. Tang, X. Li et al., “Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells,” Nature, vol. 461, no. 7268, pp. 1292–1295, 2009.
[159]
C. Bernemann, B. Greber, K. Ko et al., “Distinct developmental ground states of epiblast stem cell lines determine different pluripotency features,” Stem Cells, vol. 29, no. 10, pp. 1496–1503, 2011.
[160]
Q. Ying, J. Wray, J. Nichols et al., “The ground state of embryonic stem cell self-renewal,” Nature, vol. 453, no. 7194, pp. 519–523, 2008.
[161]
J. Silva, O. Barrandon, J. Nichols, J. Kawaguchi, T. W. Theunissen, and A. Smith, “Promotion of reprogramming to ground state pluripotency by signal inhibition,” PLoS Biology, vol. 6, no. 10, p. e253, 2008.
[162]
J. Nichols, K. Jones, J. M. Phillips et al., “Validated germline-competent embryonic stem cell lines from nonobese diabetic mice,” Nature Medicine, vol. 15, no. 7, pp. 814–818, 2009.
[163]
M. Buehr, S. Meek, K. Blair et al., “Capture of authentic embryonic stem cells from rat blastocysts,” Cell, vol. 135, no. 7, pp. 1287–1298, 2008.
[164]
F. Faunes, P. Hayward, S. M. Descalzo, et al., “A membrane-associated beta-catenin/Oct4 complex correlates with ground-state pluripotency in mouse embryonic stem cells,” Development, vol. 140, no. 6, pp. 1171–1183, 2013.
[165]
T. Shimizu, J. Ueda, J. C. Ho, et al., “Dual inhibition of Src and GSK3 maintains mouse embryonic stem cells, whose differentiation is mechanically regulated by Src signaling,” Stem Cells, vol. 30, no. 7, pp. 1394–1404, 2012.
[166]
X. Li, L. Zhu, A. Yang et al., “Calcineurin-NFAT signaling critically regulates early lineage specification in mouse embryonic stem cells and embryos,” Cell Stem Cell, vol. 8, no. 1, pp. 46–58, 2011.
[167]
M. A. Meyn III and T. E. Smithgall, “Chemical genetics identifies c-Src as an activator of primitive ectoderm formation in murine embryonic stem cells,” Science Signaling, vol. 2, no. 92, p. ra64, 2009.
[168]
M. A. Meyn III, S. J. Schreiner, T. P. Dumitrescu, G. J. Nau, and T. E. Smithgall, “Src family kinase activity is required for murine embryonic stem cell growth and differentiation,” Molecular Pharmacology, vol. 68, no. 5, pp. 1320–1330, 2005.
[169]
P. D. Rathjen, J. Lake, L. M. Whyatt, M. D. Bettess, and J. Rathjen, “Properties and uses of embryonic stem cells: prospects for application to human biology and gene therapy,” Reproduction, Fertility and Development, vol. 10, no. 1, pp. 31–47, 1998.
[170]
R. G. Edwards, “Human embryo as a source of cells,” Bone Marrow Transplantation, vol. 9, supplement 1, pp. 90–92, 1992.
[171]
N. T. Harvey, J. N. Hughes, A. Lonic et al., “Response to BMP4 signalling during ES cell differentiation defines intermediates of the ectoderm lineage,” Journal of Cell Science, vol. 123, no. 10, pp. 1796–1804, 2010.
[172]
J. N. Hughes, N. Dodge, P. D. Rathjen, and J. Rathjen, “A novel role for γ-secretase in the formation of primitive streak-like intermediates from ES cells in culture,” Stem Cells, vol. 27, no. 12, pp. 2941–2951, 2009.
[173]
M. F. Pera and P. P. L. Tam, “Extrinsic regulation of pluripotent stem cells,” Nature, vol. 465, no. 7299, pp. 713–720, 2010.
[174]
B. V. Johnson, N. Shindo, P. D. Rathjen, J. Rathjen, and R. A. Keough, “Understanding pluripotency—how embryonic stem cells keep their options open,” Molecular Human Reproduction, vol. 14, no. 9, pp. 513–520, 2008.
[175]
T. Kunath, M. K. Saba-El-Leil, M. Almousailleakh, J. Wray, S. Meloche, and A. Smith, “FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment,” Development, vol. 134, no. 16, pp. 2895–2902, 2007.
[176]
J. M. Washington, J. Rathjen, F. Felquer et al., “L-proline induces differentiation of ES cells: a novel role for an amino acid in the regulation of pluripotent cells in culture,” American Journal of Physiology, vol. 298, no. 5, pp. C982–C992, 2010.
[177]
B. S. N. Tan, A. Lonic, M. B. Morris, P. D. Rathjen, and J. Rathjen, “The amino acid transporter SNAT2 mediates l-proline-induced differentiation of ES cells,” American Journal of Physiology, vol. 300, no. 6, pp. C1270–C1279, 2011.
[178]
L. Casalino, S. Comes, G. Lambazzi et al., “Control of embryonic stem cell metastability by L-proline catabolism,” Journal of Molecular Cell Biology, vol. 3, no. 2, pp. 108–122, 2011.
[179]
T. C. Doetschman, H. Eistetter, and M. Katz, “The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium,” Journal of Embryology and Experimental Morphology, vol. 87, pp. 27–45, 1985.
[180]
C. Coffinier, D. Thépot, C. Babinet, M. Yaniv, and J. Barra, “Essential role for the homeoprotein vHNF1/HNF1β in visceral endoderm differentiation,” Development, vol. 126, no. 21, pp. 4785–4794, 1999.
[181]
E. Coucouvanis and G. R. Martin, “BMP signaling plays a role in visceral endoderm differentiation and cavitation in the early mouse embryo,” Development, vol. 126, no. 3, pp. 535–546, 1999.
[182]
E. Barbacci, M. Reber, M. Ott, C. Breillat, F. Huetz, and S. Cereghini, “Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification,” Development, vol. 126, no. 21, pp. 4795–4805, 1999.
[183]
A. Bruhat, C. Jousse, V. Carraro, A. M. Reimold, M. Ferrara, and P. Fafournoux, “Amino acids control mammalian gene transcription: activating transcription factor 2 is essential for the amino acid responsiveness of the CHOP promoter,” Molecular and Cellular Biology, vol. 20, no. 19, pp. 7192–7204, 2000.
[184]
E. Kim, “Mechanisms of amino acid sensing in mTOR signaling pathway,” Nutrition Research and Practice, vol. 3, no. 1, pp. 64–71, 2009.
[185]
S. P. Donald, X.-Y. Sun, C.-A. A. Hu et al., “Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species,” Cancer Research, vol. 61, no. 5, pp. 1810–1815, 2001.
[186]
Y. Liu, G. L. Borchert, A. Surazynski, C.-A. Hu, and J. M. Phang, “Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling,” Oncogene, vol. 25, no. 41, pp. 5640–5647, 2006.
[187]
E. Giannoni, F. Buricchi, G. Raugei, G. Ramponi, and P. Chiarugi, “Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth,” Molecular and Cellular Biology, vol. 25, no. 15, pp. 6391–6403, 2005.
[188]
H. Marks, T. Kalkan, R. Menafra et al., “The transcriptional and epigenomic foundations of ground state pluripotency,” Cell, vol. 149, no. 3, pp. 590–604, 2012.
[189]
W. B. Hamilton, K. Kaji, and T. Kunath, “ERK2 suppresses self-renewal capacity of embryonic stem cells, but is not required for multi-lineage commitment,” PLoS ONE, vol. 8, no. 4, Article ID e60907, 2013.
[190]
Y. Miyanari and M. Torres-Padilla, “Control of ground-state pluripotency by allelic regulation of Nanog,” Nature, vol. 483, no. 7390, pp. 470–473, 2012.
[191]
E. Habibi, A. B. Brinkman, J. Arand, et al., “Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells,” Cell Stem Cell, vol. 13, no. 3, pp. 360–369, 2013.
[192]
J. N. Hughes, J. M. Washington, Z. Zheng et al., “Manipulation of cell: cell contacts and mesoderm suppressing activity direct lineage choice from pluripotent primitive ectoderm-like cells in culture,” PLoS ONE, vol. 4, no. 5, Article ID e5579, 2009.
[193]
A. G. Smith, “Mouse embryo stem cells: their identification, propagation and manipulation,” Seminars in Cell and Developmental Biology, vol. 3, no. 6, pp. 385–399, 1992.
[194]
M. M. Shen and P. Leder, “Leukemia inhibitory factor is expressed by the preimplantation uterus and selectively blocks primitive ectoderm formation in vitro,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 17, pp. 8240–8244, 1992.
[195]
Z. Zheng, R. U. de Iongh, P. D. Rathjen, and J. Rathjen, “A requirement for FGF signalling in the formation of primitive streak-like intermediates from primitive ectoderm in culture,” PloS ONE, vol. 5, no. 9, Article ID e12555, 2010.
[196]
B. E. Reubinoff, M. F. Pera, C. Fong, A. Trounson, and A. Bongso, “Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro,” Nature Biotechnology, vol. 18, no. 4, pp. 399–404, 2000.
[197]
J. A. Thomson, “Embryonic stem cell lines derived from human blastocysts,” Science, vol. 282, no. 5391, pp. 1145–1147, 1998.
[198]
K. Watanabe, M. Ueno, D. Kamiya et al., “A ROCK inhibitor permits survival of dissociated human embryonic stem cells,” Nature Biotechnology, vol. 25, no. 6, pp. 681–686, 2007.
[199]
G. Chen, D. R. Gulbranson, Z. Hou et al., “Chemically defined conditions for human iPSC derivation and culture,” Nature Methods, vol. 8, no. 5, pp. 424–429, 2011.
[200]
R. C. B. Wong, M. F. Pera, and A. Pébay, “Maintenance of human embryonic stem cells by sphingosine-1-phosphate and platelet-derived growth factor,” Methods in Molecular Biology, vol. 874, pp. 167–175, 2012.
[201]
K. Hasegawa, S. Y. Yasuda, J.-L. Teo, et al., “Wnt signaling orchestration with a small molecule DYRK inhibitor provides long-term xeno-free human pluripotent cell expansion,” Stem Cells Translational Medicine, vol. 1, no. 1, pp. 18–28, 2012.
[202]
R. Xu, X. Chen, D. S. Li et al., “BMP4 initiates human embryonic stem cell differentiation to trophoblast,” Nature Biotechnology, vol. 20, no. 12, pp. 1261–1264, 2002.
[203]
A. S. Bernardo, T. Faial, L. Gardner et al., “BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages,” Cell Stem Cell, vol. 9, no. 2, pp. 144–155, 2011.
[204]
C. Buecker, H. Chen, J. M. Polo et al., “A murine ESC-like state facilitates transgenesis and homologous recombination in human pluripotent stem cells,” Cell Stem Cell, vol. 6, no. 6, pp. 535–546, 2010.
[205]
J. Hanna, A. W. Cheng, K. Saha et al., “Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 20, pp. 9222–9227, 2010.
[206]
C. J. Lengner, A. A. Gimelbrant, J. A. Erwin et al., “Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations,” Cell, vol. 141, no. 5, pp. 872–883, 2010.
[207]
Q. Gu, J. Hao, X.-Y. Zhao, et al., “Rapid conversion of human ESCs into mouse ESC-like pluripotent state by optimizing culture conditions,” Protein & Cell, vol. 3, no. 1, pp. 71–79, 2012.
[208]
O. Gafni, L. Weinberger, A. A. Mansour, et al., “Derivation of novel human ground state naive pluripotent stem cells,” Nature, vol. 504, no. 7479, pp. 282–286, 2013.
[209]
T. O'Leary, B. Heindryckx, S. Lierman et al., “Tracking the progression of the human inner cell mass during embryonic stem cell derivation,” Nature Biotechnology, vol. 30, no. 3, pp. 278–282, 2012.
[210]
T. Ezashi, B. P. Telugu, and R. M. Roberts, “Model systems for studying trophoblast differentiation from human pluripotent stem cells,” Cell and Tissue Research, vol. 349, no. 3, pp. 809–824, 2012.
[211]
M. B. Renfree and G. Shaw, “Diapause,” Annual Review of Physiology, vol. 62, pp. 353–375, 2000.
[212]
S. R. Hough, A. L. Laslett, S. B. Grimmond, G. Kolle, and M. F. Pera, “A continuum of cell states spans pluripotency and lineage commitment in human embryonic stem cells,” PLoS ONE, vol. 4, no. 11, Article ID e7708, 2009.
[213]
M. F. Pera, “Defining pluripotency,” Nature Methods, vol. 7, no. 11, pp. 885–886, 2010.
[214]
K. Takahashi and S. Yamanaka, “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors,” Cell, vol. 126, no. 4, pp. 663–676, 2006.
