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Modeling the Blood-Brain Barrier Formation and Cerebral Cavernous Malformations in human PSCs- and primary tissue-derived organoids

ABSTRACT: Modeling the Blood-Brain Barrier Formation and Cerebral Cavernous Malformations in human PSCs- and primary tissue-derived organoids

PROVIDER: PRJNA1097521 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28589153_1.fastq.gz	Fastqsanger.gz
	SRR28589153_2.fastq.gz	Fastqsanger.gz
	SRR28589154_1.fastq.gz	Fastqsanger.gz
	SRR28589154_2.fastq.gz	Fastqsanger.gz
	SRR28589155_1.fastq.gz	Fastqsanger.gz

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Modeling the Blood-Brain Barrier Formation and Cerebral Cavernous Malformations in human PSCs- and primary tissue-derived organoids

Project description:Modeling the Blood-Brain Barrier Formation and Cerebral Cavernous Malformations in human PSCs- and primary tissue-derived organoids

| PRJNA1098726 | ENA

Modeling the Blood-Brain Barrier Formation and Cerebral Cavernous Malformations in human PSCs- and primary tissue-derived organoids

Project description:The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and CNS compartments. Despite its critical physiological role, there are no reliable in vitro models that can mimic hBBB development and function. Here, we constructed hBBB assembloids from brain and blood vessel organoids derived from human pluripotent stem cells. We validated the acquisition of BBB-specific molecular, cellular, transcriptomic, and functional characteristics and uncovered an extensive neuro-vascular crosstalk with a spatial pattern within hBBB assembloids. When we used patient-derived hBBB assembloids to model cerebral cavernous malformations (CCMs), we found that these assembloids recapitulated the cavernoma anatomy and BBB breakdown observed in patients. Upon comparison of phenotypes and transcriptome between patient-derived hBBB assembloids and primary human cavernomas tissues, we uncovered CCM-related molecular and cellular alterations. Taken together, we report hBBB assembloids that mimic core properties of the human BBB and identify a potentially underlying cause of CCMs.

2024-05-15 | GSE263669 | GEO

Modeling the Blood-Brain Barrier Formation and Cerebral Cavernous Malformations in human PSCs- and primary tissue-derived organoids

2024-05-15 | GSE263425 | GEO

Systems Biology Proteomic Analysis of Cerebral Cavernous Malformation

Project description:Cerebral cavernous malformations are vascular anomalies that can cause hemorrhagic stroke. Mutations in genes encoding Krit 1 (CCM1), OSM (CCM2), and PDCD10 (CCM3) proteins cause CCM. A loss in teh expression of any of these CCM proteins disrupts normal cerebral vessel development by disrupting the cytoskeleton and thereby inhibits endothelial tube ofrmation. Examination of cellular changes based on the loss of CCM gene expression may lead to the methods for early detection and prevention of CCM associated hemorrhagic stroke.

2014-06-09 | PXD000362 | Pride

Role of pericytes in the development of cerebral cavernous malformations

Project description:Role of pericytes in the development of cerebral cavernous malformations

| PRJNA880244 | ENA

Epigenetic regulation by Polycomb Repressive Complex 1 promotes Cerebral Cavernous Malformations

Project description:Epigenetic regulation by Polycomb Repressive Complex 1 promotes Cerebral Cavernous Malformations

| PRJNA1161406 | ENA

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Project description:Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

| PRJNA802027 | ENA

Epigenetic regulation by Polycomb Repressive Complex 1 promotes Cerebral Cavernous Malformations

Project description:Cerebral cavernous malformations (CCMs) are anomalies that develop mainly in the cerebral vasculature. They result from mutations in CCM1/KRIT1, CCM2, or CCM3/PDCD10. Loss of CCM proteins triggers a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression within endothelial cells. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component of the Polycomb Repressive Complex 1, contributes to pathophysiological KLF2 signaling during zebrafish cardiovascular development. CBX7/cbx7a mRNA is strongly upregulated in lesions of CCM patients, and in human, mouse, and zebrafish CCM-deficient endothelial cells. The silencing or pharmacological inhibition of CBX7/Cbx7a suppresses pathological CCM phenotypes in ccm2 zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine CCM3 disease model. Whole-transcriptome datasets from zebrafish cardiovascular tissues and human endothelial cells reveal that CBX7/Cbx7a plays a role in the activation of KLF2 targets including genes encoding TEK, Angiopoietin1, WNT9, and endoMT proteins. Our findings uncover an intricate interplay in the regulation of Klf2-dependent biomechanical signaling by CBX7 in CCM. This work also provides insights for therapeutic strategies in the pathogenesis of CCM.

2024-09-20 | GSE277234 | GEO

Genome-Wide Sequencing Reveals Small Nucleolar RNAs Downregulated in Cerebral Cavernous Malformations

Project description:Cerebral cavernous malformations (CCM) are vascular malformations associated with abnormally dilated blood vessels and leaky capillaries that often result in hemorrhages. Despite recent advances, precise understanding of the cellular and molecular mechanism leading to the pathogenesis of CCM remains elusive. Emerging evidence indicates that small nucleolar RNAs (snoRNAs), belonging to the class of non-coding RNAs, may play a significant role as diagnostic markers in human diseases. However, there is no report till date that studied the role of snoRNAs in CCM biology. The objective of the current study was to identify snoRNAs associated with CCM pathogenesis. Using genome-wide small RNA sequencing, we identified a total of 271 snoRNAs reliably expressed in CCM. By applying additional statistical stringency, three snoRNAs (SNORD115-32, SNORD114-22 and SNORD113-3) were found to be significantly downregulated in CCM patient tissue samples (n = 3) as compared to healthy brains (n = 3). Deregulation of the selected snoRNAs was further validated by qRT-PCR. Further, cellular localization via in situ hybridization also confirmed robust reduction in the expression of SNORD115-32 and SNORD114-22 in CCM tissues as compared to the healthy controls. By applying high throughput sequencing and cellular localization analyses, we report here for the first time the genome-wide expression profile of snoRNAs in CCM tissues and a robust downregulation of candidate snoRNAs in CCM conditions. Future studies should warrant the screening in large CCM patient cohorts and will be helpful in the development of potential biomarkers and improved clinical diagnosis.

2018-12-31 | GSE111623 | GEO

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Project description:Purpose: Cerebral cavernous malformations (CCMs) are hemorrhagic neurovascular malformations that may lead to stroke, seizures and other clinical sequelae. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis; however, it remains unclear how these mutations contribute to sporadic versus familial cases. In our previous research, we’ve shown that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. The overall goal of this study was to identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). We also analyzed the plasma miRNome of patients with (1) DVA without associated CCM, as well as (2) DVA with an associated CCM) to identify circulating miRNAs that might serve as biomarkers reflecting PIK3CA activity. Methods: We collected and sequenced the plasma miRNome of 12 individuals with a sporadic CCM associated with a DVA (CCM + DVA), 6 individuals with a DVA without a CCM (DVA only), and 7 healthy controls. Results: We found that the identical PIK3CA mutation is found in endothelial cells of both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. The analyses miR-134-5p was downregulated in the groups of patients with only a DVA only group (when compared to healthy controls). This miRNA has been shown to target PIK3CA. In addition, miR-182-5p, was upregulated and targets MAP3K3; while let-7c-5p was downregulated and targets both PIK3CA and MAP3K3 in the group of patients with CCM and an associated DVA (when compared to DVA only). Conclusions: These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.

2022-02-06 | GSE195732 | GEO

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