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Leukemia inhibitory factor (LIF) withdrawal activates mTOR signaling pathway in mouse embryonic stem cells through

M Y Cherepkova1, G S Sineva1, V A Pospelov1

  • 1Laboratory of Molecular Mechanisms Cell Differentiation, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia.

Cell Death & Disease
|January 19, 2016
PubMed

Insights

Leukemia inhibitory factor (LIF) maintains mouse embryonic stem cell (ESC) pluripotency by suppressing mTOR signaling via the STAT3 pathway. LIF withdrawal activates mTOR and ERK, promoting differentiation.

Area of Science:

  • Stem cell biology
  • Molecular signaling pathways
  • Cellular differentiation

Background:

  • Leukemia inhibitory factor (LIF) is crucial for maintaining the pluripotency of mouse embryonic stem cells (ESCs).
  • The precise molecular mechanisms by which the LIF/STAT3 pathway regulates ESC self-renewal and pluripotency remain incompletely understood.
  • Mammalian target of rapamycin (mTOR) signaling is implicated in cellular differentiation processes.

Purpose of the Study:

  • To elucidate the role of the LIF/STAT3 signaling pathway in maintaining mouse ESC pluripotency.
  • To investigate the relationship between LIF/STAT3 signaling and mTOR activity in ESCs.
  • To understand the molecular events leading to ESC differentiation upon LIF withdrawal.

Main Methods:

  • Western blotting to detect protein phosphorylation (e.g., S6, 4EBP1, STAT3, ERK, TSC2).
  • Treatment of ESCs with LIF, LIF withdrawal, and specific small molecule inhibitors (e.g., WP1066).
  • Quantitative analysis of gene expression for pluripotency markers (Oct-4, Nanog, Sox2) and differentiation markers (fgf5).

Main Results:

  • LIF withdrawal rapidly increased mTOR activity, evidenced by increased phosphorylation of its targets S6 and 4EBP1.
  • Suppression of STAT3 phosphorylation also led to mTOR activation.
  • LIF withdrawal activated ERK signaling and caused phosphorylation of TSC2, relieving its inhibition on mTOR.
  • mTOR activation correlated with decreased expression of pluripotency genes (Oct-4, Nanog, Sox2) and increased expression of the differentiation marker fgf5.

Conclusions:

  • The LIF/STAT3 pathway maintains mouse ESC pluripotency by suppressing mTOR signaling.
  • LIF withdrawal triggers a transition from a pluripotent state to a primed-like state via mTOR activation and ERK signaling.
  • This transition involves the downregulation of key pluripotency factors and upregulation of early differentiation markers.

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