Transcriptomic signatures of individual cell types in cerebral cavernous malformation
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Updated: Jul 6, 2025
Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model
Published on: September 4, 2017
Ying Li1,2, Romuald Girard2, Abhinav Srinath2
1Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Insights
Cerebral cavernous malformation (CCM) involves multiple cell types. This study reveals cellular crosstalk and gene changes in CCM lesions, highlighting inflammation and angiogenesis as key pathways for potential therapeutic targets.
Area of Science:
- Neuroscience
- Genomics
- Pathology
Background:
- Cerebral cavernous malformation (CCM) is a serious hemorrhagic neurovascular disease lacking effective treatments.
- Understanding the specific roles of different cell types in CCM pathogenesis is crucial but remains unclear.
- This study employed RNA-sequencing on sorted endothelial cells (ECs), pericytes, and neuroglia from CCM lesions and controls.
Discussion:
- Common differentially expressed genes (DEGs) across cell types indicate inflammation and endothelial-to-mesenchymal transition (EndMT) are central to CCM.
- Lesional ECs contribute to aberrant angiogenesis and increased vascular permeability, while pericytes show VEGFA upregulation.
- Pericytes and neuroglia in lesions are implicated in immune responses, suggesting non-endothelial cell contributions to CCM pathology.
Key Insights:
- Dysfunctional cellular crosstalk in CCM involves inflammation, EndMT, dysregulated angiogenesis, and immune responses.
- VEGF signaling pathways are activated in lesional ECs and pericytes, promoting angiogenesis.
- CCM pathogenesis is influenced by cell-specific alterations affecting EndMT, coagulation, and hypoxia.
Outlook:
- Findings provide mechanistic hypotheses for non-endothelial cell roles in CCM lesion development.
- Identification of specific cellular pathways and gene alterations offers potential novel therapeutic targets for CCM.
- Further research into cell-specific contributions may unlock new treatment strategies for this debilitating disease.
Abstract:
Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on fluorescence-activated cell sorted endothelial cells (ECs), pericytes, and neuroglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified vascular endothelial growth factor A/ vascular endothelial growth factor receptor 2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets. Video Abstract.
