PPARdelta agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and

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A Young Jeong1, Min Young Lee, Sang Hun Lee

  • 1Department of Veterinary Physiology, Biotherapy Human Resources Center (BK 21), College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.

Cell Cycle (Georgetown, Tex.)
|February 7, 2009
PubMed

Insights

Peroxisome proliferator-activated receptor delta (PPARdelta) enhances mouse embryonic stem cell proliferation. This occurs via reactive oxygen species (ROS) production, activating p38 MAPK and Wnt/beta-catenin pathways, promoting DNA synthesis.

Area of Science:

  • Stem cell biology
  • Molecular signaling pathways
  • Nuclear receptor superfamily

Background:

  • The function of PPARdelta in cellular processes, especially stem cell biology, remains largely uncharacterized.
  • Investigating PPARdelta's role is crucial for understanding its impact on stem cell behavior.

Purpose of the Study:

  • To elucidate the effects of PPARdelta on DNA synthesis in mouse embryonic stem cells (ES cells).
  • To identify the specific signaling pathways modulated by PPARdelta in ES cells.

Main Methods:

  • Treatment of mouse ES cells with a PPARdelta agonist.
  • Measurement of reactive oxygen species (ROS) production.
  • Assessment of [(3)H] thymidine incorporation to quantify DNA synthesis.
  • Analysis of protein phosphorylation (PKC, cPLA(2), p38 MAPK) and Wnt/beta-catenin activation.
  • Evaluation of cell cycle regulator protein levels.
  • Inhibition studies using antioxidants, specific kinase inhibitors (bisindolymaleimide I, SB203580), and siRNA for beta-catenin.

Main Results:

  • PPARdelta agonist induced biphasic ROS production.
  • Significant increase in [(3)H] thymidine incorporation, indicating enhanced DNA synthesis, which was blocked by antioxidants.
  • PPARdelta activation led to increased phosphorylation of p38 MAPK and activation of Wnt/beta-catenin signaling.
  • Elevated protein levels of cell cycle regulators were observed, dependent on ROS, p38 MAPK, and Wnt/beta-catenin pathways.
  • Inhibition of these pathways abolished the proliferative effect of PPARdelta.

Conclusions:

  • PPARdelta agonist promotes proliferation of mouse ES cells.
  • The proliferative effect is mediated by ROS generation, leading to the activation of p38 MAPK and Wnt/beta-catenin signaling pathways.
  • These findings reveal a novel mechanism by which PPARdelta influences stem cell proliferation.

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