Nature 453, 519-523 (22 May 2008) | doi:10.1038/nature06968; Received 22 November 2007; Accepted 2 April 2008

The ground state of embryonic stem cell self-renewal

Qi-Long Ying1, Jason Wray2, Jennifer Nichols2, Laura Batlle-Morera2, Bradley Doble3, James Woodgett4, Philip Cohen5 & Austin Smith2

  1. Center for Stem Cell and Regenerative Medicine, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, ZNI 529, Los Angeles, California 90033, USA
  2. Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
  3. McMaster Stem Cell and Cancer Research Institute, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada
  4. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
  5. Division of Signal Transduction Therapy and MRC Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, UK

Correspondence to: Qi-Long Ying1Austin Smith2 Correspondence and requests for materials should be addressed to Q.L.Y. (Email: qying@keck.usc.edu) or A.S. (Email: ags39@cscr.cam.ac.uk).

In the three decades since pluripotent mouse embryonic stem (ES) cells were first described1, 2 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 extracts1, 2, 3, 4, 5, 6, 7. 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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