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PPARδ agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and Wnt/β-catenin

PPARδ (peroxisome proliferator-activated receptor delta) is a member of the nuclear receptor superfamily. However, its function in tissues and cells is unknown, particularly as related to stem cell biology. We therefore investigated the PPARδ effects on DNA synthesis in mouse embryonic stem cells (ES cells) and its related signal pathways. PPARδ increased biphasic reactive oxygen species (ROS) production at 15 min and at 120 min incubation. PPARδ significantly increased [3H] thymidine incorporation levels at various concentrations (10-8 M to 10-6 M) and incubation times (12 to 48 hr), and this activity was blocked by antioxidants. In addition, PPARδ increased protein kinase C (PKC), cytosolic phospholipase A2 (cPLA2), and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, and Wnt/β-catenin activation. PPARδ increased the protein levels of cell cycle regulators, and these levels were abolished by antioxidants, bisindolymaleimide I, SB203580, and β-catenin specific siRNA. In addition, the effect of PPARδ on increased [3H] thymidine incorporation was blocked by bisindolymaleimide I, SB203580, and β-catenin specific siRNA. In conclusion, PPARδ agonist enhanced mouse ES cells proliferation through ROS-mediated p38 MAPK and Wnt/β-catenin activation.