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Epigenetic Mechanisms Regulating the Transcription of BBB Genes: Role of Wnt/β-catenin signaling

ABSTRACT: To identify in CNS endothelial cell (EC) the gene cohorts that participate in blood brain barrier (BBB) formation versus maintenance. We investigated mechanisms behind the reduced Wnt/β-catenin signaling observed in adult CNS ECs We also investigated whether the adult endothelial cells can re express the EC gene cohorts required for the BBB formation.

ORGANISM(S): Mus musculus

PROVIDER: GSE214923 | GEO | 2022/11/03

REPOSITORIES: GEO

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Epigenetic Mechanisms Regulating The Transcription of BBB Genes: Role of Wnt/β-catenin signaling

Project description:To identify CNS endothelial cell (EC) the gene cohorts that participate in blood brain barrier (BBB) formation versus maintenance. We investigated mechanism behind the reduced Wnt/β-catenin signaling observed in adult CNS ECs We also investigated whether the adult endothelial cells can re express the EC gene cohorts required for the BBB formation.

2024-08-02 | GSE255967 | GEO

Establishing And Maintaining The Blood-Brain Barrier: Epigenetic And Signaling Determinants

Project description:To identify CNS endothelial cell (EC) the gene cohorts that participate in blood brain barrier (BBB) formation versus maintenance. We investigated the mechanism behind the reduced Wnt/β-catenin signaling observed in during later development We also investigated whether the adult endothelial cells can re express the EC gene cohorts required for the BBB formation.

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The Wnt/ß-catenin axis modulates early BBB development by fine-tuning TGFß signalling through ADAMTSL2

Project description:The Wnt/ß-catenin pathway is orchestrating the development of the blood-brain barrier (BBB), but its downstream mediators have remained elusive. To identify potential effectors, we generated an endothelial cell specific Axin1 over-expressing mouse model, AOEiEC. We found that in AOEiE mice Wnt/ß-catenin signalling was down regulated leading to premature regression and remodelling without directly compromising BBB integrity. Interestingly, by comparing transcriptomes of endothelial cells from control and AOEiEC mice, we identified Adamtsl2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the cerebral vasculature during development. Importantly, loss-of-function and gain-of-function experiments revealed that Adamtsl2 alone was sufficient to rescue CNS vascular defects seen upon Wnt-signalling inhibition. Furthermore, using various cell and animal models we demonstrate that Adamtsl2 exerts its function by fine-tuning the TGFβ signalling pathway in CNS vessels. In conclusion, this study implicates Adamtsl2 as a mediator of Wnt/ß-catenin signalling during BBB development by linking it to TGFβ signalling.

2019-01-31 | GSE77874 | GEO

Brain endothelial GSDMD activation mediates inflammatory BBB breakdown

Project description:The blood-brain barrier (BBB) protects the central nervous system (CNS) from external assaults by pathogenic or harmful substances. BBB impairment frequently occurs during infection, inflammatory, or other pathological conditions, which causes or exacerbates a wide range of CNS diseases. Using single cell transcriptomics, we show in this study that during systemic LPS challenges, brain endothelial cells undergo Gsdmd-mediated pyroptosis and impair the integrity of the BBB, leading to profound changes in the transcriptomic landscape of brain parenchymal populations. Analyses of the scRNA-seq dataset reveal that brain endothelial cells responded strongly to systemic LPS challenge. Further analyses of the transcriptional signatures revealed that the brain parenchymal populations displayed heterogeneous responses to BBB leakage accompanied by systemic inflammation.

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Transcriptome analysis after BBB-EC migration

Project description:A monolayer of hCMEC/D3 (BBB-EC) was grown in an insert. After reaching confluency, BBB-EC were treated with TNFa and IFNg for 24h. Next, BBB-EC were washed. Tregs were isolated from human blood (both healthy donors (HD)and untreated RRMS patients) and added to the upper chamber of the insert or were cultured in the BBB-EC medium as control (untouched_1). They were let to migrate for 24h and the upper fraction (non-migrated_2) and lower fraction (migrated_3) were collected.

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ADAMTSL2, a missing link in Wnt/ß-catenin regulated CNS vascular development

Project description:Context dependent molecular cues shape the formation of the cerebral vascular network and the function of the blood-brain barrier (BBB). The Wnt/ß-catenin pathway is orchestrating CNS vascular development, but downstream mediators have not been characterized. Here we generated an endothelial cell-specific R26-Axin1 overexpression (AOE) mouse model to inhibit Wnt/ß-catenin signaling. In AOE mice we discovered that blockade of Wnt/ß-catenin pathway leads to premature regression and remodeling without compromising BBB integrity. Importantly, by comparing transcriptomes of endothelial cells from wildtype and AOE mice, we identified ADAMTSL2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the BBB during development. Zebrafish loss-of-function and gain-of-function models, further demonstrated that ADAMTSL2 is crucial for normal vascular development and could rescue vascular phenotypes in AOE zebrafish brains. In conclusion, the studies presented here reveal a hitherto unrecognized role of ADAMTSL2 as an endothelial cell-specific mediator of Wnt/ß-catenin signaling during CNS vascular development and BBB-formation.

2019-02-22 | GSE66848 | GEO

P450 oxidoreductase (POR) Regulates Barrier Maturation by Mediating Retinoic Acid Metabolism in a Model of the Human BBB

Project description:The blood-brain barrier (BBB) is a multicellular neurovascular unit (NVU) that allows the selective passage of necessary molecules into the central nervous system (CNS), while limiting the entry of neurotoxins and most drugs. A crosstalk with pericytes and neural cells mediates the acquisition of specialized properties, such as the formation of tight junctions (TJs), in brain microvascular endothelial cells (BMECs). TJs limit the paracellular passage of solutes, thereby regulating CNS homeostasis. However, the mechanisms by which NVU cells communicate to mediate TJ formation remains a mystery. Retinoic acid (RA), a key signaling molecule during vertebrate embryonic development, is commonly used to enhance functional barrier properties in in vitro BBB models. However, its physiological relevance and affected pathways are not fully understood.

2022-08-01 | GSE202485 | GEO

Transcriptome analysis after BBB-EC migration

Project description:Transcriptome analysis after BBB-EC migration

| PRJNA1073892 | ENA

Targeted deletion of astrocytic Nhe1 stimulates Wnt/β-catenin-mediated BBB repair and angiogenesis after ischemic stroke

Project description:Roles of reactive perivascular astrocytes in dysregulation of the blood-brain barrier (BBB) function and cerebral perfusion are not well defined. Here, we investigated transformation of reactive astrocyte function for vascular repair after ischemic stroke by targeted deletion of astrocytic Na+/H+ exchanger isoform 1 in Gfap-CreERT2+/-;Nhe1f/f (Nhe1 Astro-KO) mice. Control Gfap-CreERT2+/-;Nhe1f/f (wild-type) mice displayed BBB damage (elevated endothelial transcytosis and intracellular vesicles) and persistent cerebral hypoperfusion in an ischemic stroke model (transient middle cerebral artery occlusion). In contrast, Nhe1 Astro-KO mice exhibited significantly less endothelial transcytosis and vesicle formation, and increased angiogenesis and cerebral blood perfusion (CBF) post-stroke. Bulk RNA-sequencing transcriptome analysis of isolated GFAP+ reactive astrocytes from wild-type and Nhe1 Astro-KO ischemic brains revealed that ~177 genes were differentially upregulated, with the Wnt7a mRNA among the top upregulated genes, along with additional Wnt pathway genes (Wnt7b, Fzd9, Fzd10, and Ndp). Abundant Wnt7a/b and β-catenin protein expression was detected in cerebral vessels of Nhe1 Astro-KO ischemic brains but not in the wild-type brains. Selective activation of Wnt/β-catenin pathway in cerebral vessels of Nhe1 Astro-KO ischemic brains was further validated using the Wnt reporter line TCF/LEF::H2B-eGFP; Gfap-CreERT2+/-;Nhe1f/f mice. Lastly, the role of Wnt/β-catenin pathway in resistance of Nhe1 Astro-KO mice to stroke-mediated BBB damage was tested by administration of Wnt/β-catenin inhibitor XAV-939. Taken together, we report that transforming reactive astrocyte function by upregulating astrocytic Wnt/β-catenin signaling activity is a novel mechanism to reduce the BBB endothelial damage, stimulate vascular repair, and restore cerebral blood flow after ischemic stroke.

2020-12-08 | GSE145839 | GEO

Death Receptors DR6 and TROY Regulate Brain Vascular Development

Project description:Signaling events that regulate central nervous system (CNS) angiogenesis and blood-brain barrier (BBB) formation are only beginning to be elucidated. By evaluating the gene expression profile of mouse vasculature, we identified DR6/TNFRSF21 and TROY/TNFRSF19 as regulators of CNS-specific angiogenesis in both zebrafish and mice. Furthermore, these two death receptors interact both genetically and physically and are required for vascular endothelial growth factor (VEGF)-mediated JNK activation and subsequent human brain endothelial sprouting in vitro. Increasing beta-catenin levels in brain endothelium upregulate DR6 and TROY, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for BBB development. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development. 5 replicates of 3 time points for either brain or liver/lung facs sorted vascaulture. One adult liver/lung replicate was not used as it failed QC

2012-02-15 | E-GEOD-35802 | biostudies-arrayexpress

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