The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Manu Vatish - One of the best experts on this subject based on the ideXlab platform.
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placental Syncytiotrophoblast derived extracellular vesicles carry active nep neprilysin and are increased in preeclampsia
Hypertension, 2019Co-Authors: Manjot Gill, Carolina Mottamejia, N Kandzija, William R Cooke, W Zhang, Ana Sofia Cerdeira, Claire C Bastie, C W G Redman, Manu VatishAbstract:NEP (neprilysin) is a widely expressed membrane-bound metalloprotease, which binds and cleaves a variety of peptides including vasodilators, natriuretics, and diuretics. Higher levels of NEP result in hypertension-a cardinal feature of the placental disease preeclampsia. Syncytiotrophoblast-derived extracellular vesicles (EVs), comprising microvesicles and exosomes, are released into the peripheral circulation in pregnancy and are postulated as a key mechanism coupling placental dysfunction and maternal phenotype in preeclampsia. We aimed to determine whether higher levels of active NEP are found in Syncytiotrophoblast-derived EVs in preeclampsia compared with normal pregnancy. Using immunostaining and Western blotting, we first demonstrated that NEP levels are greater not only in preeclampsia placental tissue but also in Syncytiotrophoblast-derived microvesicles and exosomes isolated from preeclampsia placentas ( P<0.05, n=5). We confirmed placental origin using antibody-coated magnetic beads to isolate NEP-bound vesicles, finding that they stain for placental alkaline phosphatase. NEP on Syncytiotrophoblast-derived EVs is active and inhibited by thiorphan ( P<0.01, n=3; specific inhibitor). Syncytiotrophoblast-derived microvesicles, isolated from peripheral plasma, demonstrated higher NEP expression in preeclampsia using flow cytometry ( P<0.05, n=8). We isolated plasma exosomes using size-exclusion chromatography and showed greater NEP activity in preeclampsia ( P<0.05, n=8). These findings show that the placenta releases active NEP into the maternal circulation on Syncytiotrophoblast-derived EVs, at significantly greater levels in preeclampsia. NEP has pathological roles in hypertension, heart failure, and amyloid deposition, all of which are features of preeclampsia. Circulating Syncytiotrophoblast-derived EV-bound NEP thus may contribute to the pathogenesis of this disease.
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Placental Syncytiotrophoblast-Derived Extracellular Vesicles Carry Active NEP (Neprilysin) and Are Increased in Preeclampsia.
Hypertension (Dallas Tex. : 1979), 2019Co-Authors: Manjot Gill, N Kandzija, William R Cooke, W Zhang, Ana Sofia Cerdeira, Claire C Bastie, Christopher W.g. Redman, Carolina Motta-mejia, Manu VatishAbstract:NEP (neprilysin) is a widely expressed membrane-bound metalloprotease, which binds and cleaves a variety of peptides including vasodilators, natriuretics, and diuretics. Higher levels of NEP result in hypertension-a cardinal feature of the placental disease preeclampsia. Syncytiotrophoblast-derived extracellular vesicles (EVs), comprising microvesicles and exosomes, are released into the peripheral circulation in pregnancy and are postulated as a key mechanism coupling placental dysfunction and maternal phenotype in preeclampsia. We aimed to determine whether higher levels of active NEP are found in Syncytiotrophoblast-derived EVs in preeclampsia compared with normal pregnancy. Using immunostaining and Western blotting, we first demonstrated that NEP levels are greater not only in preeclampsia placental tissue but also in Syncytiotrophoblast-derived microvesicles and exosomes isolated from preeclampsia placentas ( P
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Syncytiotrophoblast extracellular vesicles - Circulating biopsies reflecting placental health.
Placenta, 2016Co-Authors: Dionne S. Tannetta, Manu Vatish, Gavin P. Collett, Christopher W.g. Redman, Ian L. SargentAbstract:The ability to directly monitor the status of the placenta throughout pregnancy would be a major advance in both general and personalized obstetric care, allowing treatments to be tailored to the dynamic changes that can occur in gestation. Syncytiotrophoblast extracellular vesicles (STBEV) are membrane bound vesicles, released from the surface of the placenta directly into the maternal circulation, in the form of exosomes, microvesicles and apoptotic bodies. They carry many Syncytiotrophoblast derived factors such as proteins, lipids, glycans and nucleic acids, which together could dynamically signal to the mother the status of the placenta. We review STBEV research and discuss the potential for STBEV to be used as circulating Syncytiotrophoblast biopsies, accessible via a simple blood sample throughout pregnancy, giving a real-time readout of Syncytiotrophoblast health. We also highlight advances in the use of extracellular vesicles as circulating tumour derived biopsies in the field of cancer research, which could prove beneficial to obstetric care.
Marijke M. Faas - One of the best experts on this subject based on the ideXlab platform.
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Immune-modulatory effects of Syncytiotrophoblast extracellular vesicles in pregnancy and preeclampsia
Placenta, 2017Co-Authors: Claudia Göhner, Torsten Plösch, Marijke M. FaasAbstract:Unique immunologic adaptations exist to successfully establish and maintain pregnancy and to avoid an immune attack against the semi allogenic fetus. These adaptations occur both locally at the maternofetal interface and in the peripheral circulation and affect the innate as well as the adaptive immune system. Pregnancy is characterized by a general inflammatory state with activation of monocytes and granulocytes, but also with suppressive lymphocytes (regulatory T cells), and skewing towards T helper 2 immunity. The pregnancy complication preeclampsia is associated with an exaggerated inflammatory state and predominance of T helper 1 and 17 immunity. The Syncytiotrophoblast has been found to secrete extracellular vesicles as communication factors into the maternal circulation. Syncytiotrophoblast extracellular vesicles from normal pregnancy have been shown to interact with monocytes, granulocytes, T cells and natural killer cells and influence the function of these cells. In doing so, they may support the inflammatory state of normal pregnancy as well as the suppressive lymphocyte phenotype. During preeclampsia, Syncytiotrophoblast extracellular vesicles are not only increased in numbers but also showed an altered molecular load. Based on data from in vitro studies, it can be suggested that Syncytiotrophoblast extracellular vesicles from preeclamptic pregnancies may support the exaggerated inflammatory state during preeclampsia. In this review, we discuss the immunological functions of Syncytiotrophoblast extracellular vesicles and their involvement in adapting the maternal peripheral immunological adaptations to pregnancy.
Takeshi Maruo - One of the best experts on this subject based on the ideXlab platform.
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increased apoptosis in the Syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation
American Journal of Obstetrics and Gynecology, 2002Co-Authors: Naonori Ishihara, Hiroya Matsuo, Homare Murakoshi, Jovelle B Laoagfernandez, Takashi Samoto, Takeshi MaruoAbstract:OBJECTIVE: This study was undertaken to determine whether preeclampsia and intrauterine growth retardation are associated with an increase in placental apoptosis. STUDY DESIGN: Tissue specimens from 7 normal term placentas and each of 7 term placentas complicated by severe preeclampsia or intrauterine growth retardation were analyzed. Fas antigen and Bcl-2 protein expression were examined by the avidin/biotin immunoperoxidase method, whereas apoptosis was assessed by the terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling (TUNEL) method and transmission electron microscopy. RESULTS: Fas antigen was immunolocalized in Syncytiotrophoblasts in all placentas examined. No changes in the intensity of Fas antigen immunostaining in Syncytiotrophoblasts were apparent among those placentas. Bcl-2 protein was abundantly immunolocalized in Syncytiotrophoblasts in normal term placentas, but least abundant in term placentas complicated by severe preeclampsia or intrauterine growth retardation. Apoptosis was apparent in the nuclei of both cytotrophoblasts and Syncytiotrophoblasts. The apoptosis positive rate of Syncytiotrophoblast nuclei in severe preeclamptic and intrauterine growth retardation term placentas was significantly higher than that in normal term placentas (severe preeclampsia, P <.001; intrauterine growth retardation, P <.01). Transmission electron microscopy revealed the appearance of apoptotic nuclei in trophoblasts in severe preeclamptic term placenta. CONCLUSION: Decreased expression of Bcl-2 protein in Syncytiotrophoblasts in severe preeclamptic and intrauterine growth retardation placentas may result in the increase in apoptosis in Syncytiotrophoblasts in those placentas.
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increased apoptosis in the Syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation
American Journal of Obstetrics and Gynecology, 2002Co-Authors: Naonori Ishihara, Hiroya Matsuo, Homare Murakoshi, Jovelle B Laoagfernandez, Takashi Samoto, Takeshi MaruoAbstract:Abstract Objective: This study was undertaken to determine whether preeclampsia and intrauterine growth retardation are associated with an increase in placental apoptosis. Study Design: Tissue specimens from 7 normal term placentas and each of 7 term placentas complicated by severe preeclampsia or intrauterine growth retardation were analyzed. Fas antigen and Bcl-2 protein expression were examined by the avidin/biotin immunoperoxidase method, whereas apoptosis was assessed by the terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling (TUNEL) method and transmission electron microscopy. Results: Fas antigen was immunolocalized in Syncytiotrophoblasts in all placentas examined. No changes in the intensity of Fas antigen immunostaining in Syncytiotrophoblasts were apparent among those placentas. Bcl-2 protein was abundantly immunolocalized in Syncytiotrophoblasts in normal term placentas, but least abundant in term placentas complicated by severe preeclampsia or intrauterine growth retardation. Apoptosis was apparent in the nuclei of both cytotrophoblasts and Syncytiotrophoblasts. The apoptosis positive rate of Syncytiotrophoblast nuclei in severe preeclamptic and intrauterine growth retardation term placentas was significantly higher than that in normal term placentas (severe preeclampsia, P P Conclusion: Decreased expression of Bcl-2 protein in Syncytiotrophoblasts in severe preeclamptic and intrauterine growth retardation placentas may result in the increase in apoptosis in Syncytiotrophoblasts in those placentas.(Am J Obstet Gynecol 2002;186:158-66.)
Lawrence W. Chamley - One of the best experts on this subject based on the ideXlab platform.
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Upregulation of pannexin-1 hemichannels explains the apparent death of the Syncytiotrophoblast during human placental explant culture.
Placenta, 2020Co-Authors: Xirong Xiao, Qi Chen, Yunhui Tang, Yvette Wooff, Matt Kang, Simon J. O'carroll, Lawrence W. ChamleyAbstract:Abstract Background It has been reported that during the culture of human placental explants, the Syncytiotrophoblast dies between 3 and 24 h and is then replaced within 48 h by a new Syncytiotrophoblast layer formed by the fusion of underlying cytotrophoblasts. Most frequently the death of the Syncytiotrophoblast is indicated by the uptake of nuclear stains such as propidium iodide (PI). This process is reportedly similar in both early and late gestation placental explants. Methods We cultured first trimester placental explants for up to 48 h and tested membrane intactness by exposure to PI. Connexin and pannexin mRNAs were quantified by RT-PCR and protein levels determined by immunofluorescence. The Syncytiotrophoblast membrane leak was determined by culturing explants in the presence of hemichannel blockers. Extrusion of extracellular vesicles from the Syncytiotrophoblast was quantified. Results Nuclei of the Syncytiotrophoblast were stained with PI following approximately 4 h of culture and this was prevented by culturing the explants with pannexin-1 blockers. Expression of pannexin-1 hemichannels increased during explant culture (p = 0.0027). Extracellular vesicles were most abundantly extruded from the explants during the first 3 h of culture and the temporal pattern of extrusion was unaltered by blocking hemichannels. Discussion We show the mechanism of uptake of nuclear non-viability stains into the Syncytiotrophoblast during explant culture is via upregulation of pannexin 1 hemichannels. Contrary to suggestions by some, the production of extracellular vesicles from cultured placental explants is not an in vitro artefact resulting from the apparent death of the Syncytiotrophoblast in explant cultures.
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Antiphospholipid antibodies bind Syncytiotrophoblast mitochondria and alter the proteome of extruded syncytial nuclear aggregates.
Placenta, 2015Co-Authors: Priyadarshini Pantham, Chez A. Viall, Qi Chen, Torsten Kleffmann, Cristin G. Print, Lawrence W. ChamleyAbstract:Abstract Introduction Antiphospholipid antibodies (aPL) are autoantibodies that increase the risk of women developing the hypertensive disorder pre-eclampsia. aPL are internalised by the Syncytiotrophoblast and increase extrusion of necrotic multinucleated syncytial nuclear aggregates (SNAs), which may trigger endothelial dysfunction in pre-eclampsia. The mechanisms by which aPL alter death processes in the Syncytiotrophoblast leading to extrusion of SNAs are unknown. Methods First trimester human placentae (n = 10) were dissected into explants and cultured either with aPL (50 μg/mL), isotype-matched control antibody (50 μg/mL), or media for 24 h. Harvested SNAs underwent iTRAQ proteomic analysis. Mitochondria in Syncytiotrophoblast treated with aPL labelled with FluoroNanogold were visualised using transmission electron microscopy (TEM). Results: aPL altered the expression of 72 proteins in SNAs. Thirteen proteins were involved in mitochondrial function. TEM demonstrated that aPL bind to mitochondria in the Syncytiotrophoblast and may cause mitochondrial swelling. Discussion aPL disrupt mitochondria increasing the extrusion of SNAs with an altered proteome from the Syncytiotrophoblast. These altered SNAs may trigger endothelial dysfunction and pre-eclampsia in these pregnancies.
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Antiphospholipid antibodies internalised by human Syncytiotrophoblast cause aberrant cell death and the release of necrotic trophoblast debris.
Journal of autoimmunity, 2013Co-Authors: Chez A. Viall, Peter Stone, Qi Chen, B Liu, Anthony J. R. Hickey, Saul Snowise, Jane E. Salmon, Lawrence W. ChamleyAbstract:Antiphospholipid antibodies (aPL) are the strongest maternal risk factor for pre-eclampsia, a hypertensive disease of human pregnancy. Pre-eclampsia is triggered by a toxic factor released from the placenta that activates the maternal endothelium. Antiphospholipid antibodies cause the release of necrotic trophoblast debris from the placental Syncytiotrophoblast and this debris can activate endothelial cells. In this study, we investigated how aPL affects Syncytiotrophoblast death and production of necrotic trophoblast debris by examining the interaction between aPL and human first trimester placental explants. Human polyclonal and murine monoclonal aPL, but not control antibodies, were rapidly internalised by the Syncytiotrophoblast. Inhibitors of endocytosis or the low-density lipoprotein receptor (LDLR) family, but not toll-like receptors, decreased the internalisation of aPL and prevented the release of necrotic trophoblast debris from the Syncytiotrophoblast. Once internalised, aPL increased inner mitochondrial membrane leak and Cytochrome c release while depressing oxidative flux through Complex IV of the electron transport system in Syncytiotrophoblast mitochondria. These data suggest that the human Syncytiotrophoblast internalises aPL by antigen-dependent endocytosis involving LDLR family members. Once internalised by the Syncytiotrophoblast, aPL affects the death-regulating mitochondria, causing extrusion of necrotic trophoblast debris which can activate maternal endothelial cells thereby contributing to the pathogenesis of pre-eclampsia.
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Cytotrophoblast differentiation in the first trimester of pregnancy: evidence for separate progenitors of extravillous trophoblasts and Syncytiotrophoblast
Reproduction (Cambridge England), 2005Co-Authors: Joanna L. James, Peter Stone, Lawrence W. ChamleyAbstract:It is commonly accepted that a single pool of villous cytotrophoblasts are precursors of both Syncytiotrophoblast and extravillous trophoblasts during the first trimester. Here we present evidence that these two trophoblast subpopulations arise from separate progenitors that have different survival characteristics when studied in villous explant cultures. Dual staining with chloromethylfluorescin diacetate and ethidium bromide revealed degeneration of the Syncytiotrophoblast by non-apoptotic mechanisms within 4 h of culture. The Syncytiotrophoblast had regenerated within 48 h but at this point the vast majority of the cytotrophoblast and cells of the mesenchymal core were dead. Despite this extensive cytotrophoblast death, explants are able to produce extravillous trophoblast outgrowth for up to 3 weeks in culture. We believe that the villous cytotrophoblasts in the tips of anchoring villi are resistant to the factors that cause the death of the majority of villous cytotrophoblasts in culture. We speculate that as early as 8 weeks of gestation there are two separate villous cytotrophoblast populations, one committed to differentiate into Syncytiotrophoblast and the second committed to the extravillous differentiation pathway.
Federico Martinez - One of the best experts on this subject based on the ideXlab platform.
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Multiple functions of Syncytiotrophoblast mitochondria.
Steroids, 2015Co-Authors: Federico Martinez, Sofia Olvera-sanchez, Mercedes Esparza-perusquía, Erika Gomez-chang, Oscar Flores-herreraAbstract:The human placenta plays a central role in pregnancy, and the Syncytiotrophoblast cells are the main components of the placenta that support the relationship between the mother and fetus, in apart through the production of progesterone. In this review, the metabolic processes performed by Syncytiotrophoblast mitochondria associated with placental steroidogenesis are described. The metabolism of cholesterol, specifically how this steroid hormone precursor reaches the mitochondria, and its transformation into progesterone are reviewed. The role of nucleotides in steroidogenesis, as well as the mechanisms associated with signal transduction through protein phosphorylation and dephosphorylation of proteins is discussed. Finally, topics that require further research are identified, including the need for new techniques to study the Syncytiotrophoblast in situ using non-invasive methods.
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Atypical Cristae Morphology of Human Syncytiotrophoblast Mitochondria ROLE FOR COMPLEX V
The Journal of biological chemistry, 2011Co-Authors: Daniela De Los Rios Castillo, Federico Martinez, Mariel Zarco-zavala, Sofia Olvera-sanchez, Juan Pablo Pardo, Oscar Juárez, Guillermo Mendoza-hernández, José J. García-trejo, Oscar Flores-herreraAbstract:Mitochondrial complexes I, III2, and IV from human cytotrophoblast and Syncytiotrophoblast associate to form supercomplexes or respirasomes, with the following stoichiometries: I1:(III2)1 and I1:(III2)1–2:IV1–4. The content of respirasomes was similar in both cell types after isolating mitochondria. However, Syncytiotrophoblast mitochondria possess low levels of dimeric complex V and do not have orthodox cristae morphology. In contrast, cytotrophoblast mitochondria show normal cristae morphology and a higher content of ATP synthase dimer. Consistent with the dimerizing role of the ATPase inhibitory protein (IF1) (Garcia, J. J., Morales-Rios, E., Cortes-Hernandez, P., and Rodriguez-Zavala, J. S. (2006) Biochemistry 45, 12695–12703), higher relative amounts of IF1 were observed in cytotrophoblast when compared with Syncytiotrophoblast mitochondria. Therefore, there is a correlation between dimerization of complex V, IF1 expression, and the morphology of mitochondrial cristae in human placental mitochondria. The possible relationship between cristae architecture and the physiological function of the Syncytiotrophoblast mitochondria is discussed.
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Structural and functional changes in mitochondria associated with trophoblast differentiation: methods to isolate enriched preparations of Syncytiotrophoblast mitochondria.
Endocrinology, 1997Co-Authors: Federico Martinez, Marianthi Kiriakidou, Jerome F. StraussAbstract:The Syncytiotrophoblast of the human placenta is derived from the fusion of cytotrophoblast cells. The Syncytiotrophoblast and cytotrophoblast cells have different functional properties. Here, we document that Syncytiotrophoblast mitochondria have a distinct phenotype that differs from that of the mitochondria ofcytotrophoblast cells. Syncytiotrophoblast mitochondria are small and have a dense matrix and vesicular cristae. They contain the machinery to convert cholesterol into pregnenolone. The larger cytotrophoblast mitochondria have lamellar cristae and do not have detectable P450scc. These observations imply that trophoblast mitochondria undergo morphological and functional changes as cytotrophoblast cells differentiate into Syncytiotrophoblast. Structural changes in mitochondria and accumulation of P450scc were induced in a clonal line of BeWo choriocarcinoma cells by treatment with 8-Br-cAMP, which promotes formation of syncytial structures in these cultures. We conclude that the terminal differentiation program of trophoblast cells includes major changes in the architecture and function of mitochondria. Based on the unique features of Syncytiotrophoblast mitochondria, we developed a method to prepare highly enriched Syncytiotrophoblast mitochondria from term placenta using differential centrifugation and density gradient centrifugation.
