The Ground State of Embryonic Stem Cell Self-renewal

Overview

Journal Nature

Specialty Science

Date 2008 May 24

PMID 18497825

Citations 1697

Authors

Qi-Long Ying

Jason Wray

Jennifer Nichols

Laura Batlle-Morera

Bradley Doble

James Woodgett

Philip Cohen

Austin Smith

Affiliations

Soon will be listed here.

Abstract

In the three decades since pluripotent mouse embryonic stem (ES) cells were first described they have been derived and maintained by using various empirical combinations of feeder cells, conditioned media, cytokines, growth factors, hormones, fetal calf serum, and serum extracts. Consequently ES-cell self-renewal is generally considered to be dependent on multifactorial stimulation of dedicated transcriptional circuitries, pre-eminent among which is the activation of STAT3 by cytokines (ref. 8). Here we show, however, that extrinsic stimuli are dispensable for the derivation, propagation and pluripotency of ES cells. Self-renewal is enabled by the elimination of differentiation-inducing signalling from mitogen-activated protein kinase. Additional inhibition of glycogen synthase kinase 3 consolidates biosynthetic capacity and suppresses residual differentiation. Complete bypass of cytokine signalling is confirmed by isolating ES cells genetically devoid of STAT3. These findings reveal that ES cells have an innate programme for self-replication that does not require extrinsic instruction. This property may account for their latent tumorigenicity. The delineation of minimal requirements for self-renewal now provides a defined platform for the precise description and dissection of the pluripotent state.

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References

Buehr M, Smith A . Genesis of embryonic stem cells. Philos Trans R Soc Lond B Biol Sci. 2003; 358(1436):1397-402. PMC: 1693233. DOI: 10.1098/rstb.2003.1327. View

Stavridis M, Lunn J, Collins B, Storey K . A discrete period of FGF-induced Erk1/2 signalling is required for vertebrate neural specification. Development. 2007; 134(16):2889-94. DOI: 10.1242/dev.02858. View

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. 1999; 210(1):30-43. DOI: 10.1006/dbio.1999.9265. View

Zhen Y, Sorensen V, Jin Y, Suo Z, Wiedlocha A . Indirubin-3'-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK. Oncogene. 2007; 26(44):6372-85. DOI: 10.1038/sj.onc.1210473. View

Niwa H, Burdon T, Chambers I, Smith A . Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 1998; 12(13):2048-60. PMC: 316954. DOI: 10.1101/gad.12.13.2048. View

Ying Q, 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. 2003; 115(3):281-92. DOI: 10.1016/s0092-8674(03)00847-x. View

Chambers I, Smith A . Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene. 2004; 23(43):7150-60. DOI: 10.1038/sj.onc.1207930. View

Nichols J, Zevnik B, Anastassiadis K, Niwa H, Chambers I, Scholer H . Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998; 95(3):379-91. DOI: 10.1016/s0092-8674(00)81769-9. View

Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T . STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J. 1999; 18(15):4261-9. PMC: 1171502. DOI: 10.1093/emboj/18.15.4261. View

10.

Colman-Lerner A, Gordon A, Serra E, Chin T, Resnekov O, Endy D . Regulated cell-to-cell variation in a cell-fate decision system. Nature. 2005; 437(7059):699-706. DOI: 10.1038/nature03998. View

11.

Martin G . 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(12):7634-8. PMC: 349323. DOI: 10.1073/pnas.78.12.7634. View

12.

Burdon T, Smith A, Savatier P . Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol. 2002; 12(9):432-8. DOI: 10.1016/s0962-8924(02)02352-8. View

13.

Rathjen J, Lake J, Bettess M, Washington J, Chapman G, Rathjen P . 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. DOI: 10.1242/jcs.112.5.601. View

14.

Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S . Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003; 113(5):643-55. DOI: 10.1016/s0092-8674(03)00392-1. View

15.

Mohammadi M, McMahon G, Sun L, Tang C, Hirth P, Yeh B . Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science. 1997; 276(5314):955-60. DOI: 10.1126/science.276.5314.955. View

16.

Ogawa K, Matsui H, Ohtsuka S, Niwa H . A novel mechanism for regulating clonal propagation of mouse ES cells. Genes Cells. 2004; 9(5):471-7. DOI: 10.1111/j.1356-9597.2004.00736.x. View

17.

Bain J, Plater L, Elliott M, Shpiro N, Hastie C, McLauchlan H . The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007; 408(3):297-315. PMC: 2267365. DOI: 10.1042/BJ20070797. View

18.

Evans M, Kaufman M . Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981; 292(5819):154-6. DOI: 10.1038/292154a0. View

19.

Wilder P, Kelly D, Brigman K, Peterson C, Nowling T, Gao Q . Inactivation of the FGF-4 gene in embryonic stem cells alters the growth and/or the survival of their early differentiated progeny. Dev Biol. 1998; 192(2):614-29. DOI: 10.1006/dbio.1997.8777. View

20.

Yoshida K, Chambers I, Nichols J, Smith A, Saito M, Yasukawa K . Maintenance of the pluripotential phenotype of embryonic stem cells through direct activation of gp130 signalling pathways. Mech Dev. 1994; 45(2):163-71. DOI: 10.1016/0925-4773(94)90030-2. View