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Placental Accreta Spectrum: Upregulated Cytotrophoblast DOCK4 Contributes to Over Invasion

ABSTRACT: In humans, a subset of placental cytotrophoblasts (CTBs) invades the uterus and its vasculature, anchoring the pregnancy and ensuring adequate blood flow to the fetus. Appropriate depth is critical. Shallow invasion increases the risk of pregnancy complications, e.g., severe preeclampsia. Overly deep invasion, the hallmark of placenta accreta spectrum (PAS), increases the risk of pre-term delivery, hemorrhage and death. Previously a rare condition, the incidence of PAS has increased to 1:731 pregnancies, likely due to the rise in uterine surgeries (e.g., Cesarean sections). CTBs track along the scars deep into the myometrium and beyond. Here we compared the global gene expression patterns of CTBs from PAS cases to gestational age-matched control cells that invaded to the normal depth from preterm birth (PTB) deliveries. The mRNA encoding the guanine nucleotide exchange factor, DOCK4, mutations of which promote cancer cell invasion and angiogenesis, was the most highly differentially expressed molecule in PAS samples. Over-expression of DOCK4 increased CTB invasiveness, consistent with the PAS phenotype. Also, this analysis identified other genes with significantly altered expression in this disorder, potential biomarkers. These data suggest that CTBs from PAS cases up regulate a cancer-like pro-invasion mechanism, suggesting molecular as well as phenotypic similarities in the two pathologies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136048 | GEO | 2019/09/30

REPOSITORIES: GEO

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Placental Accreta Spectrum: Upregulated Cytotrophoblast DOCK4 Contributes to Over Invasion

Project description:Placental Accreta Spectrum: Upregulated Cytotrophoblast DOCK4 Contributes to Over Invasion

| PRJNA561109 | ENA

Placenta accreta spectrum disorder at single cell resolution: a loss of boundary limits in the uterine endothelium and decidua.

Project description:Objective: The objective of this study is to utilize advances in single-cell RNAsequencing to characterize cellular heterogeneity and transcriptomic signatures of PAS. Our findings can elucidate mechanisms of abnormal placental invasion and identify targets for potential diagnostic and therapeutic biomarkers of PAS. Results: Placental samples from PAS participants and non-PAS cesarean births were included. In total, we analyzed 31,406 individual cells expressing an average of 1,493 genes. Clustering analysis of gene expression identified multiple populations of cells representing syncytiotrophoblasts, cytotrophoblasts, extravillous trophoblasts, decidua,endothelial cells, myeloid, natural killer, and lymphoid cells. When analyzed by disease phenotype, AI showed a unique gene signature most prominently in the endothelial population. The highest expression in AI compared to AO and C was seen in the following genes: DLK1, EGFL6, HGF, APOLD1, and EDNRB. Gene set enrichment analysis of AI endothelial cells identified the following key pathways: blood vessel development, response to growth factors and hormones, regulation of cell adhesion and migration, and pathways in cancer. Conclusions: We present a comprehensive single-cell atlas of PAS across the site of invasion and site of non-adherence. By integrating expression from individual genes per cell, we identified endothelial cells as a key subpopulation in invasive accreta, with expression of genes involved in multiple angiogenic, growth, and mechanical-signaling pathways. After validation, these gene targets may be used to refine diagnostic assays for placenta accreta in early gestation, track disease progression over time, and inform Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation therapeutic discoveries.

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Culturing Cytotrophoblasts Reverses Gene Dysregulation in Preeclampsia Revealing Possible Causes

Project description:During human pregnancy, a subset of placental cytotrophoblasts (CTBs) differentiates into cells that aggressively invade the uterus and its vasculature, anchoring the progeny and rerouting maternal blood to the placenta. In preeclampsia (PE), CTB invasion is limited, reducing placental perfusion and/or creating intermittent flow. This syndrome, affecting 4-8% of pregnancies, entails maternal vascular alterations (e.g., high blood pressure, proteinuria, and edema) ± fetal growth restriction. The only cure is removal of the faulty placenta, i.e., delivery. Previously we showed that defective CTB differentiation contributes to the placental component of PE, but the causes were unknown. Here, CTBs isolated from PE and control placentas were cultured for 48 h, enabling differentiation/invasion. In various severe forms of PE, transcriptomics revealed common aberrations in CTB gene expression immediately after isolation that resolved in culture. The upregulated genes included SEMA3B. Adding this protein to normal CTBs inhibited invasion and re-created aspects of the phenotype of these cells in PE. Additionally, SEMA3B downregulated VEGF signaling through the PI3K/AKT and GSK3 pathways, effects that were observed in PE CTBs. We propose that, in severe PE, the in vivo environment dysregulates CTB gene expression, the autocrine actions of the upregulated molecules, including SEMA3B, impair differentiation/invasion/signaling and patient-specific factors determine the signs.

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Project description:Placenta accreta is a major cause of maternal morbidity and mortality in modern obstetrics. The study aims to identify the differently expressed lncRNA and mRNA in placenta accreta patients compared with controls and to determine biological pathways, which provides a novel insight ingto thepathogenesis of placneta accreta.

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Project description:To find potential biomarkers and molecular mechanism for placenta accreta spectrum disorders , we identified the differently expressed patterns of lncRNAs and mRNAs in invasive placneta and adherent normal placenta tissues. The results provided a novel insight into the pathogenesis of placenta accreta spectrum disorders .

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Discovery of diagnostic biomarker and molecular mechanisms of placenta accreta spectrum

Project description:Transcriptome analysis of FFPE placenta of placenta accreta spectrum, over increta. Pre-diagnosis is essential to safely deal with placenta accrete spectrum, but definitive diagnostic markers have not yet been established. We conducted a transcriptome analysis of FFPE placenta to establish early diagnostic markers for placenta accreta.

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Project description:We aim to elucidate regulatory miRNA and target networks contributing to Placenta accreta spectrum development using smallRNA-Seq.

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Severe Preeclampsia is Associated with Alterations in Cytotrophoblasts of the Smooth Chorion

Project description:Preeclampsia (PE), which affects ~8% of first pregnancies, is associated with faulty placentation. Extravillous cytotrophoblasts (CTBs) fail to differentiate properly, contributing to shallow uterine invasion and deficient spiral artery remodeling. We studied the effects of severe PE (sPE) on the smooth chorion portion of the fetal membranes. The results showed a significant expansion of the CTB layer. The cells displayed enhanced expression of stage-specific antigens that extravillous CTBs normally up regulate as they exit the placenta. Transcriptomics revealed the dysregulated expression of many genes (e.g., placental proteins, markers of oxidative stress). We confirmed a sPE-related increase in production of PAPPA1, which releases IGF-1 from its binding protein. IGF1 enhanced proliferation of smooth chorion CTBs (schCTB), a possible explanation for expansion of this layer, which may partially compensate for the placental deficits.

2016-12-10 | GSE91189 | GEO

Genome-Scale Profiling of DNA Methylation in Sporadic Pituitary Macroadenomas: Association with Tumor Invasion and Histopathological Subtype

Project description:The pathophysiologic mechanisms driving tumorigenesis and invasion of sporadic pituitary macroadenomas (PAs) remain unknown. We hypothesized that alterations in DNA methylation are associated with PA invasion and histopathology subtype, and that genome-scale methylation analysis may complement current classification methods for sporadic PAs. Twenty-four surgically-resected sporadic PAs with varying histopathological subtypes were assigned dichotomized Knosp invasion scores and examined using genome-wide DNA methylation patterns and RNA sequencing.

2014-01-28 | E-GEOD-54415 | biostudies-arrayexpress

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