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Updated: Dec 2, 2025
Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model
Published on: September 4, 2017
Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution
Fabrizio Orsenigo1, Lei Liu Conze2, Suvi Jauhiainen2
1Vascular Biology Unit, FIRC Institute of Molecular Oncology Foundation (IFOM), Milan, Italy.
Insights
Cerebral cavernous malformation (CCM) originates from specific venous endothelial cells, not arterial ones. This study reveals cellular origins of CCM lesions using advanced single-cell techniques.
Area of Science:
- Neuroscience
- Vascular Biology
- Genetics
Background:
- Cerebral cavernous malformation (CCM) is a rare neurovascular disorder.
- CCM is characterized by abnormal blood vessels leading to hemorrhage.
- Mutations in KRIT1, CCM2, or PDCD10 (CCM3) cause CCM.
Purpose of the Study:
- To comprehensively characterize brain endothelial cell (EC) subclasses in normal conditions and in a mouse model of CCM.
- To identify the specific EC subtypes involved in CCM lesion formation.
- To elucidate the molecular basis of CCM at the single-cell level.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq)
- Spatial transcriptomics
- Immunohistochemistry
- Mouse model of CCM with Pdcd10 deletion
Main Results:
- Arterial ECs are resistant to CCM transformation.
- A subset of angiogenic venous capillary ECs and endothelial progenitors are the origin of CCM lesions.
- scRNA-seq and spatial transcriptomics identified distinct EC subclasses involved in CCM.
Conclusions:
- CCM development involves specific venous endothelial cell populations.
- Understanding EC plasticity is key to CCM pathogenesis.
- This study provides novel single-cell insights into the molecular mechanisms of CCM disease.
Abstract:
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.
