Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE251849 | GEO | 2024/02/22
REPOSITORIES: GEO
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Project description:SAH pathophysiology includes blood-brain barrier (BBB) disruption. Gene expression changes at the endothelial cell level may provide insight into BBB pathophysiology. We used microarray gene expression data comparing freshly isolated brain endothelial cells isolated from Sham or SAH mice.
2021-04-12 | GSE155137 | GEO
Project description:Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adults is unknown. Here, conditional Gpr124 knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity but resulted in BBB disruption and microvascular hemorrhage in mouse models of ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt/beta-catenin signaling. Constitutive activation of Wnt/beta-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124 cko mice, with rescue of the endothelial tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.
2017-03-06 | GSE74052 | GEO
Project description:Our study showed that fibroblasts significantly attenuated blood-brain barrier (BBB) disruption in an in vitro intracerebral hemorrhage (ICH) model. Since fibroblasts and brain microvascular endothelial cells were not in direct contact in this model, we reasoned that fibroblasts did so by secreting molecules with BBB-protective function. Here, we further screened fibroblast-secreted molecules in this in vitro ICH model by mass spectrometry.
2022-11-14 | PXD037247 | Pride
Project description:Functional and structural dysfunction of the blood brain barrier (BBB) leads to severe alterations in brain physiology and is believed to trigger neurodegeneration. To investigate the molecular mechanisms driving the BBB dysfunction, very few human BBB cell culture models are available; of which, the human microvascular endothelial cell line (hCMEC/D3) is the most widely used. Thus far, array-based approaches or targeted seqeuncing based approaches have been employed to characterize the gene expression of the hCMEC/D3 model. However,The goal of this study is to perform deep transcriptomic sequencing of the BBB cell line and obtain features like gene expression, expressed single nucleotide variants, alternate splice forms, circular RNAs, long non-coding RNAs and micro RNAs. We have developed blood brain barriers transcriptomics landscape using RNA sequencing and micro RNA seqeuncing data obtained from replicates of hCMEC/D3 BBB cell line.
2016-03-17 | E-GEOD-76528 | biostudies-arrayexpress
Project description:Functional and structural dysfunction of the blood brain barrier (BBB) leads to severe alterations in brain physiology and is believed to trigger neurodegeneration. To investigate the molecular mechanisms driving the BBB dysfunction, very few human BBB cell culture models are available;of which, the human microvascular endothelial cell line (hCMEC/D3) is the most widely used. Thus far, array-based approaches or targeted seqeuncing based approaches have been employed to characterize the gene expression of the hCMEC/D3 model. However,The goal of this study is to perform deep transcriptomic sequencing of the BBB cell line and obtain features like gene expression, expressed single nucleotide variants, alternate splice forms, circular RNAs, long non-coding RNAs and micro RNAs. We have developed blood brain barriers transcriptomics landscape using RNA and micro RNA sequencing data obtained from replicates of hCMEC/D3 BBB cell line.
2016-03-17 | E-GEOD-76530 | biostudies-arrayexpress
Project description:Endothelial cells (ECs) in cerebral vessels are considered the primary targets in acute hemorrhagic brain injuries. EC dysfunction can aggravate neuronal injuries by causing secondary inflammatory responses and blood-brain barrier (BBB) disruption. ECs comprising the BBB are known to have a higher mitochondrial volume compared with peripheral ECs. In previous study, we reported Tek-CRIF1-knockout (KO) mice, with EC-specific deletion of the mitochondrial OxPhos-related gene, Crif1, also known as Gadd45gip1 (encoding GADD45G-interacting protein 1), display profound BBB defects accompanied by reduced expression of junctional proteins in ECs. To identify signaling pathways involved in linking EC-specific mitochondrial dysfunction and BBB disruption, we first performed RNA sequencing using isolated cerebral vessels from Tek-CRIF1 mice. This transcriptome analyses of the Tek-CRIF1-KO mouse revealed significant changes in some signaling, a pathway intimately involved in BBB maintenance.
2022-08-31 | GSE207106 | GEO
Project description:Background: Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood-brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, the identification of new endogenous molecules involved in endothelial cell disruption is essential to better understand BBB dynamics. Cortistatin is a neuroimmune mediator with anti-inflammatory and neuroprotective properties that exerts beneficial effects on the peripheral endothelium. However, its role in the healthy and injured brain endothelium remains to be evaluated. Herein, this study aimed to investigate the potential function of endogenous and therapeutic cortistatin in regulating brain endothelium dysfunction in a neuroinflammatory/neurodegenerative environment. Methods: Wild-type and cortistatin-deficient murine brain endothelium and human cells were used for an in vitro barrier model, where a simulated ischemia-like environment was mimicked. Endothelial permeability, junction integrity, and immune response in the presence and absence of cortistatin were evaluated using different size tracers, immunofluorescence labelling, qPCR, and ELISA. Cortistatin molecular mechanisms underlying brain endothelium dynamics were assessed by RNA-sequencing analysis. Cortistatin role in BBB leakage was evaluated in adult mice injected with LPS. Results: The endogenous lack of cortistatin predisposes endothelium weakening with increased permeability, tight-junctions breakdown, and dysregulated immune activity. We demonstrated that both damaged and uninjured brain endothelial cells isolated from cortistatin-deficient mice, present a dysregulated and/or deactivated genetic programming. These pathways, related to basic physiology but also crucial for the repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signalling, and metabolites transport), are dysfunctional and make brain endothelial barrier lacking cortistatin non-responsive to any further injury. Treatment with cortistatin reversed in vitro hyperpermeability, tight-junctions disruption, inflammatory response, and reduced in vivo BBB leakage. Conclusions: The neuropeptide cortistatin has a key role in the physiology of the cerebral microvasculature and its presence is crucial to develop a canonical balanced response to damage. The reparative effects of cortistatin in the brain endothelium were accompanied by the modulation of the immune function and the rescue of barrier integrity. Cortistatin-based therapies could emerge as a novel pleiotropic strategy to ameliorate neuroinflammatory/neurodegenerative disorders with disrupted BBB.
2023-09-01 | GSE207405 | GEO
Project description:Treatment of many pathologies of the brain could be improved markedly by the development of non-invasive therapeutic approaches that elicit robust, endothelial cell-selective, gene expression in specific brain regions that are targeted under MR image-guidance. While focused ultrasound (FUS) in conjunction with gas-filled microbubbles (MBs) has emerged as a non-invasive modality for MR image-guided gene delivery to the brain, it has been used exclusively to transiently disrupt the blood-brain barrier (BBB), which may induce a sterile inflammation response. Here, we introduce a new MR image-guided FUS method that elicits endothelial-selective transfection of the cerebral vasculature (i.e. “sonoselective” transfection), without opening the BBB. We first determined that activating circulating, cationic plasmid-bearing, MBs with pulsed low-pressure (0.1 MPa) 1.1 MHz FUS facilitates sonoselective gene delivery to the endothelium without MRI-detectable disruption of the BBB. The degree of endothelial selectivity varied inversely with the FUS pressure, with higher pressures (i.e. 0.3 MPa and 0.4 MPa FUS) consistently inducing BBB opening and extravascular transfection. Bulk RNA sequencing analyses revealed that the sonoselective low pressure regimen does not upregulate inflammatory or immune responses. Single cell RNA sequencing indicated that the transcriptome of sonoselectively transfected brain endothelium was unaffected by the treatment. The approach developed here permits targeted gene delivery to blood vessels and could be used to promote angiogenesis, release endothelial cell-secreted factors to stimulate nerve regrowth, or recruit neural stem cells.
2019-12-13 | GSE141922 | GEO
Project description:Treatment of many pathologies of the brain could be improved markedly by the development of non-invasive therapeutic approaches that elicit robust, endothelial cell-selective, gene expression in specific brain regions that are targeted under MR image-guidance. While focused ultrasound (FUS) in conjunction with gas-filled microbubbles (MBs) has emerged as a non-invasive modality for MR image-guided gene delivery to the brain, it has been used exclusively to transiently disrupt the blood-brain barrier (BBB), which may induce a sterile inflammation response. Here, we introduce a new MR image-guided FUS method that elicits endothelial-selective transfection of the cerebral vasculature (i.e. “sonoselective” transfection), without opening the BBB. We first determined that activating circulating, cationic plasmid-bearing, MBs with pulsed low-pressure (0.1 MPa) 1.1 MHz FUS facilitates sonoselective gene delivery to the endothelium without MRI-detectable disruption of the BBB. The degree of endothelial selectivity varied inversely with the FUS pressure, with higher pressures (i.e. 0.3 MPa and 0.4 MPa FUS) consistently inducing BBB opening and extravascular transfection. Bulk RNA sequencing analyses revealed that the sonoselective low pressure regimen does not upregulate inflammatory or immune responses. Single cell RNA sequencing indicated that the transcriptome of sonoselectively transfected brain endothelium was unaffected by the treatment. The approach developed here permits targeted gene delivery to blood vessels and could be used to promote angiogenesis, release endothelial cell-secreted factors to stimulate nerve regrowth, or recruit neural stem cells.
2019-12-11 | GSE141728 | GEO
Project description:Genetic variation in the population has an influence on the manifestation of monogenic as well as multifactorial disorders, with the underlying genetic contribution dependent on several interacting variants. Common laboratory mouse strains used for modelling human disease lack the genetic variability of the human population. Therefore, outcomes of rodent studies show limited correlation with human disease. The functionality of brain vasculature is an important modifier of brain diseases. Importantly, the restrictive interface between blood and brain – the blood-brain barrier (BBB) serves as a major obstacle for CNS drug delivery. Using genetically diverse mouse strains, we aimed to investigate the phenotypic and transcriptomic variation of the intact BBB in different inbred mouse strains.We investigated the heterogeneity of brain vasculature in recently wild-derived mouse strains (CAST/EiJ, WSB/EiJ, PWK/PhJ) and long-inbred mouse strains (129S1/SvImJ, A/J, C57BL/6J, DBA/2J, NOD/ShiLtJ) using different phenotypic arms. We used immunohistochemistry and confocal laser microscopy followed by quantitative image analysis to determine vascular density and pericyte coverage in two brain regions – cortex and hippocampus. Using a low molecular weight fluorescence tracer, sodium fluorescein and spectrophotometry analysis, we assessed BBB permeability in young and aged mice of selected strains. For further phenotypic characterization of endothelial cells in inbred mouse strains, we performed bulk RNA sequencing of sorted endothelial cells isolated from cortex and hippocampus. We did not detect differences in cortical and hippocampal vessel density and pericyte coverage among all the investigated strains. The staining patterns of endothelial arteriovenous zonation markers were similar in different strains. BBB permeability to a small fluorescent tracer, sodium fluorescein, was also similar in different strains. Transcriptomic analysis of endothelial cells revealed that sex of the animal was a major determinant of gene expression differences. In addition, the expression level of several genes implicated in endothelial function and BBB biology differed between wild-derived and long-inbred mouse strains. Our analysis shows that although there were no major differences in parenchymal vascular morphology and BBB permeability between investigated mouse strains or sexes, transcriptomic differences of brain endothelial cells point to variation in gene expression of the intact BBB. These baseline variances might be confounding factors in pathological conditions that may lead to a differential functional outcome dependent on the sex or genetic polymorphism.
2021-08-03 | GSE173793 | GEO