Non-human primate blood-brain barrier and in vitro brain endothelium: from transcriptome to the establishment of a new model
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ABSTRACT:
PROVIDER: PRJNA647856 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12287755_1.fastq.gz | Fastqsanger.gz | |||
| SRR12287755_2.fastq.gz | Fastqsanger.gz | |||
| SRR12287756_1.fastq.gz | Fastqsanger.gz | |||
| SRR12287756_2.fastq.gz | Fastqsanger.gz | |||
| SRR12287757_1.fastq.gz | Fastqsanger.gz |
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Project description:The blood-brain barrier (BBB) represents a major challenge when developing central nervous system (CNS)-active therapeutics. The non-human primate (NHP)-brain endothelium constitutes an essential alternative to human in the prediction of molecule trafficking across the BBB and in the search of new brain-specific transport mechanisms. This study presents a comparison between the NHP transcriptome of freshly isolated brain microcapillaries and in vitro-selected brain endothelial cells (BECs), focusing on important BBB features – tight junctions, receptors mediating transcytosis (RMT), ABC and SLC transporters. In vitro BECs conserved most of the BBB key elements for barrier integrity and control of molecular trafficking. We also assessed the function of RMT via the Transferrin Receptor (TFRC) in the characterized NHP-BBB model, where both human transferrin and anti-hTFRC antibody showed increased apical-to-basolateral passage in comparison to control molecules. In parallel, we investigated eventual BBB-related regional differences in 7-day in vitro-selected BECs from 5 brain structures: brainstem, cerebellum, cortex, hippocampus and striatum. Our analysis retrieved very few differences in the brain endothelium from these 5 brain regions, suggesting a rather homogeneous BBB role and function across the brain parenchyma. In conclusion, the presently established NHP-derived BBB model closely mimics the physiological BBB, therefore representing a ready-to-use tool for assessment of the penetration of biotherapeutics into the human CNS.
2020-07-23 | GSE154901 | GEO
Project description:We describe the construction a 3D blood-brain barrier model comprised of iPSC-derived brain endothelium cultured in channels within gelatin hydrogels. The iPSC-derived brain endothelium displays key features of the blood-brain barrier phenotype, including tight junction formation, efflux transporter activity, low paracellular permeability, and suppressed levels of transcytosis compared to non-blood-brain barrier endothelial controls. Collectively, this work provides the foundation for a fully human, biomimetic neurovascular model to study BBB in health and disease.
2019-03-06 | GSE122588 | 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:iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel Scaffolds
| PRJNA505675 | ENA
Project description:This SuperSeries is composed of the following subset Series: GSE22521: Gene expression in primate postnatal brain through lifespan - prefrontal cortex GSE22569: Gene expression in primate postnatal brain through lifespan - cerebellar cortex Refer to individual Series
2011-12-09 | E-GEOD-22570 | biostudies-arrayexpress
Project description:The non-human primate (NHP)-brain endothelium constitutes an essential alternative to human in the prediction of molecule trafficking across the blood-brain barrier (BBB). This study presents a comparison between the NHP transcriptome of freshly isolated brain microcapillaries and in vitro-selected brain endothelial cells (BECs), focusing on important BBB features, namely tight junctions, receptors mediating transcytosis (RMT), ABC and SLC transporters, given its relevance as an alternative model for the molecule trafficking prediction across the BBB and identification of new brain-specific transport mechanisms. In vitro BECs conserved most of the BBB key elements for barrier integrity and control of molecular trafficking. The function of RMT via the transferrin receptor (TFRC) was characterized in this NHP-BBB model, where both human transferrin and anti-hTFRC antibody showed increased apical-to-basolateral passage in comparison to control molecules. In parallel, eventual BBB-related regional differences were investigated in seven-day in vitro-selected BECs from five brain structures: brainstem, cerebellum, cortex, hippocampus, and striatum. Our analysis retrieved few differences in the brain endothelium across brain regions, suggesting a rather homogeneous BBB function across the brain parenchyma. The presently established NHP-derived BBB model closely mimics the physiological BBB, thus representing a ready-to-use tool for assessment of the penetration of biotherapeutics into the human CNS.
| S-EPMC7602447 | biostudies-literature
Project description:<h4><strong>BACKGROUND: </strong>Several studies have shown a correlation between an altered metabolome and respiratory allergies. The epithelial barrier hypothesis proposes that an epithelial barrier dysfunction can result in allergic diseases development. Der p 1 allergen from house dust mite is a renowned epithelial barrier disruptor and allergy initiator due to its cysteine-protease activity. Here, we compared the metabolic profile of the bronchial epithelium exposed or not to Der p 1 during barrier establishment to understand its active role in allergy development.</h4><h4><strong>METHODS: </strong>Calu-3 cells were cultivated in air-liquid interface cultures and exposed to either Der p 1 or Ole e 1 allergens during barrier establishment. The comparative metabolomics analysis of apical and basolateral media were performed using liquid chromatography and capillary electrophoresis both coupled to mass spectrometry.</h4><h4><strong>RESULTS: </strong>We showed that epithelial barrier disruption by Der p 1 was associated with a specific metabolic profile, which was highly dependent on the state of the epithelium at the time of contact. Moreover, an apical-basolateral distribution of the metabolites was also observed, indicating a compartmentalization of the response with differential metabolic patterns. A number of metabolites were changed by Der p 1, mainly related to amino acids metabolism, such as L-arginine, L-kynurenine and L-methionine.</h4><h4><strong>CONCLUSION: </strong>This work is the first report on the metabolic response in human bronchial epithelial cells associated with cysteine-protease Der p 1 activity, which could contribute to allergy development. Moreover, it supports a reformulated epithelial barrier hypothesis that might help to explain allergies and their increasing prevalence.</h4>
2023-08-22 | MTBLS1755 | MetaboLights
Project description:Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity
| PRJNA855254 | ENA
Project description:While genome sequencing has identified numerous non-coding alterations between primate species, which of these are regulatory and potentially relevant to the evolution of the human brain is unclear. Here, we annotate cis-regulatory elements (CREs) in the human, rhesus macaque and chimpanzee genome using ChIP-sequencing in different anatomical parts of the adult brain. We find high similarity in the genomic positioning of CREs between rhesus macaque and humans, suggesting that the majority of these elements were already present in a common ancestor 25 million years ago. Most of the observed regulatory changes between humans and rhesus macaque occurred prior to the ancestral separation of humans and chimpanzee, leaving a modest set of regulatory elements with predicted human-specificity. Our data refine previous predictions and hypotheses on the consequences of genomic changes between primate species, and allow the identification of regulatory alterations relevant to the evolution of the brain. ChIP-Sequencing for H3K27ac on 8 distinct brain regions from human (three biological replicates per brain region), chimpanzee (two biological replicates per brain region) and rhesus macaque (three biological replicates per brain region).
2016-01-13 | E-GEOD-67978 | biostudies-arrayexpress
Project description:The aim of this study was to investigate the response of human brain endothelial cells to bacterial (group B streptococcus, GBS) infection. Results: GBS WT strain infection results in a specific gene induction pattern that is different from the pilA mutant, but not other mutants such as pilB and srr-1. Conclusion: These findings suggest that the GBS PilA protein contributes to gene induction in brain endothelium.
2011-09-06 | E-MTAB-765 | biostudies-arrayexpress