Changes in mediators of pro-cell growth, senescence, and inflammation during murine gestation

Problem: Senescence of the fetal membranes and senescence-associated inflammation have been associated with parturition at term and pre-term in both mice and humans. Using a pregnant mouse model, we determined changes in multiple molecular signalers contributing to senescence and inflammation associated with parturition. Method of study: Fetal membranes were collected from timed-pregnant CD-1 mice on gestation days (E) 13, 15, 17, 18, and 19. Immunohistochemistry (IHC) localized pro-cell growth factors glycogen synthase kinase 3β (GSK3β) and β-catenin. Gestational age-associated changes in pro-cell growth vs senescence mediators (p38 mitogen-activated protein kinase [p38MAPK]), prooxidants (heme oxygenase-1 [HO-1], peroxisome proliferator-activated receptor γ [PPARγ]), and pro- and anti-inflammatory cytokines (IL-6, IL-8, IL-10, and IL-1β) were determined by Western blots and Luminex assays. Results: Fetal membrane expressions of phosphorylated forms of GSK3β (inactivation) and p38MAPK (activation) increased, while β-catenin expression decreased, as gestation progressed. Antioxidant HO-1 expression decreased while PPARγ increased toward term gestation. IL-6 and IL-8 concentrations were highest on E19 (day of delivery), while IL-10 and IL-1β concentrations were highest on E15. Conclusion: Mouse fetal membranes showed a progressive senescence marker increase coincided with downregulation of cell growth factors. Development of senescence is associated with inflammation. Senescence-associated changes are natural and physiologic and indicative of fetal membranes' readiness for parturition.