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Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells.

Publication ,  Journal Article
Detter, MR; Snellings, DA; Marchuk, DA
Published in: Circ Res
October 26, 2018

RATIONALE: Vascular malformations arise in vessels throughout the entire body. Causative genetic mutations have been identified for many of these diseases; however, little is known about the mutant cell lineage within these malformations. OBJECTIVE: We utilize an inducible mouse model of cerebral cavernous malformations (CCMs) coupled with a multicolor fluorescent reporter to visualize the contribution of mutant endothelial cells (ECs) to the malformation. METHODS AND RESULTS: We combined a Ccm3 mouse model with the confetti fluorescent reporter to simultaneously delete Ccm3 and label the mutant EC with 1 of 4 possible colors. We acquired Z-series confocal images from serial brain sections and created 3-dimensional reconstructions of entire CCMs to visualize mutant ECs during CCM development. We observed a pronounced pattern of CCMs lined with mutant ECs labeled with a single confetti color (n=42). The close 3-dimensional distribution, as determined by the nearest neighbor analysis, of the clonally dominant ECs within the CCM was statistically different than the background confetti labeling of ECs in non-CCM control brain slices as well as a computer simulation ( P<0.001). Many of the small (<100 μm diameter) CCMs consisted, almost exclusively, of the clonally dominant mutant ECs labeled with the same confetti color, whereas the large (>100 μm diameter) CCMs contained both the clonally dominant mutant cells and wild-type ECs. We propose of model of CCM development in which an EC acquires a second somatic mutation, undergoes clonal expansion to initiate CCM formation, and then incorporates neighboring wild-type ECs to increase the size of the malformation. CONCLUSIONS: This is the first study to visualize, with single-cell resolution, the clonal expansion of mutant ECs within CCMs. The incorporation of wild-type ECs into the growing malformation presents another series of cellular events whose elucidation would enhance our understanding of CCMs and may provide novel therapeutic opportunities.

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Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

October 26, 2018

Volume

123

Issue

10

Start / End Page

1143 / 1151

Location

United States

Related Subject Headings

  • Mutation
  • Mice, Inbred C57BL
  • Mice
  • Intracellular Signaling Peptides and Proteins
  • Hemangioma, Cavernous, Central Nervous System
  • Endothelial Cells
  • Clonal Evolution
  • Cardiovascular System & Hematology
  • Apoptosis Regulatory Proteins
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Detter, M. R., Snellings, D. A., & Marchuk, D. A. (2018). Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells. Circ Res, 123(10), 1143–1151. https://doi.org/10.1161/CIRCRESAHA.118.313970
Detter, Matthew R., Daniel A. Snellings, and Douglas A. Marchuk. “Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells.Circ Res 123, no. 10 (October 26, 2018): 1143–51. https://doi.org/10.1161/CIRCRESAHA.118.313970.
Detter MR, Snellings DA, Marchuk DA. Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells. Circ Res. 2018 Oct 26;123(10):1143–51.
Detter, Matthew R., et al. “Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells.Circ Res, vol. 123, no. 10, Oct. 2018, pp. 1143–51. Pubmed, doi:10.1161/CIRCRESAHA.118.313970.
Detter MR, Snellings DA, Marchuk DA. Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells. Circ Res. 2018 Oct 26;123(10):1143–1151.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

October 26, 2018

Volume

123

Issue

10

Start / End Page

1143 / 1151

Location

United States

Related Subject Headings

  • Mutation
  • Mice, Inbred C57BL
  • Mice
  • Intracellular Signaling Peptides and Proteins
  • Hemangioma, Cavernous, Central Nervous System
  • Endothelial Cells
  • Clonal Evolution
  • Cardiovascular System & Hematology
  • Apoptosis Regulatory Proteins
  • Animals