Oct4 and LIF/Stat3 Additively Induce Krüppel Factors to Sustain Embryonic Stem Cell Self-Renewal

John Hall, Sofia Morfopoulou, Ge Guo, Jason Wray, Isobel Eyres, Jennifer Nichols, Lars Grotewold, Peter Humphreys, William Mansfield, R. Walker

Research output: Contribution to journalArticlepeer-review

Abstract

Embryonic stem cell (ESC) pluripotency is dependent on an intrinsic gene regulatory network centered on Oct4. Propagation of the pluripotent state is stimulated by the cytokine leukemia inhibitory factor (LIF) acting through the transcriptional regulator Stat3. Here, we show that this extrinsic stimulus converges with the intrinsic circuitry in Krüppel-factor activation. Oct4 primarily induces Klf2 while LIF/Stat3 selectively enhances Klf4 expression. Overexpression of either factor reduces LIF dependence, but with quantitative and qualitative differences. Unlike Klf4, Klf2 increases ESC clonogenicity, maintains undifferentiated ESCs in the genetic absence of Stat3, and confers resistance to BMP-induced differentiation. ESCs expanded with Klf2 remain capable of contributing to adult chimeras. Postimplantation-embryo-derived EpiSCs lack both Klf2 and Klf4 and expression of either can reinstate naive pluripotency. These findings indicate that Oct4 and Stat3 intersect in directing expression of Klf transcriptional regulators with overlapping properties that additively reinforce ground-state ESC pluripotency, identity, and self-renewal.
Original languageEnglish
Pages (from-to)597-609
Number of pages12
JournalCell Stem Cell
Volume5
Issue number6
DOIs
Publication statusPublished - 4 Dec 2009

Keywords

  • embryonic stem cells
  • functional genomicvs
  • microarray analysis

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