Manifold roles of CCR7 chemokine GPCR in human trophoblast differentiation
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PROVIDER: PRJNA1151661 | ENA |
REPOSITORIES: ENA
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Project description:Manifold roles of CCR7 chemokine GPCR in human trophoblast differentiation
| PRJNA1146339 | ENA
Project description:CCR7 chemokine G protein-coupled receptor is expressed in extraembryonic tissues of the early human embryo, including trophectoderm and its derivatives cytotrophoblast (CTB), extravillous trophoblast (EVT), and syncytiotrophoblast (STB). However, its function in placental development remains poorly explored. Here, we generated human embryonic stem cells harboring CCR7 deletions and differentiated them into human trophoblast stem cell (hTSC) and hTSC-derived trophoblast organoids. We found that CCR7 mutant EVTs retained hTSC-like characteristics, exhibited decreased epithelial-to-mesenchymal transition, and reduced cell motility. Additionally, CCL21-CCR7 induced EVT terminal differentiation into endovascular EVT-like cells. Transcriptional profiling in CCR7 KO STBs identified reduced viral defense gene expression related to the protection against maternal-fetal transmission. Investigation of trophoblast organoids using single cell transcriptome profiling showed that CCR7 mutant trophoblast organoids comprised a smaller EVT population, but a larger STB population, compared to wild type organoids, while CellChat analysis indicated altered cell-cell communication including WNT, ACTIVIN, and IFN-I signaling pathways. Mechanistically, we found that CCR7 limited the cell-cell fusion of early STB differentiation by reducing cAMP levels. Together, our studies demonstrate that CCR7 plays multiple roles in cellular decision-making during trophoblast differentiation, promoting EVT differentiation, and limiting cell-cell fusion during early STB differentiation.
2025-08-31 | GSE275552 | GEO
Project description:CCR7 chemokine G protein-coupled receptor is expressed in extraembryonic tissues of the early human embryo, including trophectoderm and its derivatives cytotrophoblast (CTB), extravillous trophoblast (EVT), and syncytiotrophoblast (STB). However, its function in placental development remains poorly explored. Here, we generated human embryonic stem cells harboring CCR7 deletions and differentiated them into human trophoblast stem cell (hTSC) and hTSC-derived trophoblast organoids. We found that CCR7 mutant EVTs retained hTSC-like characteristics, exhibited decreased epithelial-to-mesenchymal transition, and reduced cell motility. Additionally, CCL21-CCR7 induced EVT terminal differentiation into endovascular EVT-like cells. Transcriptional profiling in CCR7 KO STBs identified reduced viral defense gene expression related to the protection against maternal-fetal transmission. Investigation of trophoblast organoids using single cell transcriptome profiling showed that CCR7 mutant trophoblast organoids comprised a smaller EVT population, but a larger STB population, compared to wild type organoids, while CellChat analysis indicated altered cell-cell communication including WNT, ACTIVIN, and IFN-I signaling pathways. Mechanistically, we found that CCR7 limited the cell-cell fusion of early STB differentiation by reducing cAMP levels. Together, our studies demonstrate that CCR7 plays multiple roles in cellular decision-making during trophoblast differentiation, promoting EVT differentiation, and limiting cell-cell fusion during early STB differentiation.
2025-09-02 | GSE274397 | GEO
Project description:Chemokine receptors are GPCRs that regulate chemotactic migration of a wide variety of cells including immune and cancer cells. Most chemokine receptors harbor molecular properties, which are associated with an ability to stimulate G proteins during b-arrestin-mediated internalization into endosomes. As endosomal signaling of certain non-GPCR receptors plays major roles in cell migration, we here investigated the potential role of endosomal chemokine receptor signaling on mechanisms governing this function. Applying cell biological approaches and spatiotemporal-resolved proteome profiling, we demonstrate that the model chemokine receptor CCR7 upon chemokine stimulation recruits G protein and b-arrestin simultaneously enabling internalized receptors to activate G protein from endosomes. Furthermore, endosomal CCR7 uniquely enriches specific Rho-GTPase regulators as compared to plasma membrane CCR7, which correlates with the activity of Rho-GTPase Rac1. As Rac1 drives the formation of membrane protrusions during chemotaxis, our findings suggest an important integrated function of endosomal chemokine receptor signaling in this physiological event.
| MSV000090362 | MassIVE
Project description:Endothelial cell and vascular smooth muscle cell were cocultured in hanging droplets to form spheroids representing an inverted vessel lumen. Control or conditioned media from an extravillous trophoblast (EVT) cell line was incubated with vascular spheroids for 24 hours. Spheroid RNA was then analyzed by Illumina Sentrix BeadChip array. Spheroids incubated with EVT conditioned medium showed significant up/downregulation of 101 genes (>1.5-fold; P<0.05), including an upregulation of C-X-C motif chemokine 10 (IP-10). C-X-C motif chemokine 10 expression was confirmed by qualitative real-time PCR and Western blot analysis of spheroids, and immunohistochemistry of first trimester decidua and ex vivo dissected nonplacental bed spiral arteries. EVT conditioned medium reduced VSMC expression of differentiation markers, and both EVT conditioned medium and C-X-C motif chemokine 10 increased motility of VSMC indicating dedifferentiation of VSMC.
2013-02-17 | E-MTAB-1462 | biostudies-arrayexpress
Project description:In order to characterize pathogen specific T cell responses against Salmonella volunteers challenged with Salmonella enterica serovar Typhi (S. Typhi) or Salmonella Paratyphi A (S. Paratyphi). we used mass cytometry, to identify effector CD4+ T cells circulating during infection. We identified a population of CCR7-CD38+ cells accumulating during infection, and via unbiased single cell cloning and expansion we demonstrated that these CCR7-CD38+ cells are enriched in Salmonella specific T cells. In this experiment we performed TCR repertoire analysis of CCR7-CD38+ and CCR7-CD38- cells to determine the clonality of CCR7-CD38+ cells, the overlap between the repertoire of CCR7-CD38+ cells and of non-activated effector CCR7-CD38- cells, and to identify within CCR7-CD38+ and CCR7-CD38- cells the presence of the CDR3b TCR sequence of the pathogen specific T cell clones isolated from CCR7-CD38+ cells
2018-05-13 | GSE113112 | GEO
Project description:Saturation mutagenesis reveals manifold determinants of exon definition
| PRJNA415408 | ENA
Project description:Inflammatory monocytes (iMO) migrate from the bone marrow to the brain during viral encephalitis. For many viruses, including Herpes simplex virus type-1 (HSV), iMO recruitment is dependent on the chemokine receptor CCR2. However, La Crosse virus (LACV) induces iMO recruitment independent of CCR2. Comparison of iMOs from HSV and LACV-infected mice showed higher expression of the g protein-coupled receptor CCR7 in LACV-induced iMOs. CCR2/CCR7 double knockout mice (DKO) had reduced iMO recruitment following LACV infection compared to CCR2 or CCR7 single knockout mice indicating that each receptor regulated iMO recruitment through complimentary roles. Thus, CCR7 is a novel, synergistic pathway to CCR2-induced iMO recruitment during virus infection. Interestingly, unlike HSV-recruited iMOs, LACV-recruited iMOs did not influence disease and had higher expression of proinflammatory and proapoptotic transcripts but reduced mitotic, phagocytic and phagolysosomal pathway transcripts. These findings indicate that virus-specific activation of iMOs may affect their survival, maturation and functional capabilities.
2024-03-18 | GSE254432 | GEO
Project description:We investigated the transcriptional profile of B cells isolated from peripheral lymph nodes of CCR7-/-C57BL/6 and C57BL/6 mice respectively. B cells were sorted as follows: CD19+, CD3-, CD11c-, CD11b-, NK1.1-, GR-1-. Very few genes were differentially regulated in CCR7-/- B cells, however the expression of a number of genes associated with B-cell activation was increased in CCR7-/- B cells compared to WT B cells. Our data suggest a role of CCR7 signaling in B-cell activation processes. 12 purified RNA samples (6 samples of each genotype), originated from 12 individually facs-sorted cell samples, were used for the microarray study. 3 RNA samples per genotype were pooled, giving rise to 2 wildtype- and 2 Ccr7 knock-out pools. In each of the 2 dual-color microarray hybridizations, samples from 1 wildtype and 1 Ccr7 knock-out pool were cohybridized. Microarray hybridizations 1 and 2 were performed in a dye-swap approach.
2011-11-21 | E-GEOD-27885 | biostudies-arrayexpress
Project description:Chemokine receptors (CKRs), a class of G protein-coupled receptors (GPCRs), interact with transducers like G proteins and β-arrestins. Many chemokines act as “biased agonists” that activate certain transducers over others. There has been limited success in pharmacologically targeting CKRs, with little evidence that differential receptor phosphorylation, or “phosphorylation barcodes,” direct biased responses. Here, we used mass spectrometry to demonstrate that CXCR3 chemokines generate different phosphorylation barcodes associated with differential activation of transducers. Chemokine stimulation resulted in distinct changes throughout the kinome in global phosphoproteomic studies. Mutation of CXCR3 phosphosites altered β-arrestin conformation and activation in molecular dynamics simulations. T-cells expressing phosphorylation-deficient CXCR3 mutants resulted in agonist- and receptor-specific chemotactic profiles not completely explained by engagement of G proteins and β-arrestins. Our results demonstrate that CXCR3 chemokines act as biased agonists through differential encoding of phosphorylation barcodes, and highlight the limitations of assessing GPCR physiology with proximal effector activity alone.
2023-05-24 | PXD034033 | JPOST Repository