Advertisement

Heterogeneity in Epiblast Stem Cells

  • Alice JouneauEmail author
Chapter
  • 861 Downloads
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1123)

Abstract

Epiblast stem cells (EpiSCs) are pluripotent cells that are derived from mouse embryos at gastrulation stages. They represent the primed state of pluripotency, in which cells are on the verge of differentiation and already express markers of the three primary lineages (mesoderm, endoderm, neurectoderm). EpiSCs display some heterogeneity intra- and inter-cell lines in the expression of some of these lineage markers. We relate this heterogeneity to signalling pathways that are active in EpiSCs, either due to addition of growth factors (FGF2 and activin) in the culture medium, or endogenously active (FGF, Nodal, and Wnt). By modulating Wnt or activin/nodal pathways, cell lines close to EpiSCs but with different properties can be obtained. These signalling pathways are all at work in vivo to pattern the pluripotent epiblast and specify cellular fates.

Keywords

Epiblast Primed Pluripotency Heterogeneity Wnt Activin/Nodal EpiSC Differentiation Fate Signalling pathways Patterning 

References

  1. 1.
    Loh KM, Lim B, Ang LT (2015) Ex uno plures: molecular designs for embryonic pluripotency. Physiol Rev 95:245–295.  https://doi.org/10.1152/physrev.00001.2014 CrossRefPubMedGoogle Scholar
  2. 2.
    Downs KM, Davies T (1993) Staging of gastrulating mouse embryos by morphological landmarks in the dissecting microscope. Development 118:1255–1266PubMedGoogle Scholar
  3. 3.
    Brons IGM, Smithers LE, Trotter MWB, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes SM, Howlett SK, Clarkson A, Ahrlund-Richter L, Pedersen RA, Vallier L (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448:191–195.  https://doi.org/10.1038/nature05950 CrossRefPubMedGoogle Scholar
  4. 4.
    Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP, Mack DL, Gardner RL, McKay RDG (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448:196–199.  https://doi.org/10.1038/nature05972 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Osorno R, Tsakiridis A, Wong F, Cambray N, Economou C, Wilkie R, Blin G, Scotting PJ, Chambers I, Wilson V (2012) The developmental dismantling of pluripotency is reversed by ectopic Oct4 expression. Development 139:2288–2298.  https://doi.org/10.1242/dev.078071 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kojima Y, Kaufman-Francis K, Studdert JB, Steiner KA, Power MD, Loebel DAF, Jones V, Hor A, de Alencastro G, Logan GJ, Teber ET, Tam OH, Stutz MD, Alexander IE, Pickett HA, Tam PPL (2014) The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell 14:107–120.  https://doi.org/10.1016/j.stem.2013.09.014 CrossRefPubMedGoogle Scholar
  7. 7.
    Greber B, Lehrach H, Adjaye J (2007) 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.  https://doi.org/10.1634/stemcells.2006-0476 CrossRefPubMedGoogle Scholar
  8. 8.
    Najm FJ, Chenoweth JG, Anderson PD, Nadeau JH, Redline RW, McKay RDG, Tesar PJ (2011) Isolation of epiblast stem cells from preimplantation mouse embryos. Cell Stem Cell 8:318–325.  https://doi.org/10.1016/j.stem.2011.01.016 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Guo G, Yang J, Nichols J, Hall JS, Eyres I, Mansfield W, Smith A (2009) Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136:1063–1069.  https://doi.org/10.1242/dev.030957 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Tosolini M, Jouneau A (2016) From naive to primed pluripotency: in vitro conversion of mouse embryonic stem cells in epiblast stem cells. Methods Mol Biol 1341:209–216.  https://doi.org/10.1007/7651_2015_208 CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang K, Li L, Huang C, Shen C, Tan F, Xia C, Liu P, Rossant J, Jing N (2010) Distinct functions of BMP4 during different stages of mouse ES cell neural commitment. Development 137:2095–2105.  https://doi.org/10.1242/dev.049494 CrossRefPubMedGoogle Scholar
  12. 12.
    Bao S, Tang F, Li X, Hayashi K, Gillich A, Lao K, Surani MA (2009) Epigenetic reversion of postimplantation epiblast cells to pluripotent embryonic stem cells. Nature 461:1292–1295.  https://doi.org/10.1038/nature08534 CrossRefPubMedGoogle Scholar
  13. 13.
    Ghimire S, Van der Jeught M, Neupane J, Roost MS, Anckaert J, Popovic M, Van Nieuwerburgh F, Mestdagh P, Vandesompele J, Deforce D, Menten B, Chuva de Sousa Lopes S, De Sutter P, Heindryckx B (2018) Comparative analysis of naive, primed and ground state pluripotency in mouse embryonic stem cells originating from the same genetic background. Sci Rep 8:5884.  https://doi.org/10.1038/s41598-018-24051-5 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Weinberger L, Ayyash M, Novershtern N, Hanna JH (2016) Dynamic stem cell states: naive to primed pluripotency in rodents and humans. Nat Rev Mol Cell Biol 17:155–169.  https://doi.org/10.1038/nrm.2015.28 CrossRefPubMedGoogle Scholar
  15. 15.
    Matsuda K, Mikami T, Oki S, Iida H, Andrabi M, Boss JM, Yamaguchi K, Shigenobu S, Kondoh H (2017) ChIP-seq analysis of genomic binding regions of five major transcription factors highlights a central role for ZIC2 in the mouse epiblast stem cell gene regulatory network. Development 144:1948–1958.  https://doi.org/10.1242/dev.143479 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Huang Y, Osorno R, Tsakiridis A, Wilson V (2012) In vivo differentiation potential of epiblast stem cells revealed by chimeric embryo formation. Cell Rep 2:1571–1578.  https://doi.org/10.1016/j.celrep.2012.10.022 CrossRefPubMedGoogle Scholar
  17. 17.
    Hayashi K, Surani MA (2009) Self-renewing epiblast stem cells exhibit continual delineation of germ cells with epigenetic reprogramming in vitro. Development 136:3549–3556.  https://doi.org/10.1242/dev.037747 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Sugimoto M, Kondo M, Koga Y, Shiura H, Ikeda R, Hirose M, Ogura A, Murakami A, Yoshiki A, Chuva de Sousa Lopes SM, Abe K (2015) A simple and robust method for establishing homogeneous mouse epiblast stem cell lines by Wnt inhibition. Stem Cell Rep 4:744–757.  https://doi.org/10.1016/j.stemcr.2015.02.014 CrossRefGoogle Scholar
  19. 19.
    Sumi T, Oki S, Kitajima K, Meno C (2013) Epiblast ground state is controlled by canonical Wnt/β-catenin signaling in the postimplantation mouse embryo and epiblast stem cells. PLoS One 8:e63378.  https://doi.org/10.1371/journal.pone.0063378 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tsukiyama T, Ohinata Y (2014) A modified EpiSC culture condition containing a GSK3 inhibitor can support germline-competent pluripotency in mice. PLoS One 9:e95329.  https://doi.org/10.1371/journal.pone.0095329 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Tsakiridis A, Huang Y, Blin G, Skylaki S, Wymeersch F, Osorno R, Economou C, Karagianni E, Zhao S, Lowell S, Wilson V (2014) Distinct Wnt-driven primitive streak-like populations reflect in vivo lineage precursors. Development 141:1209–1221.  https://doi.org/10.1242/dev.101014 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Song L, Chen J, Peng G, Tang K, Jing N (2016) Dynamic heterogeneity of brachyury in mouse epiblast stem cells mediates distinct response to extrinsic bone morphogenetic protein (BMP) signaling. J Biol Chem 291:15212–15225.  https://doi.org/10.1074/jbc.M115.705418 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kurek D, Neagu A, Tastemel M, Tüysüz N, Lehmann J, van de Werken HJG, Philipsen S, van der Linden R, Maas A, van WFJ IJ, Drukker M, ten Berge D (2015) Endogenous WNT signals mediate BMP-induced and spontaneous differentiation of epiblast stem cells and human embryonic stem cells. Stem Cell Reports 4:114–128.  https://doi.org/10.1016/j.stemcr.2014.11.007 CrossRefPubMedGoogle Scholar
  24. 24.
    Bernemann C, Greber B, Ko K, Sterneckert J, Han DW, Araúzo-Bravo MJ, Schöler HR (2011) Distinct developmental ground states of epiblast stem cell lines determine different pluripotency features. Stem Cells 29:1496–1503.  https://doi.org/10.1002/stem.709 CrossRefPubMedGoogle Scholar
  25. 25.
    Camus A, Perea-Gomez A, Moreau A, Collignon J (2006) Absence of Nodal signaling promotes precocious neural differentiation in the mouse embryo. Dev Biol 295:743–755CrossRefGoogle Scholar
  26. 26.
    Khoa LTP, Azami T, Tsukiyama T, Matsushita J, Tsukiyama-Fujii S, Takahashi S, Ema M (2016) Visualization of the epiblast and visceral endodermal cells using Fgf5-P2A-Venus BAC transgenic mice and epiblast stem cells. PLoS One 11:e0159246.  https://doi.org/10.1371/journal.pone.0159246 CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Kaufman-Francis K, Goh HN, Kojima Y, Studdert JB, Jones V, Power MD, Wilkie E, Teber E, Loebel DA, Tam PP (2014) Differential response of epiblast stem cells to Nodal and Activin signalling: a paradigm of early endoderm development in the embryo. Philos Trans R Soc B 369.  https://doi.org/10.1098/rstb.2013.0550
  28. 28.
    Greber B, Wu G, Bernemann C, Joo JY, Han DW, Ko K, Tapia N, Sabour D, Sterneckert J, Tesar P, Schöler HR (2010) Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cells. Cell Stem Cell 6:215–226.  https://doi.org/10.1016/j.stem.2010.01.003 CrossRefPubMedGoogle Scholar
  29. 29.
    Vallier L, Mendjan S, Brown S, Chng Z, Teo A, Smithers LE, Trotter MWB, Cho CH-H, Martinez A, Rugg-Gunn P, Brons G, Pedersen RA (2009) Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development 136:1339–1349.  https://doi.org/10.1242/dev.033951 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Brennan J, Lu CC, Norris DP, Rodriguez TA, Beddington RSP, Robertson EJ (2001) Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411:965–969CrossRefGoogle Scholar
  31. 31.
    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 134:2895–2902.  https://doi.org/10.1242/dev.02880 CrossRefPubMedGoogle Scholar
  32. 32.
    Lanner F, Rossant J (2010) The role of FGF/Erk signaling in pluripotent cells. Development 137:3351–3360.  https://doi.org/10.1242/dev.050146 CrossRefPubMedGoogle Scholar
  33. 33.
    Sun X, Meyers EN, Lewandoski M, Martin GR (1999) Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev 13:1834–1846CrossRefGoogle Scholar
  34. 34.
    Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR, Bradley A (1999) Requirement for Wnt3 in vertebrate axis formation. Nat Genet 22:361–365.  https://doi.org/10.1038/11932 CrossRefPubMedGoogle Scholar
  35. 35.
    Tortelote GG, Hernandez-Hernandez JM, Quaresma AJ, Nickerson JA, Imbalzano AN, Rivera-Perez JA (2013) Wnt3 function in the epiblast is required for the maintenance but not the initiation of gastrulation in mice. Dev Biol 374:164–173.  https://doi.org/10.1016/j.ydbio.2012.10.013 CrossRefPubMedGoogle Scholar
  36. 36.
    Wu J, Okamura D, Li M, Suzuki K, Luo C, Ma L, He Y, Li Z, Benner C, Tamura I, Krause MN, Nery JR, Du T, Zhang Z, Hishida T, Takahashi Y, Aizawa E, Kim NY, Lajara J, Guillen P, Campistol JM, Esteban CR, Ross PJ, Saghatelian A, Ren B, Ecker JR, Belmonte JCI (2015) An alternative pluripotent state confers interspecies chimaeric competency. Nature 521:316–321.  https://doi.org/10.1038/nature14413 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Tam PPL, Behringer RR (1997) Mouse gastrulation: the formation of a mammalian body plan. Mech Dev 68:3–25.  https://doi.org/10.1016/S0925-4773(97)00123-8 CrossRefPubMedGoogle Scholar
  38. 38.
    Arnold SJ, Robertson EJ (2009) Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat Rev Mol Cell Biol 10:91–103.  https://doi.org/10.1038/nrm2618 CrossRefPubMedGoogle Scholar
  39. 39.
    Smith JR, Vallier L, Lupo G, Alexander M, Harris WA, Pedersen RA (2008) Inhibition of Activin/Nodal signaling promotes specification of human embryonic stem cells into neuroectoderm. Dev Biol 313:107–117.  https://doi.org/10.1016/j.ydbio.2007.10.003 CrossRefPubMedGoogle Scholar
  40. 40.
    Peng G, Suo S, Chen J, Chen W, Liu C, Yu F, Wang R, Chen S, Sun N, Cui G, Song L, Tam PPL, Han J-DJ, Jing N (2016) Spatial transcriptome for the molecular annotation of lineage fates and cell identity in mid-gastrula mouse embryo. Dev Cell 36:681–697.  https://doi.org/10.1016/j.devcel.2016.02.020 CrossRefPubMedGoogle Scholar
  41. 41.
    Lawson KA, Meneses JJ, Pedersen RA (1991) Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. Development 113:891–911PubMedGoogle Scholar
  42. 42.
    Beddington RSP (1983) Histogenetic and neoplastic potential of different regions of the mouse embryonic egg cylinder. Development 75:189–204Google Scholar
  43. 43.
    Blauwkamp TA, Nigam S, Ardehali R, Weissman IL, Nusse R (2012) Endogenous Wnt signalling in human embryonic stem cells generates an equilibrium of distinct lineage-specified progenitors. Nat Commun 3:1070.  https://doi.org/10.1038/ncomms2064 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Pfister S, Steiner KA, Tam PP (2007) Gene expression pattern and progression of embryogenesis in the immediate post-implantation period of mouse development. Gene Expr Patterns 7:558–573.  https://doi.org/10.1016/j.modgep.2007.01.005 CrossRefPubMedGoogle Scholar
  45. 45.
    Liu C, Wang R, He Z, Osteil P, Wilkie E, Yang X, Chen J, Cui G, Guo W, Chen Y, Peng G, Tam PPL, Jing N (2018) Suppressing nodal signaling activity predisposes ectodermal differentiation of epiblast stem cells. Stem Cell Reports 11:43–57.  https://doi.org/10.1016/j.stemcr.2018.05.019 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hayashi K, de Sousa Lopes SMC, Surani MA (2007) Germ cell specification in mice. Science 316:394–396.  https://doi.org/10.1126/science.1137545 CrossRefPubMedGoogle Scholar
  47. 47.
    Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M (2011) Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell 146:519–532.  https://doi.org/10.1016/j.cell.2011.06.052 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Smith A (2017) Formative pluripotency: the executive phase in a developmental continuum. Development 144:365–373.  https://doi.org/10.1242/dev.142679 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Mohammed H, Hernando-Herraez I, Savino A, Scialdone A, Macaulay I, Mulas C, Chandra T, Voet T, Dean W, Nichols J, Marioni JC, Reik W (2017) Single-cell landscape of transcriptional heterogeneity and cell fate decisions during mouse early gastrulation. Cell Rep 20:1215–1228.  https://doi.org/10.1016/j.celrep.2017.07.009 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Nakamura T, Okamoto I, Sasaki K, Yabuta Y, Iwatani C, Tsuchiya H, Seita Y, Nakamura S, Yamamoto T, Saitou M (2016) A developmental coordinate of pluripotency among mice, monkeys and humans. Nature 537:57–62.  https://doi.org/10.1038/nature19096 CrossRefPubMedGoogle Scholar
  51. 51.
    Warmflash A, Sorre B, Etoc F, Siggia ED, Brivanlou AH (2014) A method to recapitulate early embryonic spatial patterning in human embryonic stem cells. Nat Methods 11:847–854.  https://doi.org/10.1038/nmeth.3016 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Morgani SM, Metzger JJ, Nichols J, Siggia ED, Hadjantonakis A-K (2018) Micropattern differentiation of mouse pluripotent stem cells recapitulates embryo regionalized cell fate patterning. elife:7.  https://doi.org/10.7554/eLife.32839
  53. 53.
    Wang C, Liu X, Gao Y, Yang L, Li C, Liu W, Chen C, Kou X, Zhao Y, Chen J, Wang Y, Le R, Wang H, Duan T, Zhang Y, Gao S (2018) Reprogramming of H3K9me3-dependent heterochromatin during mammalian embryo development. Nat Cell Biol 20:620–631.  https://doi.org/10.1038/s41556-018-0093-4 CrossRefPubMedGoogle Scholar
  54. 54.
    Zhang Y, Xiang Y, Yin Q, Du Z, Peng X, Wang Q, Fidalgo M, Xia W, Li Y, Zhao Z, Zhang W, Ma J, Xu F, Wang J, Li L, Xie W (2018) Dynamic epigenomic landscapes during early lineage specification in mouse embryos. Nat Genet 50:96–105.  https://doi.org/10.1038/s41588-017-0003-x CrossRefPubMedGoogle Scholar
  55. 55.
    Zheng H, Huang B, Zhang B, Xiang Y, Du Z, Xu Q, Li Y, Wang Q, Ma J, Peng X, Xu F, Xie W (2016) Resetting epigenetic memory by reprogramming of histone modifications in mammals. Mol Cell 63:1066–1079.  https://doi.org/10.1016/j.molcel.2016.08.032 CrossRefPubMedGoogle Scholar
  56. 56.
    Rulands S, Lee HJ, Clark SJ, Angermueller C, Smallwood SA, Krueger F, Mohammed H, Dean W, Nichols J, Rugg-Gunn P, Kelsey G, Stegle O, Simons BD, Reik W (2018) Genome-scale oscillations in DNA methylation during exit from pluripotency. Cell Syst 7:63–76.e12.  https://doi.org/10.1016/j.cels.2018.06.012 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.UMR BDR, INRA, ENVA, Université Paris SaclayJouy en JosasFrance

Personalised recommendations