scholarly journals Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells

2018 ◽  
Vol 123 (10) ◽  
pp. 1143-1151 ◽  
Author(s):  
Matthew R. Detter ◽  
Daniel A. Snellings ◽  
Douglas A. Marchuk
Keyword(s):  
Endothelial Cells ◽  
Clonal Expansion ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations

scholarly journals Cerebral Cavernous Malformations Develop through Clonal Expansion of Mutant Endothelial Cells

2018 ◽  
Author(s):  
Matthew R. Detter ◽  
Daniel A. Snellings ◽  
Douglas A. Marchuk
Keyword(s):  
Endothelial Cells ◽  
Mouse Model ◽  
Vascular Malformations ◽  
Brain Slices ◽  
Clonal Expansion ◽  
Entire Body ◽  
Cerebral Cavernous Malformations ◽  
Fluorescent Reporter ◽  
Cavernous Malformations ◽  
Dominant Mutant

AbstractRationaleVascular 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.ObjectiveWe utilize an inducible mouse model of cerebral cavernous malformations (CCMs) coupled with a multi-color fluorescent reporter to visualize the contribution of mutant endothelial cells (ECs) to the malformation.Methods and ResultsWe combined a Ccm3 mouse model with the confetti fluorescent reporter to simultaneously delete Ccm3 and label the mutant EC with one of four possible colors. We acquired Z-series confocal images from serial brain sections and created 3D 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 3D 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 (<100μm diameter) CCMs consisted, almost exclusively, of the clonally dominant mutant ECs labeled with the same confetti color whereas the large (>100μm diameter) CCMs contained both the clonally dominant mutant cells and wildtype 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 wildtype ECs to increase the size of the malformation.ConclusionsThis is the first study to visualize, with single-cell resolution, the clonal expansion of mutant ECs within CCMs. The incorporation of wildtype 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.

scholarly journals Endothelial cell clonal expansion in the development of cerebral cavernous malformations

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Matteo Malinverno ◽  
Claudio Maderna ◽  
Abdallah Abu Taha ◽  
Monica Corada ◽  
Fabrizio Orsenigo ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Clonal Expansion ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Cell Clonal Expansion

scholarly journals The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3

2015 ◽  
Vol 112 (46) ◽  
pp. 14284-14289 ◽  
Author(s):  
Xavier Cullere ◽  
Eva Plovie ◽  
Paul M. Bennett ◽  
Calum A. MacRae ◽  
Tanya N. Mayadas
Keyword(s):  
Endothelial Cells ◽  
Cavernous Malformation ◽  
Body Axis ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
Downstream Target ◽  
Density Flow

Three genes, CCM1, CCM2, and CCM3, interact genetically and biochemically and are mutated in cerebral cavernous malformations (CCM). A recently described member of this CCM family of proteins, CCM2-like (CCM2L), has high homology to CCM2. Here we show that its relative expression in different tissues differs from that of CCM2 and, unlike CCM2, the expression of CCM2L in endothelial cells is regulated by density, flow, and statins. In vitro, both CCM2L and CCM2 bind MEKK3 in a complex with CCM1. Both CCM2L and CCM2 interfere with MEKK3 activation and its ability to phosphorylate MEK5, a downstream target. The in vivo relevance of this regulation was investigated in zebrafish. A knockdown of ccm2l and ccm2 in zebrafish leads to a more severe “big heart” and circulation defects compared with loss of function of ccm2 alone, and also leads to substantial body axis abnormalities. Silencing of mekk3 rescues the big heart and body axis phenotype, suggesting cross-talk between the CCM proteins and MEKK3 in vivo. In endothelial cells, CCM2 deletion leads to activation of ERK5 and a transcriptional program that are downstream of MEKK3. These findings suggest that CCM2L and CCM2 cooperate to regulate the activity of MEKK3.

Co-expression of tissue factor and IL-6 in immature endothelial cells of cerebral cavernous malformations

2017 ◽  
Vol 37 ◽  
pp. 83-90 ◽  
Author(s):  
Shouhei Noshiro ◽  
Takeshi Mikami ◽  
Yuko Kataoka-Sasaki ◽  
Masanori Sasaki ◽  
Hirofumi Ohnishi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations

scholarly journals CCM2 deficient endothelial cells undergo a mechano-dependent reprogramming into senescence associated secretory phenotype used to recruit endothelial and immune cells

2021 ◽  
Author(s):  
Daphné Raphaëlle Vannier ◽  
Apeksha Shapeti ◽  
Florent Chuffart ◽  
Emmanuelle Planus ◽  
Sandra Manet ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Cerebrovascular Disease ◽  
Immune Cells ◽  
Cerebral Cavernous Malformations ◽  
Wild Type ◽  
Cellular Mechanics ◽  
Cavernous Malformations ◽  
Secretory Phenotype ◽  
The Brain

AbstractCerebral Cavernous Malformations (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic capillaries form focally in the brain. Whether and how defective mechanotransduction, cellular mosaicism and inflammation interplay to sustain the progression of CCM diseases is unknown. Here, we reveal that CCM1- and CCM2-silenced endothelial cells enter into senescence associated with secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the mechanical and molecular disorders provoked by ROCKs dysfunctions. By this, we identify CCM1/2 and ROCKs as parts of a scaffold controlling senescence, bringing new insights into the emerging field of the control of aging by cellular mechanics. This discovery reconciles the dysregulated traits of CCM1/2-deficient endothelial cells into a unique mechano-dependent endothelial fate that links perturbed mechanics to microenvironment remodelling and long-range activation of endothelial and immune cells.

scholarly journals Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Courtney C. Hong ◽  
Alan T. Tang ◽  
Matthew R. Detter ◽  
Jaesung P. Choi ◽  
Rui Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Wild Type ◽  
Lesion Formation ◽  
Cavernous Malformations ◽  
A Cell ◽  
Early Lesion

Cerebral cavernous malformations (CCMs) form following loss of the CCM protein complex in brain endothelial cells due to increased endothelial MEKK3 signaling and KLF2/4 transcription factor expression, but the downstream events that drive lesion formation remain undefined. Recent studies have revealed that CCM lesions expand by incorporating neighboring wild-type endothelial cells, indicative of a cell nonautonomous mechanism. Here we find that endothelial loss of ADAMTS5 reduced CCM formation in the neonatal mouse model. Conversely, endothelial gain of ADAMTS5 conferred early lesion genesis in the absence of increased KLF2/4 expression and synergized with KRIT1 loss of function to create large malformations. Lowering versican expression reduced CCM burden, indicating that versican is the relevant ADAMTS5 substrate and that lesion formation requires proteolysis but not loss of this extracellular matrix protein. These findings identify endothelial secretion of ADAMTS5 and cleavage of versican as downstream mechanisms of CCM pathogenesis and provide a basis for the participation of wild-type endothelial cells in lesion formation.

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