High-throughput differentiation of human blood vessel organoids reveals overlapping and distinct functions of the cerebral cavernous malformation proteins
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE276497 | GEO | 2025/06/06
REPOSITORIES: GEO
Similar Datasets
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
Project description:Cerebral Cavernous Malformations (CCM), caused by loss of CCM1, CCM2 or CCM3 in endothelial cells (ECs), are leaky capillaries causing seizures and stroke. CCM protein loss gives overlapping changes in biomechanical and transcriptional properties of ECs, due to common RhoA-driven alterations in cytoskeletal organization and intracellular signaling. However, EC models of 3-D tube formation show loss of each CCM protein generates distinct morphological defects in tubular structures. Computational modeling, live-cell imaging and RNA sequencing revealed distinct functional roles of CCM1 and CCM3 in regulating EC-EC and EC-matrix interactions. CCM2 has an intermediate phenotype consistent with its interaction with CCM1 and CCM3. In ECs, CCM proteins regulate SMURF1 E3 ligase ubiquitination and degradation of RhoA. Loss of CCM proteins results in loss of SMURF1 and a concomitant increase of MEKK3, a negative regulator of SMURF1 expression. We propose CCM lesions develop because of dysregulated SMURF1 resulting in RhoA and MEKK3 gain-of-function.
2019-04-05 | GSE112882 | GEO
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
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
Project description:Cerebral Cavernous Malformations (CCMs) are neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). Following onset, disease severity ranges from minimal vascular defects to numerous vascular dilations (lesions) distributed throughout the brain. Although the precise pathogenic mechanisms resulting in such a broad range of disease severity are unknown, inter-cellular communication between heterogeneous brain cell types including microvascular endothelial cells, astrocytes, and neurons are likely important in disease progression. To further understand these cell type relationships in the context of CCM, Riboseq was performed in astroctytes and mRNA expression profiling was performed from whole brain extracts as well as isolated brain microvascular endothelial cells.
2022-10-01 | GSE204979 | GEO
Project description:Cerebral Cavernous Malformations (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic blood-filled capillaries form focally in the brain. Endothelial loss-of-function mutations on any of the three CCM genes (CCM1-3) are responsible for the familial form of the disease. Whether and how the defective mechanotransduction, inflammatory response and mosaic state characteristic of these lesions interplay to sustain the progression of CCM diseases is unknown. Here, we show that CCM1- and CCM2-silenced endothelial cells enter into a senescence associated with secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the mechanical and molecular disorders provoked by ROCKs dysfunctions when CCM2 is lost. This discovery reconciles all the known dysregulated traits of CCM1/2-deficient endothelial cells into a unique mechano-dependent SASP that links perturbed cellular mechanics to microenvironment remodelling and long-range activation of WT endothelial and immune cells.
2023-07-26 | GSE165406 | GEO
Project description:Cerebral cavernous malformation (CCM) is caused by loss-of-function mutations in CCM1, CCM2, or CCM3 genes of endothelial cells. It is characterized by pericyte deficiency. However, the role of pericytes in CCMs remains poorly understood. Our study showed that pericytes in Cdh5CreERT2; Ccm1fl/fl (Ccm1ECKO) mice were high expression of PDGFRβ. The inhibition of pericyte function by CP-673451 aggravated the CCM lesion development. RNA-seq analysis revealed the molecular traits of pericytes, such as highly expressed ECM-related genes, especially Fn1. Furthermore, KLF4 coupled with phosphorylated SMAD3 promoted the transcription of fibronectin in pericytes of CCM lesions. RGDS peptide, an inhibitor of fibronectin, decreased the lesion area in the cerebella and retinas of Ccm1ECKO mice. Also, human CCM lesions had abundant fibronectin deposition, and pSMAD3- and KLF4-positive pericytes. The current data demonstrated that pericytes are essential for CCM lesion development, and fibronectin intervention may provide a novel target for therapeutic intervention in such patients.
2022-12-07 | GSE213244 | GEO
Project description:Purpose: To determine important genes, functions, and networks contributing to the pathobiology of cerebral cavernous malformation (CCM) from transcriptomic analyses across 3 species and 2 disease genotypes. Methods: Sequencing of RNA from laser microdissected neurovascular units (NVUs) of 5 human surgically resected CCM lesions, mouse brain microvascular ECs (BMECs) and C. elegans with induced Ccm gene loss, and their respective controls, provided differentially expressed genes (DEGs). DEGs from mouse and C. elegans were annotated into human homologous genes. Cross-comparisons of DEGs between species and genotypes as well as network and Gene Ontology (GO) enrichment analyses were performed. Results: Among hundreds of DEGs identified in each model, common genes and one GO term (GO:0051656 establishment of organelle localization) were commonly identified across the different species and genotypes. In addition, 24 GO functions were present in 4 out of 5 models and were related to cell-cell adhesion, neutrophil mediated immunity, ion transmembrane transporter activity, and responses to oxidative stress. We provide a comprehensive transcriptome library of CCM disease across species, and for the first time in Ccm1/Krit1 versus Ccm3/Pdcd10 genotypes Conclusion: We provide examples of how results can be used in hypothesis generation or mechanistic confirmatory studies.
2018-12-18 | GSE123968 | GEO
Project description:We analyzed CCM1/KRIT1, CCM2/MGC4607, and CCM3/PCDP10 among 41 patients with cerebral cavernous malformation. Then, we found two novel pathological variants of CCM1 (c.1846delA and c.485+1G>C) and one novel variants of CCM2 (c.401_402insGCCC).
| PRJEB31953 | ENA
Project description:Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with anendothelial cell-specific ablation of the Ccm3 gene (Ccm3iECKO), we show that endothelial cells from Ccm3iECKO mice have anincreased expression of inflammation-related genes.
2023-10-31 | GSE246373 | GEO