scholarly journals Where Polarity Meets Fusion: Role of Par6 in Trophoblast Differentiation during Placental Development and Preeclampsia

Endocrinology ◽  
2013 ◽  
Vol 154 (3) ◽  
pp. 1296-1309 ◽  
Author(s):  
Tharini Sivasubramaniyam ◽  
Julia Garcia ◽  
Andrea Tagliaferro ◽  
Megan Melland-Smith ◽  
Sarah Chauvin ◽  
...  
Keyword(s):  
Tight Junction ◽  
Cell Polarity ◽  
Cell Fusion ◽  
Trophoblast Cell ◽  
Placental Development ◽  
Trophoblast Differentiation ◽  
Cytoskeleton Dynamics ◽  
Insight Into ◽  
Cells Cultured

Abstract Trophoblast cell fusion is a prerequisite for proper human placental development. Herein we examined the contribution of Par6 (Partitioning defective protein 6), a key regulator of cell polarity, to trophoblast cell fusion in human placental development. During early placentation, Par6 localized to nuclei of cytotrophoblast cells but with advancing gestation Par6 shifted its localization to the cytoplasm and apical brush border of the syncytium. Exposure of primary isolated trophoblasts to 3% O2 resulted in elevated Par6 expression, maintenance of tight junction marker ZO-1 at cell boundaries, and decreased fusogenic syncytin 1 expression compared with cells cultured at 20% O2. Treatment of choriocarcinoma BeWo cells with forskolin, a known inducer of fusion, increased syncytin 1 expression but decreased that of Par6 and ZO-1. Par6 overexpression in the presence of forskolin maintained ZO-1 at cell boundaries while decreasing syncytin 1 levels. In contrast, silencing of Par6 disrupted ZO-1 localization at cell boundaries and altered the expression and distribution of acetylated α-tubulin. Par6 expression was elevated in preeclamptic placentas relative to normotensive preterm controls and Par6 located to trophoblast cells expressing ZO-1. Together, our data indicate that Par6 negatively regulates trophoblast fusion via its roles on tight junctions and cytoskeleton dynamics and provide novel insight into the contribution of this polarity marker in altered trophoblast cell fusion typical of preeclampsia.

scholarly journals Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity

2019 ◽  
Author(s):  
Jenna Treissman ◽  
Victor Yuan ◽  
Jennet Baltayeva ◽  
Hoa T. Le ◽  
Barbara Castellana ◽  
...  
Keyword(s):  
Lysyl Oxidase ◽  
Atmospheric Oxygen ◽  
Extravillous Trophoblast ◽  
Low Oxygen ◽  
Placental Development ◽  
Trophoblast Differentiation ◽  
Expression Of Genes ◽  
Summary Statement ◽  
Insight Into

ABSTRACTEarly placental development and the establishment of the invasive trophoblast lineage take place within a low oxygen environment. However, conflicting and inconsistent findings have obscured the role of oxygen in regulating invasive trophoblast differentiation. In this study, the effect of hypoxic, normoxic, and atmospheric oxygen on invasive extravillous pathway progression was examined using a human placental explant model. Here, we show that exposure to low oxygen enhances extravillous column outgrowth and promotes the expression of genes that align with extravillous trophoblast (EVT) lineage commitment. By contrast, super-physiological atmospheric levels of oxygen promote trophoblast proliferation while simultaneously stalling EVT progression. Low oxygen-induced EVT differentiation coincided with elevated transcriptomic levels of lysyl oxidase (LOX) in trophoblast anchoring columns, where functional experiments established a role for LOX activity in promoting EVT column outgrowth. The findings of this work support a role for low oxygen in potentiating the differentiation of trophoblasts along the extravillous pathway. Additionally, these findings generate insight into new molecular processes controlled by oxygen during early placental development.Summary StatementLow oxygen promotes extravillous trophoblast differentiation

scholarly journals Involvement of nephrin in human placental trophoblast syncytialization

Reproduction ◽  
2015 ◽  
Vol 149 (4) ◽  
pp. 339-346 ◽  
Author(s):  
Yue Li ◽  
Ru Zheng ◽  
Rui Wang ◽  
Xiaoyin Lu ◽  
Cheng Zhu ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Connexin 43 ◽  
Transmembrane Protein ◽  
First Trimester ◽  
Trophoblast Cell ◽  
Term Pregnancy ◽  
Fusion Model ◽  
Placental Development ◽  
Functional Conservation ◽  
Ig Superfamily

The placenta has numerous functions, such as transporting oxygen and nutrients and building the immune tolerance of the fetus. Cell fusion is an essential process for placental development and maturation. In human placental development, mononucleated cytotrophoblast (CTB) cells can fuse to form a multinucleated syncytiotrophoblast (STB), which is the outermost layer of the placenta. Nephrin is a transmembrane protein that belongs to the Ig superfamily. Previous studies have shown that nephrin contributes to the fusion of myoblasts into myotubes in zebrafish and mice, presenting a functional conservation with its Drosophila ortholog sticks and stones. However, whether nephrin is involved in trophoblast syncytialization remains unclear. In this study, we report that nephrin was localized predominantly in the CTB cells and STB of human placenta villi from first trimester to term pregnancy. Using a spontaneous fusion model of primary CTB cells, the expression of nephrin was found to be increased during trophoblast cell fusion. Moreover, the spontaneous syncytialization and the expression of syncytin 2, connexin 43, and human chorionic gonadotropin beta were significantly inhibited by nephrin-specific siRNAs. The above results demonstrate that nephrin plays an important role in trophoblast syncytialization.

scholarly journals Effects of adiponectin on human trophoblast invasion

2010 ◽  
Vol 207 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Delphine Benaitreau ◽  
Esther Dos Santos ◽  
Marie-Christine Leneveu ◽  
Nadia Alfaidy ◽  
Jean-Jacques Feige ◽  
...  
Keyword(s):  
First Trimester ◽  
Extravillous Trophoblast ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Independent Manner ◽  
Human Trophoblast ◽  
Pathological Conditions ◽  
First Trimester Of Pregnancy ◽  
Insight Into

Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory, anti-atherogenic, and anti-proliferative effects. The expression of specific adiponectin receptors in the placenta and in the endometrium suggests a role for this cytokine in placental development, but this role has not yet been elucidated. The invasion of trophoblast cells during the first trimester of pregnancy being crucial to placentation process, we have studied adiponectin effects on human trophoblast invasive capacities. We found that adiponectin stimulated human trophoblast cell migration in HTR-8/SVneo cells in a dose-independent manner. In addition, adiponectin also significantly enhanced invasion of HTR-8/SVneo cells and of human extravillous trophoblast from first trimester placenta. These pro-invasive effects of adiponectin in human trophoblasts seem to be mediated in part via increased matrix metalloproteinases (MMP2 and MMP9) activities and via repression of TIMP2 mRNA expression. Our results suggest that adiponectin could be a positive regulator of the early invasion process by modulating the MMP/TIMP balance. Moreover, these results provide an insight into the role of adiponectin in pathological conditions characterized by insufficient or excessive trophoblast invasion.

scholarly journals PPARγ/RXRα Heterodimers Are Involved in Human CGβ Synthesis and Human Trophoblast Differentiation

Endocrinology ◽  
2001 ◽  
Vol 142 (10) ◽  
pp. 4504-4514 ◽  
Author(s):  
Anne Tarrade ◽  
Kristina Schoonjans ◽  
Jean Guibourdenche ◽  
Jean Michel Bidart ◽  
Michel Vidaud ◽  
...  
Keyword(s):  
Regulatory Region ◽  
Additive Effect ◽  
Placental Lactogen ◽  
Placental Development ◽  
Trophoblast Differentiation ◽  
Human Trophoblast ◽  
Transcript Levels ◽  
Nuclear Extracts

Abstract Recent studies performed with null mice suggested a role of either RXRα or PPARγ in murine placental development. We report here that both PPARγ and RXRα are strongly expressed in human villous cytotrophoblasts and syncytiotrophoblasts. Moreover, specific ligands for RXRs or PPARγ (but not for PPARα or PPARδ) increase both human CGβ transcript levels and the secretion of human CG and its free β-subunit. When combined, these ligands have an additive effect on human CG secretion. Pan-RXR and PPARγ ligands also have an additive effect on the synthesis of other syncytiotrophoblast hormones such as human placental lactogen, human placental GH, and leptin. Therefore, in human placenta, PPARγ/RXRα heterodimers are functional units during cytotrophoblast differentiation into the syncytiotrophoblast in vitro. Elements located in the regulatory region of the human CGβ gene (β5) were found to bind RXRα and PPARγ from human cytotrophoblast nuclear extracts, suggesting that PPARγ/RXRα heterodimers directly regulate human CGβ transcription. Altogether, these data show that PPARγ/RXRα heterodimers play an important role in human placental development.

scholarly journals Could the Human Endogenous Retrovirus-Derived Syncytialization Inhibitor, Suppressyn, Limit Heterotypic Cell Fusion Events in the Decidua?

2021 ◽  
Vol 22 (19) ◽  
pp. 10259
Author(s):  
Jun Sugimoto ◽  
Sehee Choi ◽  
Megan Sheridan ◽  
Iemasa Koh ◽  
Yoshiki Kudo ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Cell Types ◽  
Trophoblast Cell ◽  
Endogenous Retroviruses ◽  
Extravillous Trophoblast ◽  
Human Endogenous Retrovirus ◽  
Decidual Cell ◽  
Placental Development ◽  
Adverse Pregnancy ◽  
Herv Expression

Proper placental development relies on tightly regulated trophoblast differentiation and interaction with maternal cells. Human endogenous retroviruses (HERVs) play an integral role in modulating cell fusion events in the trophoblast cells of the developing placenta. Syncytin-1 (ERVW-1) and its receptor, solute-linked carrier family A member 5 (SLC1A5/ASCT2), promote fusion of cytotrophoblast (CTB) cells to generate the multi-nucleated syncytiotrophoblast (STB) layer which is in direct contact with maternal blood. Another HERV-derived protein known as Suppressyn (ERVH48-1/SUPYN) is implicated in anti-fusogenic events as it shares the common receptor with ERVW-1. Here, we explore primary tissue and publicly available datasets to determine the distribution of ERVW-1, ERVH48-1 and SLC1A5 expression at the maternal-fetal interface. While SLC1A5 is broadly expressed in placental and decidual cell types, ERVW-1 and ERVH48-1 are confined to trophoblast cell types. ERVH48-1 displays higher expression levels in CTB and extravillous trophoblast, than in STB, while ERVW-1 is generally highest in STB. We have demonstrated through gene targeting studies that suppressyn has the ability to prevent ERVW-1-induced fusion events in co-culture models of trophoblast cell/maternal endometrial cell interactions. These findings suggest that differential HERV expression is vital to control fusion and anti-fusogenic events in the placenta and consequently, any imbalance or dysregulation in HERV expression may contribute to adverse pregnancy outcomes.

scholarly journals The postmitotic midbody: Regulating polarity, stemness, and proliferation

2019 ◽  
Vol 218 (12) ◽  
pp. 3903-3911 ◽  
Author(s):  
Eric Peterman ◽  
Rytis Prekeris
Keyword(s):  
Cell Division ◽  
Cell Polarity ◽  
Final Stage ◽  
Cell Membranes ◽  
Daughter Cell ◽  
Endocytic Trafficking ◽  
Microtubule Severing ◽  
Daughter Cells ◽  
Cytoskeleton Dynamics

Abscission, the final stage of cell division, requires well-orchestrated changes in endocytic trafficking, microtubule severing, actin clearance, and the physical sealing of the daughter cell membranes. These processes are highly regulated, and any missteps in localized membrane and cytoskeleton dynamics often lead to a delay or a failure in cell division. The midbody, a microtubule-rich structure that forms during cytokinesis, is a key regulator of abscission and appears to function as a signaling platform coordinating cytoskeleton and endosomal dynamics during the terminal stages of cell division. It was long thought that immediately following abscission and the conclusion of cell division, the midbody is either released or rapidly degraded by one of the daughter cells. Recently, the midbody has gained prominence for exerting postmitotic functions. In this review, we detail the role of the midbody in orchestrating abscission, as well as discuss the relatively new field of postabscission midbody biology, particularly focusing on how it may act to regulate cell polarity and its potential to regulate cell tumorigenicity or stemness.

108. FUNCTIONAL ROLE OF HtrA3 IN TROPHOBLAST CELL INVASION DURING HUMAN PLACENTAL DEVELOPMENT

2009 ◽  
Vol 21 (9) ◽  
pp. 27
Author(s):  
H. Singh ◽  
G. Nie
Keyword(s):  
Cell Invasion ◽  
Stromal Cells ◽  
Functional Role ◽  
First Trimester ◽  
Trophoblast Cell ◽  
Extravillous Trophoblast ◽  
Placental Development ◽  
Decidual Cells

Controlled invasion of extravillous trophoblast (EVT) through the maternal decidua is important for placental development and function. Serine protease HtrA3 is highly expressed in the decidual cells in the late secretory phase of the menstrual cycle and throughout pregnancy. It is highly expressed in first trimester in most trophoblast cell types, but not in the invading interstitial trophoblast. HtrA3 and its family members are down-regulated in a number of cancers and are proposed as tumor-suppressors. We hypothesized that HtrA3 is an inhibitor of trophoblast invasion and is down-regulated in invading EVTs, while up-regulation of decidual HtrA3 controls the process. The current study investigated HtrA3 expression in human endometrial stromal cells (HESC) during decidualization in vitro and whether HtrA3 inhibits EVT cell invasion. Stromal cells isolated from human endometrium were decidualized in vitro with estrogen, progesterone and cAMP. Quantitative RT-PCR and western showed HtrA3 mRNA and protein expression was significantly increased in decidualized HESC compared to controls. Indirect immunofluorescence showed homogeneous pattern and increase in intensity of HtrA3 staining in decidualized HESC compared to non-decidualized cells. HTR-8 cells derived from first trimester of pregnancy EVT showed higher levels of HtrA3 mRNA expression compared to other human choriocarcinoma cell lines (AC-1M88, AC-1M32, JEG-3 and BeWo). Both intracellular and extracellular HtrA3 staining was observed in HTR8 cells. Functional role of HtrA3 in cell invasion was determined in HTR-8 cells using an in vitro invasion assay. Exogenous addition of mutant HtrA3 (inhibitor) resulted in a significant increase in HTR-8 cells invading through matrigel coated membrane compared with controls. TGFβ-1 (as positive control) completely inhibited invasion of HTR-8 cells. HtrA3 is tightly regulated during decidualization of HESC in vitro. Inhibition of HtrA3 activity in trophoblastic HTR-8 cells increased invasiveness supporting its functional role during placental development.

scholarly journals Cdc42p GDP/GTP Cycling Is Necessary for Efficient Cell Fusion during Yeast Mating

2006 ◽  
Vol 17 (6) ◽  
pp. 2824-2838 ◽  
Author(s):  
Sophie Barale ◽  
Derek McCusker ◽  
Robert A. Arkowitz
Keyword(s):  
Cell Polarity ◽  
Cell Fusion ◽  
Critical Role ◽  
Specific Cell ◽  
Yeast Saccharomyces Cerevisiae ◽  
Cytoskeleton Organization ◽  
Ring Assembly ◽  
Yeast Mating ◽  
Fusion Defect

The highly conserved small Rho G-protein, Cdc42p plays a critical role in cell polarity and cytoskeleton organization in all eukaryotes. In the yeast Saccharomyces cerevisiae, Cdc42p is important for cell polarity establishment, septin ring assembly, and pheromone-dependent MAP-kinase signaling during the yeast mating process. In this study, we further investigated the role of Cdc42p in the mating process by screening for specific mating defective cdc42 alleles. We have identified and characterized novel mating defective cdc42 alleles that are unaffected in vegetative cell polarity. Replacement of the Cdc42p Val36 residue with Met resulted in a specific cell fusion defect. This cdc42[V36M] mutant responded to mating pheromone but was defective in cell fusion and in localization of the cell fusion protein Fus1p, similar to a previously isolated cdc24 (cdc24-m6) mutant. Overexpression of a fast cycling Cdc42p mutant suppressed the cdc24-m6 fusion defect and conversely, overexpression of Cdc24p suppressed the cdc42[V36M] fusion defect. Taken together, our results indicate that Cdc42p GDP–GTP cycling is critical for efficient cell fusion.

Plasminogen Activation In Vivo upon Intravenous Infusion of DDAVP

1992 ◽  
Vol 67 (01) ◽  
pp. 111-116 ◽  
Author(s):  
Marcel Levi ◽  
Jan Paul de Boer ◽  
Dorina Roem ◽  
Jan Wouter ten Cate ◽  
C Erik Hack
Keyword(s):  
Monoclonal Antibodies ◽  
Plasminogen Activator ◽  
Plasma Levels ◽  
Fold Increase ◽  
Fibrinolytic System ◽  
Plasminogen Activation ◽  
Plasminogen Activator Activity ◽  
Insight Into

SummaryInfusion of desamino-d-arginine vasopressin (DDAVP) results in an increase in plasma plasminogen activator activity. Whether this increase results in the generation of plasmin in vivo has never been established.A novel sensitive radioimmunoassay (RIA) for the measurement of the complex between plasmin and its main inhibitor α2 antiplasmin (PAP complex) was developed using monoclonal antibodies preferentially reacting with complexed and inactivated α2-antiplasmin and monoclonal antibodies against plasmin. The assay was validated in healthy volunteers and in patients with an activated fibrinolytic system.Infusion of DDAVP in a randomized placebo controlled crossover study resulted in all volunteers in a 6.6-fold increase in PAP complex, which was maximal between 15 and 30 min after the start of the infusion. Hereafter, plasma levels of PAP complex decreased with an apparent half-life of disappearance of about 120 min. Infusion of DDAVP did not induce generation of thrombin, as measured by plasma levels of prothrombin fragment F1+2 and thrombin-antithrombin III (TAT) complex.We conclude that the increase in plasminogen activator activity upon the infusion of DDAVP results in the in vivo generation of plasmin, in the absence of coagulation activation. Studying the DDAVP induced increase in PAP complex of patients with thromboembolic disease and a defective plasminogen activator response upon DDAVP may provide more insight into the role of the fibrinolytic system in the pathogenesis of thrombosis.

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