Preeclampsia is associated with reduced ISG15 levels impairing extravillous trophoblast invasion.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA719566 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Preeclampsia (PE), a major cause of excess maternal and perinatal morbidity and mortality, has a worldwide prevalence of 2-8%. Excess inflammation with immune maladaptation in the maternal decidua causes shallow trophoblast invasion, resulting in incomplete spiral artery transformation that are characteristic of PE. To mimic the separate and combined paracrine effects of IL-11 and IL-6 on trophoblasts in normal versus preeclamptic pregnancies, primary cytotrophoblast (CTB) cultures treated with IL-11 or IL-6 or IL-11+IL-6 were analyzed by whole genome microarray. These microarray analyses revealed that IL-11 treated CTBs displayed a total of 283 differentially expressed genes (159 of which are up-regulated and 124 are down-regulated), whereas IL-6 treated CTBs displayed a total of 243 differentially expressed genes (120 are up-regulated and 123 are down-regulated) compared control group. However, IL-11+IL-6 co-treated CTBs exhibited 276 differentially expressed genes (146 of which are up-regulated and 130 are down-regulated) compared to control group. Since IL-11 and IL-6 can compete to activate target cells through binding their shared receptor, the global transcription repertoire of CTB cultures treated with IL-11+IL-6 was compared to those treated with either IL-11 or IL-6. A total of seven genes are differentially regulated by IL-11+IL-6 co-treatment vs. treatment with IL-11 alone (four of which are up-regulated and three down-regulated), whereas compared to IL-6 alone, a total of six genes are differentially regulated by IL-6+IL-11 (all of which are down-regulated). Microarray results of this study support that co-existence of IL-6 and IL-11 impairs the global transcription repertoire of trophoblasts compared to the presence of IL-11 alone, most probably through a mechanism that partial or complete IL-6 binding to gp130 blocks IL-11 action. Importantly, ISG15 is the only commonly affected gene and is downregulated by IL-6 and IL-11 co-treatment compared to control or treatment with either IL-11 or IL-6 alone, suggesting its involvement in PE.
2021-04-04 | GSE171439 | GEO
Project description:Among several interleukin (IL)-6 family members, only IL-6 and IL-11 require a gp130 protein homodimer for intracellular signaling due to lack of intracellular signaling domain in the IL-6 receptor (IL-6R) and IL-11R. We previously reported enhanced decidual IL-6 and IL-11 levels at the maternal-fetal interface with significantly higher peri-membranous IL-6 immunostaining in adjacent interstitial trophoblasts in preeclampsia (PE) vs. gestational age (GA)-matched controls. This led us to hypothesize that competitive binding of these cytokines to the gp130 impairs extravillous trophoblast (EVT) differentiation, proliferation and/or invasion. Using global microarray analysis, the current study identified inhibition of interferon-stimulated gene 15 (ISG15) as the only gene affected by both IL-6 plus IL-11 vs. control or IL-6 or IL-11 treatment of primary human cytotrophoblast cultures. ISG15 immunostaining was specific to EVTs among other trophoblast types in the first and third trimester placental specimens, and significantly lower ISG15 levels were observed in EVT from PE vs. GA-matched control placentae (p = 0.006). Induction of primary trophoblastic stem cell cultures toward EVT linage increased ISG15 mRNA levels by 7.8-fold (p = 0.004). ISG15 silencing in HTR8/SVneo cultures, a first trimester EVT cell line, inhibited invasion, proliferation, expression of ITGB1 (a cell migration receptor) and filamentous actin while increasing expression of ITGB4 (a receptor for hemi-desmosomal adhesion). Moreover, ISG15 silencing further enhanced levels of IL-1β-induced pro-inflammatory cytokines (CXCL8, IL-6 and CCL2) in HTR8/SVneo cells. Collectively, these results indicate that ISG15 acts as a critical regulator of EVT morphology and function and that diminished ISG15 expression is associated with PE, potentially mediating reduced interstitial trophoblast invasion and enhancing local inflammation at the maternal-fetal interface. Thus, agents inducing ISG15 expression may provide a novel therapeutic approach in PE.
| S-EPMC9274133 | biostudies-literature
Project description:Preeclampsia (PE) is a hypertensive pregnancy disorder with increased risk of maternal and fetal morbidity and mortality. Abnormal extravillous trophoblast (EVT) development and function is considered to be the underlying cause of PE, but has not previously been modeled in vitro. We previously derived induced pluripotent stem cells (iPSC) from placentas of PE patients and characterized abnormalities in formation of syncytiotrophoblast and responses to changes in oxygen tension. In this study, we converted these primed iPSC to naïve iPSC, then derived trophoblast stem cells (TSC) and EVT to evaluate molecular mechanisms underlying PE. We found that primed (but not naïve) iPSC-derived PE-EVT have reduced surface HLA-G, blunted invasive capacity, and altered EVT-specific gene expression. These abnormalities correlated with promotor hypermethylation of genes associated with the epithelial-mesenchymal transition pathway, specifically in primed-iPSC derived PE-EVT. Our findings indicate that abnormal epigenetic regulation might play a role in the PE pathogenesis.
2024-03-27 | GSE243579 | GEO
Project description:Comparison of genes associated with the EMT between undifferentiated cytotrophoblast cells (CTB) and differentiated extravillous trophoblast cells (EVT) from third trimester human placenta. Cells isolated from control (placenta previa) and cases (preeclampsia). Cells isolated by immunomagnetic separation using anti-integrin beta4 antibody to purify CTB and anti-HLA-G antibody to purify EVT.
2022-02-26 | GSE188313 | GEO
Project description:Placentation requires the proper regulation of extravillous trophoblast (EVT) migration and invasion into the decidua and maternal vasculature, processes which are initiated in physiologic hypoxic conditions. Abnormal EVT migration and/or invasion have been suggested to lead to pregnancy complications, such as preeclampsia. The objectives of this study are to determine how exposure to hypoxia impacts gene expression and cellular motility of first trimester trophoblasts, and to assess if expression of migration-associated genes is dysregulated in 2nd trimester chorionic villous samples (CVS) from preeclampsia pregnancies relative to CVS from healthy pregnancies. The 1st trimester trophoblast cell line, HTR8/SVneo, was used to investigate the relationship between hypoxia and Notch signaling in trophoblast migration and invasion. RNA sequencing and quantitative RT-PCR analyses show that exposure to hypoxia (2.5% O2) activates Notch signaling in HTR-8/SVneo. We demonstrate that exposure of HTR-8/SVneo to hypoxia induces expression of genes associated with cellular migration and invasion and increases HTR-8/SVneo cellular migration and invasion, whereas inhibition of gamma-secretase decreases Notch signaling and decreases HTR-8/SVneo migration and invasion. Analysis of RNA sequencing data from CVS of preeclampsia and uncomplicated pregnancies identified significant differentially expressed genes that are involved in cellular migration and invasion. Decreased expression of migration and invasion genes in CVS from preeclampsia pregnancies, may impair trophoblast migration and invasion in the 2nd trimester of pregnancy, resulting in the development of preeclampsia.
2021-08-05 | GSE155750 | GEO
Project description:Uterine Natural Killer (uNK) cells regulate essential developmental processes at the maternal-fetal interface during early pregnancy. Uterine NK cell functions are tightly regulated during early placentation to stimulate trophoblast invasion and remodel uterine spiral arteries. Access to human 1st and 2nd trimester uterine tissues allowed us to investigate the transcriptional changes in uNK cells during the early stages of early human pregnancy. Microarray analysis identified 97 upregulated genes in 2nd compared to 1st trimester purified uNK cells of which the majority (61%) clustered as interferon-stimulated-genes (ISG), with ISG15 and ISG20 being upregulated profoundly. Type I interferons (IFNα/β), but not type II interferon (IFNɣ) increased expression of the identified interferon target genes ISG15 and ISG20 in uNK cells in vitro. Moreover, the cytokine-like protein ISG15 stimulated in vitro trophoblast invasion. Second trimester uNK cells promoted trophoblast invasion in vitro, whereas both 1st and 2nd trimester uNK cells stimulated endothelial tube formation. IFNα but not IFNβ stimulation of 1st trimester uNK cells enhanced their capacity to promote trophoblast invasion. In conclusion, the uNK cell interferon transcriptome is upregulated during the 2nd trimester allowing uNK cells to promote trophoblast invasion. Type I interferon signaling regulates uNK cell-induced trophoblast invasion via induction of effector molecules like ISG15. First trimester uNK cells can be induced to act like second trimester uNK cells by IFNα with respect to promotion of trophoblast invasion. Key words: Gene expression profiling ■ uterine natural killer cells ■ extravillous trophoblast invasion ■ interferon alpha ■ ISG15
2020-01-30 | GSE64898 | GEO
Project description:Preeclampsia (PE) is a hypertensive pregnancy disorder with increased risk of maternal and fetal morbidity and mortality. Abnormal extravillous trophoblast (EVT) development and function is considered to be the underlying cause of PE, but has not been previously modeled in vitro. We previously derived induced pluripotent stem cells (iPSCs) from placentas of PE patients and characterized abnormalities in formation of syncytiotrophoblast and responses to changes in oxygen tension. In this study, we converted these primed iPSC to naïve iPSC, and then derived trophoblast stem cells (TSCs) and EVT to evaluate molecular mechanisms underlying PE. We found that primed (but not naïve) iPSC-derived PE-EVT have reduced surface HLA-G, blunted invasive capacity, and altered EVT-specific gene expression. These abnormalities correlated with promoter hypermethylation of genes associated with the epithelial-mesenchymal transition pathway, specifically in primed-iPSC derived PE-EVT. Our findings indicate that abnormal epigenetic regulation might play a role in PE pathogenesis.
| S-EPMC11016801 | biostudies-literature
Project description:Decidual spiral arteriole (SpA) remodelling is essential to ensure optimal uteroplacental blood flow during human pregnancy. Decidual uterine natural killer cells and macrophages infiltrate the SpA and are proposed to initiate remodelling before colonisation by extravillous trophoblasts. Microarrays were used to measure the effect of extravillous trophoblasts conditioned medium on the transcriptome of human uterine microvascular endothelial cells.
2017-10-16 | E-MTAB-5467 | biostudies-arrayexpress
Project description:To better understand how DNA methylation influences placentation, DNA from first trimester primary trophoblast populations (side-population trophoblasts, cytotrophoblasts and extravillous trophoblasts) isolated using FACS underwent reduced representation bisulfite sequencing and were compared to publicly available data of blastocyst-derived and somatic cell populations.
2018-12-25 | GSE109682 | GEO
Project description:We assessed how lack of ISG15 influences the levels of transcripts after IFNa stimulation. Expression data from ISG15 deficient patients (P1, P2, P3) and control (C1, C6, C16) hTert fibroblasts
2014-12-01 | GSE60359 | GEO