The ground state of embryonic stem cell self-renewal

Qi-Long Ying, Jason Wray, Jennifer Nichols, Laura Batlle-Morera, Bradley Doble, James Woodgett, Philip Cohen, Austin Smith

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)519-23
Number of pages5
JournalNature
Volume453
Issue number7194
DOIs
Publication statusPublished - 22 May 2008

Keywords

  • Animals
  • Benzamides
  • Cell Differentiation
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Diphenylamine
  • Embryonic Stem Cells
  • Glycogen Synthase Kinase 3
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinases
  • Pluripotent Stem Cells
  • Pyridines
  • Pyrimidines
  • Regeneration
  • STAT3 Transcription Factor

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