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Regulatory Networks in Stem Cells pp 37–53Cite as

Maintenance of Embryonic Stem Cell Pluripotency by Nanog-Mediated Dedifferentiation of Committed Mesoderm Progenitors

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Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

Embryonic stem (ES) cells can be propagated indefinitely in culture while retaining the ability to differentiate into any cell type in the organism. The molecular and cellular mechanisms underlying ES cell pluripotency are, however, poorly understood. Here, we characterize a population of early mesoderm-committed (EM) progenitors that is generated from mouse ES cells by bone morphogenetic protein (BMP) stimulation. We further show that EM progenitors are actively dedifferentiated to ES cells by the action of Nanog, which, in turn, is directly up-regulated in EM progenitors by the combined action of leukemia inhibitory factor (LIF) and the early mesoderm transcription factor T/Brachyury. Finally, we demonstrate that this negative feedback mechanism contributes to the maintenance of ES cell pluripotency. These findings uncover specific roles of LIF, Nanog, and BMP in the self-renewal of ES cells and provide novel insights into the cellular bases of ES cell pluripotency.

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References

  1. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981;78:7634–8.

    Article  PubMed  CAS  Google Scholar 

  2. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–6.

    Article  PubMed  CAS  Google Scholar 

  3. Smith AG. Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol. 2001;17:435–62.

    Article  PubMed  CAS  Google Scholar 

  4. Chambers I, Smith A. Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene. 2004;23:7150–60.

    Article  PubMed  CAS  Google Scholar 

  5. Smith AG, Heath JK, Donaldson DD, et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988;336:688–90.

    Article  PubMed  CAS  Google Scholar 

  6. Williams RL, Hilton DJ, Pease S, et al. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature. 1988;336:684–7.

    Article  PubMed  CAS  Google Scholar 

  7. Ying QL, Nichols J, Chambers I, et al. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell. 2003;115: 281–92.

    Article  PubMed  CAS  Google Scholar 

  8. Nichols J, Zevnik B, Anastassiadis K, et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998;95:379–91.

    Article  PubMed  CAS  Google Scholar 

  9. Mitsui K, Tokuzawa Y, Itoh H, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 2003;113:631–42.

    Article  PubMed  CAS  Google Scholar 

  10. Chambers I, Colby D, Robertson M, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003;113:643–55.

    Article  PubMed  CAS  Google Scholar 

  11. Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 2000;24:372–6.

    Article  PubMed  CAS  Google Scholar 

  12. Shamblott MJ, Axelman J, Wang S, et al. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci U S A. 1998;95:13726–31.

    Article  PubMed  CAS  Google Scholar 

  13. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–7.

    Article  PubMed  CAS  Google Scholar 

  14. Rao M. Conserved and divergent paths that regulate self-renewal in mouse and human embryonic stem cells. Dev Biol. 2004;275: 269–86.

    Article  PubMed  CAS  Google Scholar 

  15. Herrmann BG, Labeit S, Poustka A, et al. Cloning of the T gene required in mesoderm formation in the mouse. Nature. 1990;343:617–22.

    Article  PubMed  CAS  Google Scholar 

  16. Wilkinson DG, Bhatt S, Herrmann BG. Expression pattern of the mouse T gene and its role in mesoderm formation. Nature. 1990;343:657–9.

    Article  PubMed  CAS  Google Scholar 

  17. Ramalho-Santos M, Yoon S, Matsuzaki Y, et al. “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science. 2002;298:597–600.

    Article  PubMed  CAS  Google Scholar 

  18. Raz R, Lee CK, Cannizzaro LA, et al. Essential role of STAT3 for embryonic stem cell pluripotency. Proc Natl Acad Sci U S A. 1999;96:2846–51.

    Article  PubMed  CAS  Google Scholar 

  19. Gossen M, Freundlieb S, Bender G, et al. Transcriptional activation by tetracyclines in mammalian cells. Science. 1995;268: 1766–9.

    Article  PubMed  CAS  Google Scholar 

  20. Hoffmann A, Czichos S, Kaps C, et al. The T-box transcription factor Brachyury mediates cartilage development in mesenchymal stem cell line C3H10T1/2. J Cell Sci. 2002;115:769–81.

    PubMed  CAS  Google Scholar 

  21. Kispert A, Herrmann BG. The Brachyury gene encodes a novel DNA binding protein. EMBO J. 1993;12:3211–20.

    PubMed  CAS  Google Scholar 

  22. Hiroi Y, Kudoh S, Monzen K, et al. Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet. 2001;28:276–80.

    Article  PubMed  CAS  Google Scholar 

  23. Stennard FA, Costa MW, Elliott DA, et al. Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart. Dev Biol. 2003;262:206–24.

    Article  PubMed  CAS  Google Scholar 

  24. Garg V, Kathiriya IS, Barnes R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003;424:443–7.

    Article  PubMed  CAS  Google Scholar 

  25. Zhu M, John S, Berg M, et al. Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling. Cell. 1999;96:121–30.

    Article  PubMed  CAS  Google Scholar 

  26. Collum RG, Brutsaert S, Lee G, et al. A Stat3-interacting protein (StIP1) regulates cytokine signal transduction. Proc Natl Acad Sci U S A. 2000;97:10120–5.

    Article  PubMed  CAS  Google Scholar 

  27. Dale L, Howes G, Price BM, et al. Bone morphogenetic protein 4: a ventralizing factor in early Xenopus development. Development. 1992;115:573–85.

    PubMed  CAS  Google Scholar 

  28. Jones CM, Lyons KM, Lapan PM, et al. DVR-4 (bone morphogenetic protein-4) as a posterior-ventralizing factor in Xenopus mesoderm induction. Development. 1992;115:639–47.

    PubMed  CAS  Google Scholar 

  29. Johansson BM, Wiles MV. Evidence for involvement of activin A and bone morphogenetic protein 4 in mammalian mesoderm and hematopoietic development. Mol Cell Biol. 1995;15: 141–51.

    PubMed  CAS  Google Scholar 

  30. Finley MF, Devata S, Huettner JE. BMP-4 inhibits neural differentiation of murine embryonic stem cells. J Neurobiol. 1999;40: 271–87.

    Article  PubMed  CAS  Google Scholar 

  31. Czyz J, Wobus A. Embryonic stem cell differentiation: the role of extracellular factors. Differentiation. 2001;68:167–74.

    Article  PubMed  CAS  Google Scholar 

  32. Holley SA, Neul JL, Attisano L, et al. The Xenopus dorsalizing factor noggin ventralizes Drosophila embryos by preventing DPP from activating its receptor. Cell. 1996;86:607–17.

    Article  PubMed  CAS  Google Scholar 

  33. Zimmerman LB, De Jesus-Escobar JM, Harland RM. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell. 1996;86:599–606.

    Article  PubMed  CAS  Google Scholar 

  34. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.

    Article  PubMed  CAS  Google Scholar 

  35. Hollnagel A, Oehlmann V, Heymer J, et al. Id genes are direct targets of bone morphogenetic protein induction in embryonic stem cells. J Biol Chem. 1999;274:19838–45.

    Article  PubMed  CAS  Google Scholar 

  36. Nakashima K, Takizawa T, Ochiai W, et al. BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc Natl Acad Sci U S A. 2001;98:5868–73.

    Article  PubMed  CAS  Google Scholar 

  37. Feng XH, Zhang Y, Wu RY, et al. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev. 1998;12:2153–63.

    Article  PubMed  CAS  Google Scholar 

  38. Janknecht R, Wells NJ, Hunter T. TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev. 1998;12:2114–9.

    Article  PubMed  CAS  Google Scholar 

  39. Pearson KL, Hunter T, Janknecht R. Activation of Smad1-mediated transcription by p300/CBP. Biochim Biophys Acta. 1999;1489:354–64.

    PubMed  CAS  Google Scholar 

  40. Latinkic BV, Umbhauer M, Neal KA, et al. The Xenopus Brachyury promoter is activated by FGF and low concentrations of activin and suppressed by high concentrations of activin and by paired-type homeodomain proteins. Genes Dev. 1997;11: 3265–76.

    Article  PubMed  CAS  Google Scholar 

  41. Kim J, Johnson K, Chen HJ, et al. Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic. Nature. 1997;388:304–8.

    Article  PubMed  CAS  Google Scholar 

  42. Rathjen J, Lake JA, Bettess MD, et al. Formation of a primitive ectoderm like cell population, EPL cells, from ES cells in response to biologically derived factors. J Cell Sci. 1999;112 (Pt 5): 601–12.

    PubMed  CAS  Google Scholar 

  43. Lake J, Rathjen J, Remiszewski J, et al. Reversible programming of pluripotent cell differentiation. J Cell Sci. 2000;113(Pt 3): 555–66.

    PubMed  CAS  Google Scholar 

  44. Tropepe V, Hitoshi S, Sirard C, et al. Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism. Neuron. 2001;30: 65–78.

    Article  PubMed  CAS  Google Scholar 

  45. Rathjen PD, Nichols J, Toth S, et al. Developmentally programmed induction of differentiation inhibiting activity and the control of stem cell populations. Genes Dev. 1990;4:2308–18.

    Article  PubMed  CAS  Google Scholar 

  46. Nichols J, Chambers I, Taga T, et al. Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines. Development. 2001;128:2333–9.

    PubMed  CAS  Google Scholar 

  47. Daheron L, Opitz SL, Zaehres H, et al. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells. 2004;22:770–8.

    Article  PubMed  CAS  Google Scholar 

  48. Suzuki A, Raya A, Kawakami Y, et al. Maintenance of embryonic stem cell pluripotency by Nanog-mediated reversal of mesoderm specification. Nat Clin Pract Cardiovasc Med. 2006;3 Suppl 1:S114–22.

    Article  PubMed  CAS  Google Scholar 

  49. Suzuki A, Raya A, Kawakami Y, et al. Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells. Proc Natl Acad Sci U S A. 2006;103:10294–9.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 N, Torrey Pines Rd., La Jolla, CA 92037

    Atsushi Suzuki, Ángel Raya, Yasuhiko Kawakami, Masanobu Morita, Takaaki Matsui, Kinichi Nakashima, Fred H. Gage, Concepción Rodríguez-Esteban & Juan Carlos Izpisúa Belmonte

  2. Center of Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08029 Barcelona, Spain

    Ángel Raya, Concepción Rodríguez-Esteban & Juan Carlos Izpisúa Belmonte

  3. Research Unit for Organ Regeneration, Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan

    Atsushi Suzuki

  4. ICREA, 5CIBER-BBN, Gene Regulation Research, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma 630-0101, Japan

    Ángel Raya & Takaaki Matsui

  5. Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma 630-0101, Japan

    Kinichi Nakashima

Authors
  1. Atsushi Suzuki
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  2. Ángel Raya
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  3. Yasuhiko Kawakami
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  7. Fred H. Gage
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  8. Concepción Rodríguez-Esteban
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  9. Juan Carlos Izpisúa Belmonte
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Editor information

Editors and Affiliations

  1. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Vinagolu K. Rajasekhar MSc, MPhil, PhD

  2. Invitrogen Corporation, Frederick, MD, USA

    Mohan C. Vemuri Ph.D.

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© 2009 Humana Press, a part of Springer Science+Business Media, LLC, a part of Springer Science+Business Media, LLC

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Suzuki, A. et al. (2009). Maintenance of Embryonic Stem Cell Pluripotency by Nanog-Mediated Dedifferentiation of Committed Mesoderm Progenitors. In: Rajasekhar, V.K., Vemuri, M.C. (eds) Regulatory Networks in Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-60327-227-8_4

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