Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Self-renewal of teratocarcinoma and embryonic stem cells

Oncogene volume 23, pages 7150–7160 (2004)Cite this article

Abstract

Pluripotent stem cells derived from preimplantation embryos, primordial germ cells or teratocarcinomas are currently unique in undergoing prolonged symmetrical self-renewal in culture. For mouse embryonic stem (ES) cells, self-renewal is dependent on signals from the cytokine leukaemia inhibitory factor (LIF) and from either serum or bone morphogenetic proteins (BMPs). In addition to the extrinsic regulation of gene expression, intrinsic transcriptional determinants are also required for maintenance of the undifferentiated state. These include Oct4, a member of the POU family of homeodomain proteins and a second recently identified homeodomain protein, Nanog. When overexpressed, Nanog allows ES cells to self-renew in the absence of the otherwise obligatory LIF and BMP signals. Although Nanog can act independent of the LIF signal, a contribution of both pathways provides maximal self-renewal efficiency. Nanog function also requires Oct4. Here, we review recent progress in ES cell self-renewal, relate this to the biology of teratocarcinomas and offer testable hypotheses to expose the mechanics of ES cell self-renewal.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Ambrosetti DC, Scholer HR, Dailey L and Basilico C . (2000). J. Biol. Chem., 275, 23387–23397.

  • Amit M, Shariki C, Margulets V and Itskovitz-Eldor J . (2004). Biol. Reprod., 70, 837–845.

  • Andrews PW . (2002). Philos. Trans. R. Soc. Lond. Ser. B., 357, 405–417.

  • Aubert J, Dunstan H, Chambers I and Smith A . (2002). Nat. Biotechnol., 20, 1240–1245.

  • Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N and Lovell-Badge R . (2003). Genes Dev., 17, 126–140.

  • Bain J, McLauchlan H, Elliott M and Cohen P . (2003). Biochem. J., 371, 199–204.

  • Beddington RSP and Robertson EJ . (1989). Development, 105, 733–737.

  • Ben-Shushan E, Thompson JR, Gudas LJ and Bergman Y . (1998). Mol. Cell. Biol., 18, 1666–1878.

  • Bradley A, Evans MJ, Kaufman MH and Robertson E . (1984). Nature, 309, 255–256.

  • Brinster RL . (1974). J. Exp. Med., 140, 1049–1056.

  • Brook FA and Gardner RL . (1997). Proc. Natl. Acad. Sci. USA, 94, 5709–5712.

  • Buehr M and Smith A . (2003). Philos. Trans. R. Soc. Lond. Ser. B., 358, 1397–1402 (discussion 1402).

  • Burdon T, Chambers I, Stracey C, Niwa H and Smith A . (1999a). Cells Tissues Organs, 165, 131–143.

  • Burdon T, Smith A and Savatier P . (2002). Trends Cell Biol., 12, 432.

  • Burdon T, Stracey C, Chambers I, Nichols J and Smith A . (1999b). Dev. Biol., 210, 30–43.

  • Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S and Smith A . (2003). Cell, 113, 643–655.

  • Cheng AM, Saxton TM, Sakai R, Kulkarni S, Mbamalu G, Vogel W, Tortorice CG, Cardiff RD, Cross JC, Muller WJ and Pawson T . (1998). Cell, 95, 793–803.

  • Clark AT, Rodriguez RT, Bodnar MS, Abeyta MJ, Cedars MI, Turek PJ, Firpo MT and Reijo Pera RA . (2004). Stem Cells, 22, 169–179.

  • Dani C, Chambers I, Johnstone S, Robertson M, Ebrahimi B, Saito M, Taga T, Li M, Burdon T, Nichols J and Smith A . (1998). Dev. Biol., 203, 149–162.

  • Di Cristofano A, Pesce B, Cordon-Cardo C and Pandolfi PP . (1998). Nat. Genet., 19, 348–355.

  • Diwan SB and Stevens LC . (1976). J. Natl. Cancer Inst., 57, 937–942.

  • Draper JS, Smith K, Gokhale P, Moore HD, Maltby E, Johnson J, Meisner L, Zwaka TP, Thomson JA and Andrews PW . (2004). Nat. Biotechnol., 22, 53–54.

  • Duval D, Reinhardt B, Kedinger C and Boeuf H . (2000). FASEB J., 14, 1577–1584.

  • Evans MJ and Kaufman MH . (1981). Nature, 292, 154–156.

  • Finch BW and Ephrussi B . (1967). Proc. Natl. Acad. Sci. USA, 57, 615–621.

  • Frame S and Cohen P . (2001). Biochem. J., 359, 1–16.

  • Fujikura J, Yamato E, Yonemura S, Hosoda K, Masui S, Nakao K, Miyazaki Ji J and Niwa H . (2002). Genes Dev., 16, 784–789.

  • Gardner RL . (1983). Int. Rev. Exp. Pathol., 24, 63–133.

  • Gidekel S, Pizov G, Bergman Y and Pikarsky E . (2003). Cancer Cell, 4, 361–370.

  • Guo Y, Costa R, Ramsey H, Starnes T, Vance G, Robertson K, Kelley M, Reinbold R, Scholer H and Hromas R . (2002). Proc. Natl. Acad. Sci. USA, 99, 3663–3667.

  • Hanna LA, Foreman RK, Tarasenko IA, Kessler DS and Labosky PA . (2002). Genes Dev., 16, 2650–2661.

  • Hart AH, Hartley L, Ibrahim M and Robb L . (2004). Dev. Dyn., 230, 187–198.

  • Hay DC, Sutherland L, Clark J and Burdon T . (2004). Stem Cells, 22, 225–235.

  • Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G and Schaper F . (2003). Biochem. J., 374, 1–20.

  • Hooper ML, Hardy K, Handyside A, Hunter S and Monk M . (1987). Nature, 326, 292–295.

  • Jirmanova L, Afanassieff M, Gobert-Gosse S, Markossian S and Savatier P . (2002). Oncogene, 21, 5515–5528.

  • Kappen C, Schughart K and Ruddle FH . (1993). Genomics, 18, 54–70.

  • Kawase E, Suemori H, Takahashi N, Okazaki K, Hashimoto K and Nakatsuji N . (1994). Int. J. Dev. Biol., 38, 385–390.

  • Kimura T, Suzuki A, Fujita Y, Yomogida K, Lomeli H, Asada N, Ikeuchi M, Nagy A, Mak TW and Nakano T . (2003). Development, 130, 1691–1700.

  • Kleinsmith LJ and Pierce GB . (1964). Cancer Res., 24, 1544–1552.

  • Lako M, Lindsay S, Lincoln J, Cairns PM, Armstrong L and Hole N . (2001). Mech. Dev., 103, 49–59.

  • Layton MJ, Lock P, Metcalf D and Nicola NA . (1994). J. Biol. Chem., 269, 17048–17055.

  • Lloyd S, Fleming TP and Collins JE . (2003). Gene Expr. Patterns, 3, 309–312.

  • Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G and Oosterhuis JW . (2003). Cancer Res., 63 (9), 2244–2250.

  • Martin GR . (1981). Proc. Natl. Acad. Sci. USA, 78, 7634–7638.

  • Martin GR and Evans MJ . (1975). Teratomas and Differentiation Sherman MI and Solter D (eds). Academic Press: New York, pp 169–187.

    Google Scholar 

  • Matin MM, Walsh JR, Gokhale PJ, Draper JS, Bahrami AR, Morton I, Moore HD and Andrews PW . (2004). Stem Cells (in press).

  • Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T and Yokota T . (1999). EMBO J., 18, 4261–4269.

  • Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M and Yamanaka S . (2003). Cell, 113, 631–642.

  • Mostert MC, Verkerk AJ, van de Pol M, Heighway J, Marynen P, Rosenberg C, van Kessel AG, van Echten J, de Jong B, Oosterhuis JW and Looijenga LH . (1998). Oncogene, 16, 2617–2627.

  • Nakashima K, Takizawa T, Ochiai W, Yanagisawa M, Hisatsune T, Nakafuku M, Miyazono K, Kishimoto T, Kageyama R and Taga T . (2001). Proc. Natl. Acad. Sci. USA, 98, 5868–5873.

  • Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K and Taga T . (1999). Science, 284, 479–482.

  • Nichols J, Chambers I and Smith A . (1994). Exp. Cell Res., 215, 237–239.

  • Nichols J, Chambers I, Taga T and Smith A . (2001). Development, 128, 2333–2339.

  • Nichols J, Davidson D, Taga T, Yoshida K, Chambers I and Smith A . (1996). Mech. Dev., 57, 123–131.

  • Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H and Smith A . (1998). Cell, 95, 379–391.

  • Niwa H . (2001). Cell Struct. Funct., 26, 137–148.

  • Niwa H, Burdon T, Chambers I and Smith A . (1998). Genes Dev., 12, 2048–2060.

  • Niwa H, Masui S, Chambers I, Smith AG and Miyazaki J . (2002). Mol. Cell. Biol., 22, 1526–1536.

  • Niwa H, Miyazaki J and Smith AG . (2000). Nat. Genet., 24, 372–376.

  • Norton JD . (2000). J. Cell Sci., 113 (Part 22), 3897–3905.

  • Palmieri SL, Peter W, Hess H and Scholer HR . (1994). Dev. Biol., 166, 259–267.

  • Pardal R, Clarke MF and Morrison SJ . (2003). Nat. Rev. Cancer, 3, 895–902.

  • Payer B, Saitou M, Barton SC, Thresher R, Dixon JP, Zahn D, Colledge WH, Carlton MB, Nakano T and Surani MA . (2003). Curr. Biol., 13, 2110–2117.

  • Pera MF, Filipczyk AA, Hawes SM and Laslett AL . (2003). Methods Enzymol., 365, 429–446.

  • Pesce M and Scholer HR . (2001). Stem Cells, 19, 271–278.

  • Pierce GB . (1967). Curr. Top. Dev. Biol., 2, 223–246.

  • Qu CK and Feng GS . (1998). Oncogene, 17, 433–439.

  • Reubinoff BE, Pera MF, Fong CY, Trounson A and Bongso A . (2000). Nat. Biotechnol., 18, 399–404.

  • Rodriguez S, Jafer O, Goker H, Summersgill BM, Zafarana G, Gillis AJ, van Gurp RJ, Oosterhuis JW, Lu YJ, Huddart R, Cooper CS, Clark J, Looijenga LH and Shipley JM . (2003). Oncogene, 22, 1880–1891.

  • Ruzinova MB and Benezra R . (2003). Trends Cell Biol., 13, 410–418.

  • Saijoh Y, Fukii H, Meno C, Sato M, Hirota Y, Nagamatsu S, Ikeda M and Hamada H . (1996). Genes Cells, 1, 239–252.

  • Sato N, Meijer L, Skaltsounis L, Greengard P and Brivanlou AH . (2004). Nat. Med., 10, 55–63.

  • Skotheim RI, Monni O, Mousses S, Fossa SD, Kallioniemi OP, Lothe RA and Kallioniemi A . (2002). Cancer Res., 62, 2359–2364.

  • Skotheim RI and Lothe RA . (2003). APMIS, 111, 136–151.

  • Smith AG . (2001). Ann. Rev. Cell Dev. Biol., 17, 435–462.

  • Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M and Rogers D . (1988). Nature, 336, 688–690.

  • Smith AG and Hooper ML . (1987). Dev. Biol., 121, 1–9.

  • Smith TA and Hooper ML . (1983). Exp. Cell Res., 145, 458–462.

  • Solter D, Skreb N and Damjanov I . (1970). Nature, 227, 503–504.

  • Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA and Hilton DJ . (1997). Nature, 387, 917–921.

  • Stevens LC . (1968). J. Embryol. Exp. Morphol., 20, 329–341.

  • Stevens LC . (1970). Dev. Biol., 21, 364–382.

  • Stevens LC . (1983). Teratocarcinoma Stem Cells Silver LM, Martin GR and Strickland S (eds). Cold Spring Harbor Laboratory: New York, pp. 23–36.

    Google Scholar 

  • Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F and Abbondanzo SJ . (1992). Nature, 359, 76–79.

  • Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X and Wu H . (1999). Proc. Natl. Acad. Sci. USA, 96, 6199–6204.

  • Takahashi K, Mitsui K and Yamanaka S . (2003). Nature, 423, 541–545.

  • Thompson S, Clarke AR, Pow AM, Hooper ML and Melton DW . (1989). Cell, 56, 313–321.

  • Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS and Jones JM . (1998). Science, 282, 1145–1147.

  • Tu Z, Ninos JM, Ma Z, Wang JW, Lemos MP, Desponts C, Ghansah T, Howson JM and Kerr WG . (2001). Blood, 98, 2028–2038.

  • van der Weyden L, Adams DJ and Bradley A . (2002). Physiol. Genom., 11, 133–164.

  • Vernallis AB, Hudson KR and Heath JK . (1997). J. Biol. Chem., 272, 26947–26952.

  • Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA and Gough NM . (1988). Nature, 336, 684–687.

  • Xu C, Inokuma MS, Denham J, Golds K, Kundu P, Gold JD and Carpenter MK . (2001). Nat. Biotechnol., 19, 971–974.

  • Ying QL, Nichols J, Chambers I and Smith A . (2003). Cell, 115, 281–292.

  • Yoshida K, Chambers I, Nichols J, Smith A, Saito M, Yasukawa K, Shoyab M, Taga T and Kishimoto T . (1994). Mech. Dev., 45, 163–171.

  • Zhang JG, Owczarek CM, Ward LD, Howlett GJ, Fabri LJ, Roberts BA and Nicola NA . (1997). Biochem. J., 325 (Part 3), 693–700.

Download references

Acknowledgements

We thank Susan Tweedie for assistance with Figure 2. The authors' research is supported by grants from the Biotechnology and Biological Sciences Research Council and the Medical Research Council of the United Kingdom.

Author information

Authors and Affiliations

  1. MRC Centre Development in Stem Cell Biology, Institute for Stem Cell Research, University of Edinburgh, King's Buildings, West Mains Rd., Edinburgh, EH9 3JQ, Scotland, UK

    Ian Chambers & Austin Smith

Authors
  1. Ian Chambers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Austin Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ian Chambers or Austin Smith.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chambers, I., Smith, A. Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene 23, 7150–7160 (2004). https://doi.org/10.1038/sj.onc.1207930

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207930

Keywords

This article is cited by

Search

Advanced search

Quick links