Differential senescence in feto-maternal tissues during mouse pregnancy

Background: Human studies show that fetal membranes have a limited lifespan and undergo telomere-dependent cellular senescence that is augmented by oxidative stress and mediated by p38 mitogen activated protein kinase (MAPK). Further, these studies suggest that fetal membranes are anatomically and physiologically positioned to transmit senescence signals that may initiate parturition at term. Methods: Longitudinal evaluation of feto-maternal tissues from mouse pregnancies was undertaken to determine the molecular progression of senescence during normal pregnancy. On days 10-18 of gestation, C57BL/6 mice were euthanized. Fetal membranes, placenta, and decidua/uterus were collected. Tissues were examined for Telomere length (TL) and the presence of Phosphorylated (P) p38MAPK and p53, p21 and senescence associated beta-Galactosidase (SA-beta-Gal). Findings: Linear regression modeling of observed telomere length as a function of gestational age revealed that beta (beta), the slope of the linear regression was negative and significantly different from zero for each tissue (fetal membranes, beta = -0.1901 -0.03125, p < 0.0001; placenta beta = -0.09000 -0.03474, p = 0.0135; decidua/uterus beta = -0.1317 +/- 0.03264, p = 0.0003). Progressive activation p38MAPK was observed in all tissues from days 10 to day 18, with the highest activation observed in fetal membranes. Activation of p53 was progressive in fetal membranes. In contrast, active p53 was constitutive in placenta and decidua/uterus throughout gestation. Detection of p21 indicated that pro-senescent change was higher in all compartments on day 18 as compared to other days. The number of SA-beta-Gal positive cells increased in fetal membranes as gestation progressed. However, in placenta and uterus and decidua/uterus SA-beta-Gal was seen only in days 15 and 18. Conclusions: Telomere dependent p38 and p53 mediated senescence progressed in mouse fetal membranes as gestation advanced. Although senescence is evident, telomere dependent events were not dominant in placenta or decidua/uterus. Fetal membrane senescence may significantly contribute to mechanisms of parturition at term. (C) 2016 Elsevier Ltd. All rights reserved.