CXCL10 promotes vascular permeability upon TNF-induced release from pericytes
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ABSTRACT:
PROVIDER: PRJNA841060 | ENA |
REPOSITORIES: ENA
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Project description:Tumor necrosis factor alpha induces vascular permeability, playing an important role in inflammation. Also, TNF-induced vascular leakage is involved in the increased extravasation of nanoparticle formulated chemotherapeutics improving drug delivery and subsequently tumor response, and we found a positive correlation between the presence of pericytes in the tumor-associated vasculature and TNF-induced leakage. RNA sequencing and pathway analysis of TNF-stimulated versus non-stimulated pericytes and endothelial cells show significant upregulation of several pathways involving interferon regulating pathways with a high expression of CXCL10, also known as Interferon gamma-inducible protein 10 (IP-10) in TNF-stimulated pericytes. In addition, CXCL10 protein production was significantly increased in conditioned medium from TNF-exposed pericytes compared to the other conditions. In our animal studies, we observed that tumor types with high pericyte covered vessels show enhanced permeability when exposed to TNF, which can be blocked with a neutralizing CXCL10 antibody. Vice versa, tumors with vessels low in pericyte number do not respond to TNF, i.e., do not express elevated permeability. Importantly, this lack of pericyte coverage can be compensated by co-administration of CXCL10. Our finding reveals a mechanism where TNF induces CXCL10 release from pericytes, being at the basis of increased permeability and thus vascular leakage.
2022-07-01 | GSE203505 | GEO
Project description:Despite the prevalence of pericytes amongst the microvasculature of the heart, the role of pericytes during ischemia-induced remodeling remains unclear. Using chondroitin sulfate proteoglycan 4 (Cspg4) lineage mouse reporters we observed pericytes migrating to the site of injury, expressing pro-fibrotic genes, and causing increased vessel leakage after myocardial infarction. Single cell RNA-sequencing of injured cardiac pericytes exhibited increased expression of genes related to vascular permeability, extracellular matrix production, basement membrane degradation and transforming growth factor-b (TGFb) signaling. Deletion of TGFb receptor 1 in Cspg4-expressing cells improved cardiac ejection fraction and reduced fibrosis post-MI. Whereas genetic ablation of Cspg4-expressing cells resulted in a rapid decline in cardiac function and increased vascular permeability following MI. Collectively, we show that cardiac pericytes participate in the post-fibrotic response after acute ischemic injury, information that will help guide the development of novel strategies to preserve vascular integrity and attenuate cardiac fibrosis.
2023-05-10 | GSE201947 | GEO
Project description:Background: Pericytes are capillary-associated mural cells especially prominent in the central nervous system where they regulate vascular permeability and blood-brain barrier integrity. Despite their relevance for neurovascular unit homeostasis and their involvement in the pathobiology of neurodegenerative diseases, signalling mechanisms responsible for functional specialization and intercellular communication remain elusive. Objectives: The main goal of this study is to understand the relevance of Rbpj (the common downstream mediator of Notch signalling, an important mediator of cell-to-cell communication) in brain pericytes. In particular, the ChIP-Seq results aimed at the identification of genes bound to RBPJ in cultured mouse brain pericytes.
2019-05-12 | GSE120482 | GEO
Project description: Not available
| S-EPMC6363463 | biostudies-literature
Project description:This study aims to investigate differentially expressed proteins in tumor pericytes with or without TCAF2-ovexpression. Tumor pericytes were isolated from tumor of patients with colorectal cancer. Then, tumor pericytes were cultured, transfected with vector or TCAF2 overexpressing plasmid. Top ten cytokines were screened and Wnt5a was the most significant one.
2024-01-26 | PXD032935 | Pride
Project description:This study aims to investigate differentially expressed proteins in tumor pericytes derived from colorectal cancer patients with or without liver metastasis. Tumor pericytes were isolated from tumor of colorectal cancer patients with or without liver metastasis. Then, tumor pericytes were cultured and subjected to proteomic analysis. TCAF2 was significantly increased in tumor pericytes from liver metastasis patients.
2024-01-26 | PXD033011 | Pride
Project description:The objective of this array was to determine the global gene expression profile of human placental pericytes for comparison with other publicly available arrays of pericytes and mesenchymal stromal cells isolated from various human tissues. Pericytes are critical cellular components of the microvasculature that play a major role in vascular development and pathologies, yet their study has been hindered by lack of a standardized method for their isolation and growth. Here we report a method for culturing human pericytes from a readily available tissue source, placenta, and provide a thorough characterization of resultant cell populations. We developed an optimized protocol for obtaining pericytes by outgrowth from microvessel fragments recovered after enzymatic digestion of human placental tissue. We characterized outgrowth populations by immunostaining, by gene expression analysis, and by functional evaluation of cells implanted in vivo. Our approach yields human pericytes that may be serially expanded in culture and that uniformly express the cellular markers NG2, CD90, CD146, α-SMA, and PDGFR-β, but lack markers of smooth muscle cells, endothelial cells, and leukocytes. When co-implanted with human endothelial cells into C.B-17 SCID/bg mice, human pericytes invest and stabilize developing human endothelial cell-lined microvessels. We conclude that our method for culturing pericytes from human placenta results in the expansion of functional pericytes that may be used to study a variety of questions related to vascular biology. Total RNA from three different pericyte isolations at subculture 1 was collected and examined for relative gene expression.
2010-04-14 | E-GEOD-21332 | biostudies-arrayexpress
Project description:Mutations in the RMRP gene are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in the RMRP gene lead to skeletal dysplasia. Viperin is a known substrate of RMRP. Since chondrogenic differentiation of the growth plate is required for development of the long bones, we hypothesized that viperin functions as a chondrogenic regulator downstream of RMRP. Viperin protein is expressed throughout the stages of chondrogenic differentiation in vivo. Viperin gene expression is increased during knockdown of Rmrp RNA in the ATDC5 model for chondrogenic differentiation. Viperin is expressed during ATDC5 chondrogenic differentiation. Viperin knockdown reduces, while viperin overexpression increases overall protein secretion, with CXCL10 identified as a potential target via mass spectrometry-proteomics. CXCL10 protein expression is reduced during knockdown and increased during overexpression of viperin and CXCL10 protein expression coincides with viperin expression in ATDC5 chondrogenic differentiation. Viperin knockdown induces, while viperin overexpression reduces TGFβ activity. Furthermore, viperin knockdown conditioned media increases, while viperin overexpression conditioned media reduces chondrogenic differentiation of ATDC5 cells. TGFβ target genes Pai1 and Smad7 are increased during knockdown and reduced during overexpression of viperin. Moreover, TGFβ activity is reduced when differentiating ATDC5 cells are exposed to CXCL10 and, acting as a viperin overexpression mimic, CXCL10 similarly reduces chondrogenic differentiation of ATDC5. Lastly, we show that in CHH patient cells, RMRP expression is reduced and viperin expression is increased, coinciding with reduced chondrogenic differentiation and increased CXCL10 expression, possibly explaining the CHH phenotype. Together our data show that viperin may play a pivotal role in chondrogenic differentiation, with potential consequences for cartilage-hair hypoplasia pathobiology.
2019-02-15 | PXD006999 | Pride
Project description:Background: Pericytes are capillary-associated mural cells especially prominent in the central nervous system where they regulate vascular permeability and blood-brain barrier integrity. Despite their relevance for neurovascular unit homeostasis and their involvement in the pathobiology of neurodegenerative diseases, signalling mechanisms responsible for functional specialization and intercellular communication remain elusive. Objectives: The main goal of this study is to understand the relevance of Rbpj (the common downstream mediator of Notch signalling, an important mediator of cell-to-cell communication) in brain pericytes and to identify molecular signatures associated to Rbpj deletion. Methods: We used mouse genetic experiments to knockout Rbpj specifically in pericytes using a mural cell-specific Cre-driver (PdgfrbCreERT2). Inclusion of the Rpl22-HA (RiboTag) construct allowed Cre-mediated HA-labeling of ribosomal proteins and consequent isolation of actively translating mRNA from pericytes. PdgfrbCreERT2 transgenic mice were used to drive recombination of Rpl22-HA (RiboTag) allele and/or Rbpj-lox conditional knockout. Tamoxifen administration from postnatal day 1 (P1) to P3 allowed efficient recombination in pericytes. Brain cortices were collected at P7 or P10 and HA-tagged polyribosomes were immunoprecipitated using anti-HA coated beads. Total RNA was extracted and sequencing libraries prepared. Results: Pericyte-specific Rbpj deletion induces severe changes in the neurovascular unit characterized by defects in vascular morphogenesis, brain hemorrhaging, altered extracellular matrix composition and strong inflammatory responses. Analysis of pericytes translatome of Rbpj-KO mice compared to controls revealed profound changes in pericyte identity, increased expression of vascular smooth muscle cell markers and increased signaling through TGFbeta, among other alterations in mural cell behavior.
2019-05-11 | GSE117083 | GEO
Project description:Clinical approaches to treat advanced melanoma include immune therapies, whose benefits depend on tumor-reactive T-cells to infiltrate metastases. However, most tumors lack significant immune infiltration prior to therapy, and some immune therapies are hindered by a persistent lack of immune cell infiltration. CXCL10 has been implicated as a critical chemokine supporting T-cell migration into tumors; thus agents that induce CXCL10 in tumors may improve patient responses to systemic immune therapy. We find that melanoma cells treated with TLR2/6 agonists (MALP-2 or FSL-1) and interferon-gamma (IFNgamma) upregulate CXCL10 production, when compared to IFNgamma treatment alone or no treatment. Gene profiling of melanoma cells lines treated with TLR2/6 agonists and IFNgamma demonstrate that a selective profile of genes are induced which may be favorable for promoting immune cell infiltration of tumors. TLR2 and TLR6 are widely expressed on human melanoma cells, and treatment of melanoma cells with TLR2/6 agonists and IFNgamma does not hinder melanoma cell apoptosis or promote proliferation. Furthermore, melanoma cells from surgically resected patient tumors upregulate CXCL10 production after treatment with TLR2/6 agonists and IFNgamma when compared to treatment with either agent alone. Collectively, these data identify TLR2/6 agonists and IFNgamma as a novel target for promoting CXCL10 production directly from melanoma cells. Samples from four human melanoma cell lines, VMM1 (n=6), DM13 (n=6), DM93 (n=6) and VMM39 (n=6), were treated with media alone, MALP-2 (TLR2/6 agonist), FSL-1 (TLR2/6 agonist), IFNgamma alone, MALP-2 and IFNgamma, or FSL-1 and IFNgamma.
2015-11-22 | E-GEOD-64506 | biostudies-arrayexpress