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Neuroinflammation and immunothrombosis transcriptional patterns in CCM lesions revealed by spatial transcriptomics

ABSTRACT: Cerebral cavernous malformation (CCM) immunothrombosis is the connection between immune cells, platelet activation, coagulation cascades and astrocyte-CCM endothelium interaction, and its excessive activation may contribute to neurological disabilities in CCM disease. We characterized the spatial organization of CCM immunothrombosis observed in Pdcd10BECKObrains under normoxic conditions using the murine 10X Genomics Visium Spatial Gene Expression platform.

ORGANISM(S): Mus musculus

PROVIDER: GSE236164 | GEO | 2024/09/23

REPOSITORIES: GEO

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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.

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Circulating Plasma miRNA Homologs in Mice and Humans Reflect Familial Cerebral Cavernous Malformation Disease [Human]

Project description:Patients with familial cerebral cavernous malformation (CCM) inherit germline loss of function mutations and are susceptible to progressive development of brain lesions and neurological sequelae during their lifetime. To date, no homologous circulat- ing molecules have been identified that can reflect the presence of germ line pathogenetic CCM mutations, either in animal models or patients. We hypothesize that homologous differentially expressed (DE) plasma miRNAs can reflect the CCM germline mutation in preclinical murine models and patients. Herein, homologous DE plasma miRNAs with mechanistic putative gene targets within the transcriptome of preclinical and human CCM lesions were identified. Several of these gene targets were additionally found to be associated with CCM-enriched pathways identified using the Kyoto Encyclopedia of Genes and Genomes. DE miRNAs were also identified in familial-CCM patients who developed new brain lesions within the year following blood sample collection. The miRNome results were then validated in an independent cohort of human subjects with real-time-qPCR quantification, a technique facilitating plasma assays. Finally, a Bayesian-informed machine learning approach showed that a combination of plasma levels of miRNAs and circulating proteins improves the associa- tion with familial-CCM disease in human subjects to 95% accuracy. These findings act as an important proof of concept for the future development of translatable circulating biomarkers to be tested in preclinical studies and human trials aimed at monitoring and restoring gene function in CCM and other diseases.

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