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Mapping endothelial-cell diversity in cerebral cavernous malformations at single cell resolution

ABSTRACT: Mapping endothelial-cell diversity in cerebral cavernous malformations at single cell resolution

PROVIDER: PRJNA655629 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12399702.fastq.gz	Fastqsanger.gz
	SRR12399703.fastq.gz	Fastqsanger.gz
	SRR12399704.fastq.gz	Fastqsanger.gz
	SRR12399705.fastq.gz	Fastqsanger.gz
	SRR12399706.fastq.gz	Fastqsanger.gz

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Mapping endothelial-cell diversity in cerebral cavernous malformations at single cell resolution

Project description:Cerebral cavernous malformation (CCM) is a rare neurovascular disease that is characterized by enlarged and irregular blood vessels that often lead to cerebral hemorrhage. Loss-of-function mutations to any of three genes results in CCM lesion formation; namely, CCM1, CCM2, and CCM3. Here, we report for the first time in-depth single-cell RNA sequencing, combined with spatial transcriptomics and immunohistochemistry, to comprehensively characterize subclasses of brain endothelial cells under both normal conditions and after deletion of Ccm3 in a mouse model of CCM. Integrated single-cell analysis identifies arterial endothelial cells as refractory to CCM transformation. Conversely, a subset of angiogenic venous capillary endothelial cells and respective resident endothelial progenitors is at the origin of CCM lesions. These data are relevant for the understanding of the plasticity of the brain vascular system and provide novel insights into the molecular basis of CCM disease at the single cell level.

2020-11-04 | GSE155788 | 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.

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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.

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Thrombospondin1 replacement prevents cerebral cavernos malformations

Project description:We have purified primary brain microvascular endothelial cells (BMEC) from mice bearing floxed alleles of Krit1 (Krit1fl/fl) and an endothelial specific tamoxifen-regulated Cre recombinase (Pdgfb-iCreERT2), and used these to delete Krit1 in a time-controlled manner (Krit1ECKO). To elucidate the pathogenesis of cerebral cavernous malformations (CCM) we used genome-wide RNA sequencing (RNA-seq) to characterize the transcriptome of primary BMEC following acute genetic inactivation of Krit1.

2017-09-25 | GSE85657 | GEO

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Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution.

Project description:Cerebral cavernous malformation (CCM) is a rare neurovascular disease that is characterized by enlarged and irregular blood vessels that often lead to cerebral hemorrhage. Loss-of-function mutations to any of three genes results in CCM lesion formation; namely, KRIT1, CCM2, and PDCD10 (CCM3). Here, we report for the first time in-depth single-cell RNA sequencing, combined with spatial transcriptomics and immunohistochemistry, to comprehensively characterize subclasses of brain endothelial cells (ECs) under both normal conditions and after deletion of Pdcd10 (Ccm3) in a mouse model of CCM. Integrated single-cell analysis identifies arterial ECs as refractory to CCM transformation. Conversely, a subset of angiogenic venous capillary ECs and respective resident endothelial progenitors appear to be at the origin of CCM lesions. These data are relevant for the understanding of the plasticity of the brain vascular system and provide novel insights into the molecular basis of CCM disease at the single cell level.

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Force-mediated recruitment and reprogramming of healthy endothelial cells in cerebral cavernous malformations

Project description:Cerebral cavernous malformations (CCMs) are vascular abnormalities in the brain characterized by clusters of leaky, tumor-like vessels that often lead to cerebral hemorrhage. Disruptions in signaling pathways involved in endothelial mechanotransduction and angiogenesis due to loss-of-function mutations in CCM genes are known to contribute to lesion formation. Recent studies have highlighted the critical role of wild-type cell recruitment from the surrounding endothelium by CCM mutants in lesion progression. However, the specific mechanisms underlying this recruitment process remain poorly understood. We report here that hyper-angiogenic CCM2-deficient endothelial cells enhance angiogenic invasion of neighboring wild-type cells. Mechanically hyperactive CCM2-deficient tips generate pulling forces on wild-type stalk cells and leave degraded paths in the matrix as cues to promote invasion. We wanted to further answer if mutant cells are capable of modifying the transcriptomic signature of neighbouring healthy endothelial changes in addition to the phenotypic modifications. We used single-cell RNA-sequencing (10x Genomics Chromium) to identifiy endothelial cell clusters. We enriched the endothelial cells and then used 10X Genomics Chromium technology to capture 1434 cells. The analysis was then performed using Seurat to identify each cell cluster. The results revealed that mutant cells were able to reprogram wild-type cells into stalk cells, with the activation of matrisome and DNA replication programs, eventually leading to cell proliferation. These findings unveil a novel mechanism by which proliferative wild-type cells contribute to CCM lesion growth and identify dysregulated cell mechanics as a “third hit” in CCM pathogenesis.

2024-09-18 | GSE246174 | GEO

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