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      Placenta-Specific Genes, Their Regulation During Villous Trophoblast Differentiation and Dysregulation in Preterm Preeclampsia

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          Abstract

          The human placenta maintains pregnancy and supports the developing fetus by providing nutrition, gas-waste exchange, hormonal regulation, and an immunological barrier from the maternal immune system. The villous syncytiotrophoblast carries most of these functions and provides the interface between the maternal and fetal circulatory systems. The syncytiotrophoblast is generated by the biochemical and morphological differentiation of underlying cytotrophoblast progenitor cells. The dysfunction of the villous trophoblast development is implicated in placenta-mediated pregnancy complications. Herein, we describe gene modules and clusters involved in the dynamic differentiation of villous cytotrophoblasts into the syncytiotrophoblast. During this process, the immune defense functions are first established, followed by structural and metabolic changes, and then by peptide hormone synthesis. We describe key transcription regulatory molecules that regulate gene modules involved in placental functions. Based on transcriptomic evidence, we infer how villous trophoblast differentiation and functions are dysregulated in preterm preeclampsia, a life-threatening placenta-mediated obstetrical syndrome for the mother and fetus. In the conclusion, we uncover the blueprint for villous trophoblast development and its impairment in preterm preeclampsia, which may aid in the future development of non-invasive biomarkers for placental functions and early identification of women at risk for preterm preeclampsia as well as other placenta-mediated pregnancy complications.

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          Pre-eclampsia: pathophysiology and clinical implications

          Pre-eclampsia is a common disorder that particularly affects first pregnancies. The clinical presentation is highly variable but hypertension and proteinuria are usually seen. These systemic signs arise from soluble factors released from the placenta as a result of a response to stress of syncytiotrophoblast. There are two sub-types: early and late onset pre-eclampsia, with others almost certainly yet to be identified. Early onset pre-eclampsia arises owing to defective placentation, whilst late onset pre-eclampsia may center around interactions between normal senescence of the placenta and a maternal genetic predisposition to cardiovascular and metabolic disease. The causes, placental and maternal, vary among individuals. Recent research has focused on placental-uterine interactions in early pregnancy. The aim now is to translate these findings into new ways to predict, prevent, and treat pre-eclampsia.
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            Pre-eclampsia part 1: current understanding of its pathophysiology.

            Pre-eclampsia is characterized by new-onset hypertension and proteinuria at ≥20 weeks of gestation. In the absence of proteinuria, hypertension together with evidence of systemic disease (such as thrombocytopenia or elevated levels of liver transaminases) is required for diagnosis. This multisystemic disorder targets several organs, including the kidneys, liver and brain, and is a leading cause of maternal and perinatal morbidity and mortality. Glomeruloendotheliosis is considered to be a characteristic lesion of pre-eclampsia, but can also occur in healthy pregnant women. The placenta has an essential role in development of this disorder. Pathogenetic mechanisms implicated in pre-eclampsia include defective deep placentation, oxidative and endoplasmic reticulum stress, autoantibodies to type-1 angiotensin II receptor, platelet and thrombin activation, intravascular inflammation, endothelial dysfunction and the presence of an antiangiogenic state, among which an imbalance of angiogenesis has emerged as one of the most important factors. However, this imbalance is not specific to pre-eclampsia, as it also occurs in intrauterine growth restriction, fetal death, spontaneous preterm labour and maternal floor infarction (massive perivillous fibrin deposition). The severity and timing of the angiogenic imbalance, together with maternal susceptibility, might determine the clinical presentation of pre-eclampsia. This Review discusses the diagnosis, classification, clinical manifestations and putative pathogenetic mechanisms of pre-eclampsia.
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              Placental Origins of Chronic Disease.

              Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, for organ systems are at their most plastic when progenitor cells are proliferating and differentiating. Influences operating at this time can permanently affect their structure and functional capacity, and the activity of enzyme systems and endocrine axes. It is now appreciated that such effects lay the foundations for a diverse array of diseases that become manifest many years later, often in response to secondary environmental stressors. Fetal development is underpinned by the placenta, the organ that forms the interface between the fetus and its mother. All nutrients and oxygen reaching the fetus must pass through this organ. The placenta also has major endocrine functions, orchestrating maternal adaptations to pregnancy and mobilizing resources for fetal use. In addition, it acts as a selective barrier, creating a protective milieu by minimizing exposure of the fetus to maternal hormones, such as glucocorticoids, xenobiotics, pathogens, and parasites. The placenta shows a remarkable capacity to adapt to adverse environmental cues and lessen their impact on the fetus. However, if placental function is impaired, or its capacity to adapt is exceeded, then fetal development may be compromised. Here, we explore the complex relationships between the placental phenotype and developmental programming of chronic disease in the offspring. Ensuring optimal placentation offers a new approach to the prevention of disorders such as cardiovascular disease, diabetes, and obesity, which are reaching epidemic proportions.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                17 January 2020
                January 2020
                : 21
                : 2
                : 628
                Affiliations
                [1 ]Systems Biology of Reproduction Lendulet Group, Institute of Enzymology, Research Centre for Natural Sciences, H-1117 Budapest, Hungary; szilagyi.andras@ 123456ttk.hu (A.S.); gelzsolt@ 123456gmail.com (Z.G.); peter0kiraly@ 123456gmail.com (P.K.); ammdemeter@ 123456gmail.com (A.D.); palhalmi@ 123456gmail.com (J.P.); ho12ember@ 123456gmail.com (K.J.)
                [2 ]Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD 20692, and Detroit, MI 48201, USA; romeror@ 123456mail.nih.gov (R.R.); yxu@ 123456med.wayne.edu (Y.X.); erezof@ 123456bgu.ac.il (O.E.); atarca@ 123456med.wayne.edu (A.L.T.)
                [3 ]Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA
                [4 ]Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI 48824, USA
                [5 ]Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
                [6 ]Detroit Medical Center, Detroit, MI 48201, USA
                [7 ]Department of Obstetrics and Gynecology, Florida International University, Miami, FL 33199, USA
                [8 ]Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA
                [9 ]Laboratory of Proteomics, Institute of Biology, Eotvos Lorand University, H-1117 Budapest, Hungary; gyorffy.balazs88@ 123456gmail.com (B.A.G.); kakekesi@ 123456ttk.elte.hu (K.A.K.)
                [10 ]Maternity Private Clinic of Obstetrics and Gynecology, H-1126 Budapest, Hungary; hupuczi.petronella@ 123456maternity.hu (P.H.); pzorvosihetilap@ 123456maternity.hu (Z.P.)
                [11 ]Department of Physiology and Neurobiology, Eotvos Lorand University, H-1117 Budapest, Hungary
                [12 ]Department of Obstetrics and Gynecology, Reproductive Biology Unit, Medical University of Vienna, Vienna A-1090, Austria; gudrun.meinhardt@ 123456meduniwien.ac.at (G.M.); martin.knoefler@ 123456meduniwien.ac.at (M.K.)
                [13 ]Department of Obstetrics and Gynecology, Semmelweis University, H-1088 Budapest, Hungary
                [14 ]Department of Computer Science, Wayne State University College of Engineering, Detroit, MI 48202, USA; sorin@ 123456wayne.edu
                [15 ]Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel
                [16 ]1st Department of Pathology and Experimental Cancer Research, Semmelweis University, H-1085 Budapest, Hungary
                Author notes
                [* ]Correspondence: than.gabor@ 123456ttk.hu ; Tel.: +36-1-382-6788
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-1773-6861
                https://orcid.org/0000-0002-4448-5121
                https://orcid.org/0000-0003-0239-021X
                https://orcid.org/0000-0003-0654-0641
                https://orcid.org/0000-0002-1267-7364
                https://orcid.org/0000-0003-3042-4878
                https://orcid.org/0000-0002-8115-8867
                https://orcid.org/0000-0002-0786-8377
                https://orcid.org/0000-0002-2213-8129
                https://orcid.org/0000-0003-1712-7588
                https://orcid.org/0000-0001-6625-8950
                https://orcid.org/0000-0001-9385-7019
                Article
                ijms-21-00628
                10.3390/ijms21020628
                7013556
                31963593
                4473b9ca-a398-4126-b48f-0d449abb2be0
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 December 2019
                : 08 January 2020
                Categories
                Article

                Molecular biology
                development,immune tolerance,metabolism,microarray,omics,transcriptional network
                Molecular biology
                development, immune tolerance, metabolism, microarray, omics, transcriptional network

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