Evidence of oxidative stress-induced senescence in mature, post-mature and pathological human placentas
Tereza Cindrova-Davies, Norah M E Fogarty, Carolyn J P Jones, John Kingdom, Graham J Burton, Tereza Cindrova-Davies, Norah M E Fogarty, Carolyn J P Jones, John Kingdom, Graham J Burton
Abstract
Introduction: Premature ageing has been implicated in placental dysfunction. Senescence can be activated by oxidative stress, a key intermediary in the pathophysiology of pre-eclampsia. We examined senescence markers across normal gestation, and in pathological and post-mature pregnancies. Inducers of oxidative stress were used to mimic senescence changes in term explants.
Methods: Placental samples were collected with ethical approval and informed consent: first and second trimester samples from surgical terminations; term and pre-term controls, and early-onset pre-eclampsia samples from caesarean deliveries. Paraffin and EM blocks of post-mature placentas were from an archival collection. Term explants were subjected to hypoxia-reoxygenation (HR) or hydrogen peroxide (H2O2).
Results: p21 was increased significantly in term homogenates compared to first and second trimester samples, and was significantly higher in PE compared to term controls. Immunostaining revealed nuclear localisation of p21 and phosphorylated histone γH2AX in syncytiotrophoblast, with abundant foci in pathological and post-mature placentas. Abnormal nuclear appearances were observed in post-mature placentas. Sudan-Black-B staining demonstrated abundant lipofuscin, an aggregate of oxidised proteins, lipids and metals, in post-mature and pathological placentas. The percentage of nuclei positive for 8-hydroxy-2'-deoxy-guanosine, a marker of oxidised DNA/RNA, was increased in pathological placentas compared to age-matched controls. These changes could be mimicked by challenge with HR or H2O2.
Discussion: Senescence markers increase in normal placentas with gestational age, and are exaggerated in post-mature and pathological cases. Oxidative stress triggers equivalent changes in explants, and may precipitate senescence in vivo. The consequent pro-inflammatory senescence-associated secretory phenotype may contribute to the pathophysiology of pre-eclampsia.
Keywords: Oxidative stress; Senescence; Syncytiotrophoblast.
Copyright © 2018. Published by Elsevier Ltd.
Figures
References
- Bartek J., Bartkova J., Lukas J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene. 2007;26(56):7773–7779.
- Krishnamurthy J., Torrice C., Ramsey M.R., Kovalev G.I., Al-Regaiey K., Su L., Sharpless N.E. Ink4a/Arf expression is a biomarker of aging. JCI (J. Clin. Investig.) 2004;114(9):1299–1307.
- Wang C., Jurk D., Maddick M., Nelson G., Martin-Ruiz C., von Zglinicki T. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell. 2009;8(3):311–323.
- Minamino T., Komuro I. Vascular cell senescence: contribution to atherosclerosis. Circ. Res. 2007;100(1):15–26.
- Bhat R., Crowe E.P., Bitto A., Moh M., Katsetos C.D., Garcia F.U., Johnson F.B., Trojanowski J.Q., Sell C., Torres C. Astrocyte senescence as a component of Alzheimer's disease. PLoS One. 2012;7(9)
- Chuprin A., Gal H., Biron-Shental T., Biran A., Amiel A., Rozenblatt S., Krizhanovsky V. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 2013;27(21):2356–2366.
- Collado M., Serrano M. Senescence in tumours: evidence from mice and humans. Nature reviews. 2010;10(1):51–57.
- van Deursen J.M. The role of senescent cells in ageing. Nature. 2014;509(7501):439–446.
- Narita M., Narita M., Krizhanovsky V., Nunez S., Chicas A., Hearn S.A., Myers M.P., Lowe S.W. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell. 2006;126(3):503–514.
- Zhang R., Chen W., Adams P.D. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol. Cell Biol. 2007;27(6):2343–2358.
- Rodier F., Coppe J.P., Patil C.K., Hoeijmakers W.A., Munoz D.P., Raza S.R., Freund A., Campeau E., Davalos A.R., Campisi J. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 2009;11(8):973–979.
- Coppe J.P., Patil C.K., Rodier F., Sun Y., Munoz D.P., Goldstein J., Nelson P.S., Desprez P.Y., Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology. 2008;6(12):2853–2868.
- Passos J.F., Nelson G., Wang C., Richter T., Simillion C., Proctor C.J., Miwa S., Olijslagers S., Hallinan J., Wipat A., Saretzki G., Rudolph K.L., Kirkwood T.B., von Zglinicki T. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 2010;6:347.
- Campisi J. Cellular senescence: putting the paradoxes in perspective. Curr. Opin. Genet. Dev. 2011;21(1):107–112.
- Georgakopoulou E.A., Tsimaratou K., Evangelou K., Fernandez Marcos P.J., Zoumpourlis V., Trougakos I.P., Kletsas D., Bartek J., Serrano M., Gorgoulis V.G. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues, Aging (Albany NY) 2013;5(1):37–50.
- Dou Z., Ghosh K., Vizioli M.G., Zhu J., Sen P., Wangensteen K.J., Simithy J., Lan Y., Lin Y., Zhou Z., Capell B.C., Xu C., Xu M., Kieckhaefer J.E., Jiang T., Shoshkes-Carmel M., Tanim K., Barber G.N., Seykora J.T., Millar S.E., Kaestner K.H., Garcia B.A., Adams P.D., Berger S.L. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017;550(7676):402–406.
- Gluck S., Guey B., Gulen M.F., Wolter K., Kang T.W., Schmacke N.A., Bridgeman A., Rehwinkel J., Zender L., Ablasser A. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 2017;19(9):1061–1070.
- Martin B.J., Spicer S.S. Ultrastructural features of cellular maturation and aging in human trophoblast. J Ultrastruct Res. 1973;43(1):133–149.
- Burstein R., Frankel S., Soule S.D., Blumenthal H.T. Aging of the placenta: autoimmune theory of senescence. Am. J. Obstet. Gynecol. 1973;116(2):271–276.
- Rosso P. Placenta as an aging organ. Curr. Concepts Nutr. 1976;4:23–41.
- Maiti K., Sultana Z., Aitken R.J., Morris J., Park F., Andrew B., Riley S.C., Smith R. Evidence that fetal death is associated with placental aging. Am. J. Obstet. Gynecol. 2017;217(4):441. e1-441 e14.
- Froen J.F., Arnestad M., Frey K., Vege A., Saugstad O.D., Stray-Pedersen B. Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo, Norway, 1986-1995. Am. J. Obstet. Gynecol. 2001;184(4):694–702.
- Nohr E.A., Bech B.H., Davies M.J., Frydenberg M., Henriksen T.B., Olsen J. Prepregnancy obesity and fetal death: a study within the Danish National Birth Cohort. Obstet. Gynecol. 2005;106(2):250–259.
- Redman C.W.G., Sargent I.L. Placental debris, oxidative stress and pre-eclampsia. Placenta. 2000;21:597–602.
- Hubel C.A. Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol Med. 1999;222(3):222–235.
- Burton G.J., Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia. J. Soc. Gynecol. Invest. 2004;11:342–352.
- Brosens J.J., Pijnenborg R., Brosens I.A. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies: a review of the literature. Am. J. Obstet. Gynecol. 2002;187:1416–1423.
- Biron-Shental T., Sukenik-Halevy R., Sharon Y., Goldberg-Bittman L., Kidron D., Fejgin M.D., Amiel A. Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction. Am. J. Obstet. Gynecol. 2010;202(4):e1–7. 381.
- Londero A.P., Orsaria M., Marzinotto S., Grassi T., Fruscalzo A., Calcagno A., Bertozzi S., Nardini N., Stella E., Lelle R.J., Driul L., Tell G., Mariuzzi L. Placental aging and oxidation damage in a tissue micro-array model: an immunohistochemistry study. Histochem. Cell Biol. 2016;146(2):191–204.
- C. Jones, PhD Thesis, (1976).
- Lu L., Kingdom J., Burton G.J., Cindrova-Davies T. Placental stem villus arterial remodeling associated with reduced hydrogen sulfide synthesis contributes to human fetal growth restriction. Am. J. Pathol. 2017;187(4):908–920.
- Cindrova-Davies T., Herrera E.A., Niu Y., Kingdom J., Giussani D.A., Burton G.J. Reduced cystathionine gamma-lyase and increased miR-21 expression are associated with increased vascular resistance in growth-restricted pregnancies: hydrogen sulfide as a placental vasodilator. Am. J. Pathol. 2013;182(4):1448–1458.
- Lausman A., McCarthy F.P., Walker M., Kingdom J. Screening, diagnosis, and management of intrauterine growth restriction. J. Obstet. Gynaecol. Can. 2012;34(1):17–28.
- Cindrova-Davies T., Spasic-Boskovic O., Jauniaux E., Charnock-Jones D.S., Burton G.J. Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins. Am. J. Pathol. 2007;170(5):1511–1520.
- Romero-Calvo I., Ocon B., Martinez-Moya P., Suarez M.D., Zarzuelo A., Martinez-Augustin O., de Medina F.S. Reversible Ponceau staining as a loading control alternative to actin in Western blots. Anal. Biochem. 2010;401(2):318–320.
- Cindrova-Davies T., Yung H.W., Johns J., Spasic-Boskovic O., Korolchuk S., Jauniaux E., Burton G.J., Charnock-Jones D.S. Oxidative stress, gene expression, and protein changes induced in the human placenta during labor. Am. J. Pathol. 2007;171(4):1168–1179.
- Brosens I., Pijnenborg R., Vercruysse L., Romero R. The "Great Obstetrical Syndromes" are associated with disorders of deep placentation. Am. J. Obstet. Gynecol. 2011;204(3):193–201.
- Redman C.W., Sacks G.P., Sargent I.L. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am. J. Obstet. Gynecol. 1999;180(2 Pt 1):499–506.
- Cindrova-Davies T., van Patot M.T., Gardner L., Jauniaux E., Burton G.J., Charnock-Jones D.S. Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development. Mol. Hum. Reprod. 2015;21(3):296–308.
- Hung T.-H., Skepper J.N., Charnock-Jones D.S., Burton G.J. Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ. Res. 2002;28:1274–1281.
Source: PubMed