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 MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation

2018 ◽  
Vol 50 (1) ◽  
pp. 10-19 ◽  
Author(s):  
Lucy Li ◽  
Lewis P. Rubin ◽  
Xiaoming Gong
Keyword(s):  
Transcription Factors ◽  
Human Placenta ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Dominant Negative ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Cytotrophoblast Cell ◽  
Adverse Pregnancy

Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders.

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 Human endogenous retrovirus-W envelope (syncytin) is expressed in both villous and extravillous trophoblast populations

2006 ◽  
Vol 87 (7) ◽  
pp. 2067-2071 ◽  
Author(s):  
A. Muir ◽  
A. M. L. Lever ◽  
A. Moffett
Keyword(s):  
Cell Lines ◽  
First Trimester ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Extravillous Trophoblast ◽  
Human Endogenous Retrovirus ◽  
Human Trophoblast ◽  
Human Endogenous Retroviruses ◽  
Normal Tissues ◽  
Villous Trophoblast

The placenta is unique amongst normal tissues in transcribing numerous different human endogenous retroviruses at high levels. In this study, RT-PCR and immunohistochemistry were used to investigate the expression of syncytin in human trophoblast. Syncytin transcripts were found in first-trimester trophoblast cells with both villous and extravillous phenotypes and also in the JAR and JEG-3 choriocarcinoma cell lines. Syncytin protein was detected in villous trophoblast and in all extravillous trophoblast subpopulations of first- and second-trimester placental tissues. It was also present in ectopic trophoblast from tubal implantations. This study confirms that syncytin is expressed widely by a variety of normal human trophoblast populations, as well as choriocarcinoma cell lines.

Abstract 27: Unravelling Cell-specific Interactions At The Preeclamptic Maternal-foetal Interface From Early To Late Pregnancy

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Olivia Nonn ◽  
Olivia Debnath ◽  
Daniela S Valdes ◽  
Cornelius Fischer ◽  
Kerim Secener ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Communication ◽  
Late Pregnancy ◽  
Cell Types ◽  
Decidual Cell ◽  
Placental Development ◽  
Communication Analysis ◽  
Trophoblast Stem Cells ◽  
Late Control ◽  
D Cell

Preeclamptic syndrome arrises in the fetal part of the placenta (villi). In this study, we analyse placental development by single nuclei RNA-sequencing in early and term pregnancy and draw conclusions about pathological processes in preeclampsia (PE) that originate early in gestation. We profiled the transcriptome of 101,067 nuclei obtained from a total of 12 pregnancies, spanning early, term and PE doners. Using unsupervised computational approaches, we identified 12 and 16 different cell types and states in decidua and villi, respectively. Our comprehensively identified catalogue of cell types and states aligns well with the previous single cell studies. We identified different subpopulations of syncytiotrophoblast and GATA3+/GREM2+ trophoblast stem cells (TSC) in villi. Through gestation, gene expression in cell populations from the matrisome or vascular environments show dynamic expression reflecting vascular development associated with spiral artery remodelling and concordant decidual stroma reorganisation. Global differential gene expression analysis shows that trophoblast cell types are most dysregulated in PE. Cell-cell communication analysis revealed important dysregulation between villi and decidual cell types. The secretory signalling characteristic of this trophoblastic disease may be used for early biomarker screening. Overall, this study paves the way to a deeper understanding of the early pathophysiology of PE. Figure 1: Villi (v) and decidua (d) cell clusters from early, late control and preeclampsia (PE) villi and decidua visualised as a UMAP. Datasets were integrated separately for each tissue and merged for embedding.

315. HOMEOBOX GENES ARE DIFFERENTIALLY EXPRESSED IN PRIMARY VILLOUS AND EXTRAVILLOUS TROPHOBLAST CELL LINEAGES DURING EARLY PREGNANCY

2010 ◽  
Vol 22 (9) ◽  
pp. 115
Author(s):  
P. Murthi ◽  
N. A. Pathirage ◽  
R. Keogh ◽  
M. Cocquebert ◽  
N. Segond ◽  
...  
Keyword(s):  
Gene Expression ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Trophoblast Cell ◽  
Differentially Expressed ◽  
Extravillous Trophoblast ◽  
Mrna Levels ◽  
Placental Development ◽  
Cell Lineages

During human placental development trophoblast cells differentiate along either the villous cytotrophoblast (VCT) lineage to form the syncytiotrophoblast (ST) or the invasive extravillous cytotrophoblast (EVCT) lineage (1). Abnormalities in early differentiation processes are characteristic of poor placentation, which is associated with fetal growth restriction (FGR) and pre-eclampsia (PE), the major clinical complications of human pregnancy (2). A large family of homeobox gene transcription factors controls “cell-fate decisions” during development (3), but the expression profile and role of homeobox genes in the human trophoblast cell lineages is not well understood. The aim of the study was to determine homeobox gene expression in primary cultures of mononuclear VCT (2h) and EVCT (2 h) obtained from first trimester human chorionic villi of 8–12 weeks of gestation and in vitro differentiated ST (72 h) and invasive EVCT (48 h), respectively. The isolation and characterization of freshly isolated VCT, EVCT and in vitro differentiated ST and invasive EVCT were performed as described previously (1,4). The homeobox gene mRNA profile was performed using PCR arrays in a pooled sample of VCT and EVCT (n = 6 in each group) and further validated by real-time PCR. Homeobox gene expression studies revealed MSX2 mRNA levels were the highest in VCT (2 h) but undetectable in EVCT (2 h). Further comparisons of homeobox gene expression in in vitro differentiated ST to invasive EVCT showed marked increase in MSX2, DLX3, DLX4 and MEIS1 mRNA levels in ST, which are regulators of cellular differentiation in many studies. Homeobox genes HLX and HHEX, which are implicated in regulating cellular proliferation showed decreased mRNA levels in ST compared to invasive EVCT. Our results demonstrated several known placental and novel homeobox genes are differentially expressed in trophoblast cell lineages. Functional studies of these candidate genes will provide a better understanding of the molecular mechanisms of early placental development. (1) Tarrade et al. (2001) Lab Invest. 81, 1199–1211.(2) LokeYW and King A (1995) Cell Biology and Immunology, Cambridge ed.(3) J Cross et al. (2002) Recent Progress in Hormone Research 57: 221–234.(4) Handschuh et al. (2007) Placenta, 28, 175–184.

scholarly journals TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

2020 ◽  
Vol 6 (19) ◽  
pp. eaba0310 ◽  
Author(s):  
Yang Zhang ◽  
Trieu Le ◽  
Ryan Grabau ◽  
Zahra Mohseni ◽  
Hoejeong Kim ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Fusion ◽  
Cell Types ◽  
Placental Development ◽  
Cellular Mechanisms ◽  
Phospholipid Scramblase ◽  
Perinatal Lethality ◽  
Cell Type Specific ◽  
Multicellular Organisms ◽  
Cell Cell

Cell-cell fusion or syncytialization is fundamental to the reproduction, development, and homeostasis of multicellular organisms. In addition to various cell type–specific fusogenic proteins, cell surface externalization of phosphatidylserine (PS), a universal eat-me signal in apoptotic cells, has been observed in different cell fusion events. Nevertheless, the molecular underpinnings of PS externalization and cellular mechanisms of PS-facilitated cell-cell fusion are unclear. Here, we report that TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), plays an essential role in placental trophoblast fusion by translocating PS to cell surface independent of apoptosis. The placentas from the TMEM16F knockout mice exhibit deficiency in trophoblast syncytialization and placental development, which lead to perinatal lethality. We thus identified a new biological function of TMEM16F CaPLSase in trophoblast fusion and placental development. Our findings provide insight into understanding cell-cell fusion mechanism of other cell types and on mitigating pregnancy complications such as miscarriage, intrauterine growth restriction, and preeclampsia.

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 GCMa Regulates the Syncytin-mediated Trophoblastic Fusion

2002 ◽  
Vol 277 (51) ◽  
pp. 50062-50068 ◽  
Author(s):  
Chenchou Yu ◽  
Kuofeng Shen ◽  
Meiyao Lin ◽  
Porchun Chen ◽  
Chenchen Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Family Member ◽  
Cell Fusion ◽  
Hela Cells ◽  
Binding Sites ◽  
Integration Site ◽  
Human Endogenous Retrovirus ◽  
Placental Development ◽  
Fusion Event ◽  
Syncytiotrophoblast Layer

The human placental trophoblast cell can be classified as either a cytotrophoblast or a syncytiotrophoblast. Cytotrophoblasts can function as stem cells for the development of the syncytiotrophoblast layer via cell fusion. Anenvelopegene of the human endogenous retrovirus family W (HERV-W) calledsyncytinis specifically expressed in the syncytiotrophoblast layer. Syncytin is a fusogenic membrane protein; therefore, it can mediate the fusion of cytotrophoblasts into the syncytiotrophoblast layer, which is essential for pregnancy maintenance. GCMa is a placenta-specific transcription factor and is required for placental development. To study the placenta-specific fusion mediated by syncytin, we tested whether GCMa is involved in this process by regulatingsyncytingene expression. In this report, we demonstrate that GCMa was able to regulatesyncytingene expression via two GCMa-binding sites upstream of the 5′-long terminal repeat of thesyncytin-harboring HERV-W family member in BeWo and JEG3 cells but not in HeLa cells. Furthermore, adenovirus-directed expression of GCMa enhancedsyncytingene expression and syncytin-mediated cell fusion in BeWo and JEG3 cells but not in HeLa cells. Therefore, the integration site of thesyncytin-harboring HERV-W family member in the human genome is close to the functional GCMa-binding sites by which GCMa can specifically transactivatesyncytingene expression in trophoblast cells. Our results may help to explain the mechanism underlying the cell fusion event specific for syncytiotrophoblast formation.

PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development

2015 ◽  
Vol 309 (4) ◽  
pp. E357-E369 ◽  
Author(s):  
Vanessa Garnier ◽  
Wael Traboulsi ◽  
Aude Salomon ◽  
Sophie Brouillet ◽  
Thierry Fournier ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Trophoblast Cell ◽  
Extravillous Trophoblast ◽  
Trophoblast Invasion ◽  
Migration And Invasion ◽  
Placental Development ◽  
Human Trophoblast ◽  
Pparγ Agonist

PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used: 1) in vitro, using human primary isolated cytotrophoblasts and the extravillous trophoblast cell line (HTR-8/SVneo); 2) ex vivo, using human placental explants ( n = 46 placentas); and 3) in vivo, using gravid wild-type PPARγ+/− and PPARγ−/− mice. Major processes of placental development that are known to be controlled by PPARγ, such as trophoblast proliferation, migration, and invasion, were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. In both human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγ agonist, 1) increased EG-VEGF secretion, 2) increased EG-VEGF and its receptors mRNA and protein expression, 3) increased placental vascularization via PROKR1 and PROKR2, and 4) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ−/− mouse placentas, EG-VEGF levels were significantly decreased, supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγ effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion.

scholarly journals Human Endogenous Retrovirus Expression Is Associated with Head and Neck Cancer and Differential Survival

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 956 ◽  
Author(s):  
Allison R. Kolbe ◽  
Matthew L. Bendall ◽  
Alexander T. Pearson ◽  
Doru Paul ◽  
Douglas F. Nixon ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Normal Tissue ◽  
Endogenous Retroviruses ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Human Endogenous Retrovirus ◽  
Adjacent Normal Tissue ◽  
Herv Expression

Human endogenous retroviruses (HERVs) have been implicated in a variety of human diseases including cancers. However, technical challenges in analyzing HERV sequence data have limited locus-specific characterization of HERV expression. Here, we use the software Telescope (developed to identify expressed transposable elements from metatranscriptomic data) on 43 paired tumor and adjacent normal tissue samples from The Cancer Genome Atlas Program to produce the first locus-specific retrotranscriptome of head and neck cancer. Telescope identified over 3000 expressed HERVs in tumor and adjacent normal tissue, and 1078 HERVs were differentially expressed between the two tissue types. The majority of differentially expressed HERVs were expressed at a higher level in tumor tissue. Differentially expressed HERVs were enriched in members of the HERVH family. Hierarchical clustering based on HERV expression in tumor-adjacent normal tissue resulted in two distinct clusters with significantly different survival probability. Together, these results highlight the importance of future work on the role of HERVs across a range of cancers.

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