Nardhy Gomez-Lopez1, Roberto Romero2, Olesya Plazyo3, George Schwenkel3, Valeria Garcia-Flores3, Ronald Unkel3, Yi Xu3, Yaozhu Leng3, Sonia S Hassan3, Bogdan Panaitescu3, Jeeyeon Cha4, Sudhansu K Dey4. 1. Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/US Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Department of Immunology, Microbiology, and Biochemistry, Wayne State University School of Medicine, Detroit, MI. Electronic address: ngomezlo@med.wayne.edu. 2. Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/US Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI. Electronic address: prbchiefstaff@med.wayne.edu. 3. Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/US Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI. 4. Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
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 signs of cellular senescence. STUDY DESIGN: Chorioamniotic membrane samples were collected from women who underwent spontaneous preterm labor or labor at term. Gestational age-matched nonlabor 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 nonlabor 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 (TP53) pathway; (3) the expression of TP53 was down-regulated in the term in labor and preterm in labor groups compared to their nonlabor 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 nonlabor 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 nonlabor 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 membranes from women who underwent spontaneous labor at term did not show consistent signs of cellular senescence in the absence of histologic chorioamnionitis. These results suggest that different pathways are implicated in the pathological and physiological processes of labor. Published by Elsevier Inc.
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 signs of cellular senescence. STUDY DESIGN: Chorioamniotic membrane samples were collected from women who underwent spontaneous preterm labor or labor at term. Gestational age-matched nonlabor 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 nonlabor 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 (TP53) pathway; (3) the expression of TP53 was down-regulated in the term in labor and preterm in labor groups compared to their nonlabor 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 nonlabor counterparts; (5) the expression of the cyclin kinase CDK2 and cyclinsCCNA2, 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 nonlabor 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 membranes from women who underwent spontaneous labor at term did not show consistent signs of cellular senescence in the absence of histologic chorioamnionitis. These results suggest that different pathways are implicated in the pathological and physiological processes of labor. Published by Elsevier Inc.
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