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Updated: Feb 3, 2026
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Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model
Published on: September 4, 2017
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Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells
Matthew R Detter1,2, Daniel A Snellings1, Douglas A Marchuk1
1From the Molecular Genetics and Microbiology Department (M.R.D., D.A.S., D.A.M.), Duke University School of Medicine, Durham, NC.
Circulation Research
|October 26, 2018
Summary
Cerebral cavernous malformations (CCMs) develop from a single mutant endothelial cell (EC) that expands clonally. Larger CCMs incorporate wild-type ECs, suggesting a model for disease progression and potential therapeutic targets.
Area of Science:
- Vascular biology
- Genetics
- Cell biology
Background:
- Vascular malformations, including cerebral cavernous malformations (CCMs), are caused by genetic mutations.
- The specific cell lineages contributing to CCM development are not well understood.
Purpose of the Study:
- To visualize the contribution of mutant endothelial cells (ECs) to CCMs using an inducible mouse model.
- To elucidate the cellular mechanisms underlying CCM formation and growth.
Main Methods:
- Utilized an inducible mouse model of CCMs combined with a multicolor fluorescent reporter (confetti).
- Simultaneously deleted Ccm3 and labeled mutant ECs with distinct colors.
- Acquired 3D confocal images and reconstructed CCMs to analyze mutant EC contribution.
Main Results:
- CCMs were predominantly lined by ECs of a single clonal color, indicating clonal expansion.
- The distribution of clonally dominant ECs within CCMs was statistically significant (P<0.001).
- Small CCMs were mainly composed of clonally expanded mutant ECs, while larger CCMs incorporated wild-type ECs.
Conclusions:
- This study provides the first single-cell resolution visualization of clonal EC expansion in CCMs.
- A model of CCM development is proposed involving initial clonal expansion followed by wild-type EC incorporation.
- Understanding these cellular events may reveal novel therapeutic strategies for CCMs.
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