Preterm labor in the absence of acute histologic chorioamnionitis is characterized by cellular senescence of the chorioamniotic membranes

Abstract

Background Decidual senescence has been considered a mechanism of disease for spontaneous preterm labor in the absence of severe acute inflammation. Yet, signs of cellular senescence have also been observed in the chorioamniotic membranes from women who underwent the physiological process of labor at term. Objective We aimed to investigate whether, in the absence of acute histologic chorioamnionitis, the chorioamniotic membranes from women who underwent spontaneous preterm labor or labor at term exhibit markers of cellular senescence. Study Design Chorioamniotic membrane samples were collected from women who underwent spontaneous preterm labor or labor at term. Gestational age-matched non-labor controls were also included. Senescence-associated genes/proteins were determined using reverse transcription quantitative polymerase chain reaction analysis (n=7–9 each for array; n= 26–28 each for validation), enzyme-linked immunosorbent assays (n=7–9 each), immunoblotting (n=6–7 each) and immunohistochemistry (n=7–8 each). Senescence-associated β-galactosidase activity (n=7–11 each) and telomere length (n=15–22 each) were also evaluated. Results In the chorioamniotic membranes without acute histologic chorioamnionitis: 1) the expression profile of senescence-associated genes was different between the labor groups (term in labor and preterm in labor) and the non-labor groups (term no labor and preterm no labor); yet, there were differences between the term in labor and preterm in labor groups; 2) most of the differentially expressed genes among the groups were closely related to the tumor suppressor protein 53 (TP53) pathway; 3) the expression of TP53 was down-regulated in the term in labor and preterm in labor groups compared to their non-labor counterparts; 4) the expression of CDKN1A (gene coding for p21) was up-regulated in the term in labor and preterm in labor groups compared to their non-labor counterparts; 5) the expression of the cyclin kinase CDK2 and cyclins CCNA2, CCNB1 and CCNE1 was down-regulated in the preterm in labor group compared to the preterm no labor group; 6) the concentration of TP53 was lower in the preterm in labor group than in the preterm no labor and term in labor groups; 7) the senescence-associated β-galactosidase activity was greater in the preterm in labor group than in the preterm no labor and term in labor groups; 8) the concentration of phospho-S6 ribosomal protein was reduced in the term in labor group compared to its non-labor counterpart but no differences were observed between the preterm in labor and preterm no labor groups, and 9) no significant differences were observed in relative telomere length among the study groups (term no labor, term in labor, preterm no labor, and preterm in labor). Conclusion In the absence of acute histologic chorioamnionitis, signs of cellular senescence are present in the chorioamniotic membranes from women who underwent spontaneous preterm labor compared to those who delivered preterm in the absence of labor. However, the chorioamniotic me...

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Amnion epithelial cell–derived exosomes induce inflammatory changes in uterine cells

“…Based on recent findings of senescence in various gestational tissues that coincide with fetal growth, and our findings in fetal membrane models showing that membrane senescence and damage are associated with parturition, we hypothesized that senescent fetal membranes generate inflammatory mediators to signal fetal readiness for parturition. 25,73,74 We propose that these signals are propagated from fetal tissues to the uterine parturition effector tissues (decidua and myometrium) via fetal cell derived exosomes.…”

Premature placental aging in term small‐for‐gestational‐age and growth‐restricted fetuses

“…Altered placental aging has been described in several obstetric complications 23 including stillbirth 24,25 , spontaneous preterm labor [26][27][28] , poorly controlled maternal diabetes 29 , pre-eclampsia and FGR 30,31 . Previous studies in placentas of pregnancies complicated by FGR showed markers of placental aging, including shorter telomeres, telomerase activity suppression [32][33][34] and increased apoptosis mediated by the p53 pathway [35][36][37] .…”