Genome amplification and cellular senescence are hallmarks of human placenta development
Philipp VelickyGudrun MeinhardtKerstin PlesslSigrid VondraTamara WeissPeter HaslingerThomas LendlKarin AumayrMario MairhoferXiaowei ZhuBirgit SchützRoberta L. HannibalRobert LindauBeatrix WeilJan ErnerudhJürgen NeesenGerda EggerMario MikulaClemens RöhrlAlexander E. UrbanJulie C. BakerMartin KnöflerJürgen Pollheimer
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Abstract:
Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human placenta development. During pregnancy, placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo. This process is critically dependent on continuous cell proliferation and differentiation, which is thought to follow the classical model of cell cycle arrest prior to terminal differentiation. Strikingly, flow cytometry and DNAseq revealed that EVT formation is accompanied with a genome-wide polyploidization, independent of mitotic cycles. DNA replication in these cells was analysed by a fluorescent cell-cycle indicator reporter system, cell cycle marker expression and EdU incorporation. Upon invasion into the decidua, EVTs widely lose their replicative potential and enter a senescent state characterized by high senescence-associated (SA) β-galactosidase activity, induction of a SA secretory phenotype as well as typical metabolic alterations. Furthermore, we show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma. Senescence is decreased in CHM-EVTs, accompanied by exacerbated endoreduplication and hyperploidy. We propose induction of cellular senescence as a ploidy-limiting mechanism during normal human placentation and unravel a link between excessive polyploidization and reduced senescence in CHM.Keywords:
Senescence
Endoreduplication
Decidua
Placentation
Placentation
Decidua
Decidualization
Trophoblast
Notch proteins
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Abstract The placenta regulates maternal-fetal communication, and its defect leads to significant pregnancy complications. The maternal and embryonic circulations are primitively connected in early placentation, but the function of the placenta during this developmentally essential period is relatively unknown. We thus performed a comparative proteomic analysis of the placenta before and after primary placentation and found that the metabolism and transport of lipids were characteristically activated in this period. The placental fatty acid (FA) carriers in specific placental compartments were upregulated according to gestational age, and metabolomic analysis also showed that the placental transport of FAs increased in a time-dependent manner. Further analysis of two mutant mice models with embryonic lethality revealed that lipid-related signatures could reflect the functional state of the placenta. Our findings highlight the importance of the nutrient transport function of the primary placenta in the early gestational period and the role of lipids in embryonic development. Summary Sentence The placenta is activated characteristically in terms of lipid transport during primary placentation, and the lipid-related signatures closely reflect the functional state of the placenta.
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Trophoblast
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Placenta mediates the transfer of nutrients, oxygen and drugs from mother to fetus. It is constituted by two cellular layers separated by the intervillous space: the outer is in direct contact with maternal blood (decidua placenta), and the inner (villi) directly in contact with the fetus. Environmental contaminants, such as per- and polyfluoroalkyl substances (PFAS) also demonstrated the ability to cross the tissue multiple layers, posing at risk the health of the fetus. The aim of the present study was to analyse the PFAS amount in decidua and villi placenta explants and to study differences in their distribution among the two side of this organ. The determination of 23 PFAS was carried out by liquid chromatography coupled to high-resolution accurate mass spectrometry (LC-HRAM). Our research included women who delivered at term between 2021 and 2022. Our data indicated that all samples contained at least one PFAS, demonstrating the ubiquitarian presence of these compounds in our population. A high occurrence of PFOS, PFOA and PFHxS, followed by PFHxA, PFBS and PFUnA was found. The fluorotelomer 6:2 FTS was also present in more than 40% of samples and this represent the first data on placenta explants. Mean and median PFAS values for decidual explants were 0.5 ng/g and 0.4 ng/g (SD 0.3), while for villi explants mean and median values were 0.6 ng/g and 0.4 ng/g (SD 0.4). A different pattern of accumulation was observed between villi and decidual explants for PFOS, PFOA and PFUnA (villi > decidua) and PFHxA, PFHxS, PFBS and 6:2 FTS (decidua > villi). Even if the mechanism of this selectively accumuation is not yet understood, molecular degree of ionization and its lipophilicity could at least in part explain this difference. This study expands the limited data describing PFAS levels in the placenta and pose attention on PFAS exposure during pregnancy.
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Intervillous space
Chorionic villi
Decidual cells
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Introduction. Complications of pregnancy, which cause high perinatal morbidity and mortality, are accompanied by pathological changes in the placenta, namely, placental dysfunction (PD). 50.7% of PD are diagnosed in pregnant women with a low‐lying placenta (LLP). Aim. Тo study the pathomorphological parameters of placental dysfunction against the background of low placentation. Morphological and histometric features of the placenta from pregnant women with placental dysfunction (PD) against a background of low placental location were studied. The conducted studies show that the formation of placental dysfunction in pregnant women with a low location of the placenta is due to the violation of the physiological mechanisms of the formation of the feto-placental system in the first and second trimesters of gestation, as evidenced by: the predominance of the placenta of oval and anomalous forms (pleated, waist, with additional lobules ); the domination of the eccentric type of attachment of the umbilical cord and the main and intermediate types of branching of vessels. The manifestation of a positive type of compensatory-adaptive reactions at the organ level was a reduction in the thickness of the placenta in combination with an increase in the area of its maternal surface. A negative type of reaction in women with PD on a background of low placentation is a decrease in the volume of the placenta. At the tissue level in placentas from women with PD on a background of low placentation, compensatory-adaptive reactions were diagnosed in 70% of cases: a high percentage of terminal villi (69.4%), terminal villi with SCM (62.3%) and syncytial knots formation (29.5%), increased vascularization of villi (29.5%). In 25% of cases the degree of compensatory-adaptive reactions was significantly lower than in the control. Conclusions. In pregnant women with abnormal placentation, it is advisable to prevent the development of placental dysfunction from early gestation.
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Placentation
Placental insufficiency
Trophoblast
Human placenta
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During pregnancy the viviparous vertebrates develop a complex system of nutritional membranes surrounding the fetus. In place of the union or apposition of the fetal membranes with the uterine lining is formed the placenta. The placental types may be categorized into several complementary levels that reflect placental characteristics, being the swine placenta classified as chorioallantoic, diffuse, pleated, epitheliochorial and cross to counter-current. Structures, as the yolk sac, have function even before the appearance of the chorioallantoic placenta. The areola is also an accessory structure of the placenta, which may be found in ungulates. The extraembryonic membranes are linked intimately in the placentation, and these are important in swine early pregnancy, since the definitive placenta starts developing by the 18th day of gestation. Modifications in the swine placenta, like the presence of areolas, might have arisen as domestic species adaptions in order to supply nourishing needs during the development of concept.
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