Endothelial cell clonal expansion in the development of cerebral cavernous malformations

Malinverno, Matteo; Maderna, Claudio; Taha, Abdallah Abu; Corada, Monica; Orsenigo, Fabrizio; Valentino, Mariaelena; Pisati, Federica; Fusco, Carmela; Graziano, Paolo; Giannotta, Monica; Yu, Qing; Zeng, Yi Arial; Lampugnani, Maria Grazia; Magnusson, Peetra U.; Dejana, Elisabetta

doi:10.1038/s41467-019-10707-x

Cited by 107 publications

(136 citation statements)

References 52 publications

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“…Our data also illustrate that the lining endothelium within human cavernous tissues is not a homogeneous cellular compartment of ECs that all had acquired a second postzygotic loss-of-function variant ( CCM1 −/− ), but a mosaic of ECs with retained CCM1 expression and with complete CCM1 inactivation. This observation is reminiscent to what has recently been shown in two mouse models for CCM3, in which endothelial mosaicism of mutant and wild-type ECs was observed in expanded lesions 13 14. Similarly, the large cavernoma of our index patient is most likely the product of a clonally expanded CCM1 −/− EC and heterozygous CCM1 +/− ECs (figure 1G).…”

Section: Discussionsupporting

confidence: 87%

“…Thus, only little experimental evidence has been published to support a genetic two-step inactivation of CCM1, CCM2 and CCM3 (table 1). 8–12 Recent data from two murine models implicate that clonal expansion of ECs after biallelic Ccm3 inactivation initiates cavernoma formation, while incorporation of ECs without a second mutation contributes to their growth 13 14. Lately, a novel human EC culture model specified that CCM3 inactivation results in a survival benefit of functionally impaired ECs that are unable to form spheroids 15…”

Section: Introductionmentioning

confidence: 99%

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Postzygotic mosaicism in cerebral cavernous malformation

et al. 2019

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BackgroundCerebral cavernous malformations (CCMs) can cause severe neurological morbidity but our understanding of the mechanisms that drive CCM formation and growth is still incomplete. Recent experimental data suggest that dysfunctional CCM3-deficient endothelial cell clones form cavernous lesions in conjunction with normal endothelial cells.ObjectiveIn this study, we addressed the question whether endothelial cell mosaicism can be found in human cavernous tissue of CCM1 germline mutation carriers.Methods and resultsBringing together single-molecule molecular inversion probes in an ultra-sensitive sequencing approach with immunostaining to visualise the lack of CCM1 protein at single cell resolution, we identified a novel late postzygotic CCM1 loss-of-function variant in the cavernous tissue of a de novo CCM1 germline mutation carrier. The extended unilateral CCM had been located in the right central sulcus causing progressive proximal paresis of the left arm at the age of 15 years. Immunohistochemical analyses revealed that individual caverns are lined by both heterozygous (CCM1+/−) and compound heterozygous (CCM1−/−) endothelial cells.ConclusionWe here demonstrate endothelial cell mosaicism within single caverns of human CCM tissue. In line with recent in vitro data on CCM1-deficient endothelial cells, our results provide further evidence for clonal evolution in human CCM1 pathogenesis.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Postzygotic mosaicism in cerebral cavernous malformation

et al. 2019

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“…Considering that our group recently reported that cavernomas have clonal origins from expansion of Pdcd10 -ko progenitor cells ( Malinverno et al, 2019 ), we investigated the distribution of cells that expressed progenitor cell markers in the STREAM-generated trajectories. We therefore quantified each branch for the proportions of cells positive for Bst1 , Peg3 , Procr , and Cd200 (i.e.…”

Section: Resultsmentioning

confidence: 99%

Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution

Orsenigo

Conze

Jauhiainen

et al. 2020

eLife

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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.

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“…Normal intussusceptive angiogenesis requires an orderly patterning of high and low flow signaling 33 The dilated multi-cavernous CVP lesions described here resemble human multicavernous CCM 3 and their formation required mosaicism. Recent elegant studies found that multi-cavernous murine CCM are mosaic for inactivation of Ccm3 45,46 . The mouse studies emphasized that simply dilated vessels are not mosaic and contained only Ccm3 null endothelial cells 45,46 .…”

Section: Ccm2 Mosaicism Causes Multi-cavernous Malformationsmentioning

confidence: 99%

Abortive Intussusceptive Angiogenesis Causes Multi-Cavernous Vascular Malformations

Tran

Shaked

et al. 2020

Preprint

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Mosaic inactivation of CCM2 in humans causes cerebral cavernous malformations (CCMs) containing adjacent dilated blood-filled multi-cavernous lesions. We used CRISPR-Cas9 mutagenesis to inactivate zebrafish ccm2 resulting in novel lethal multi-cavernous lesions in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic intussusceptive angiogenesis; however, the pillars failed to fuse to split the pre-existing vessel in two. Abortive intussusceptive angiogenesis stemmed from mosaic inactivation of ccm2 leading to patchy klf2a over-expression and resulting aberrant flow signaling. Surviving adult fish manifested histologically-typical hemorrhagic CCM. Formation of mammalian CCM requires flow-regulated transcription factors, KLF2 and KLF4; fish CCM and the embryonic CVP lesion failed to form in klf2a null fish indicating a common pathogenesis with the mammalian lesion. These studies describe the first zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.

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Endothelial cell clonal expansion in the development of cerebral cavernous malformations

Cited by 107 publications

References 52 publications

Postzygotic mosaicism in cerebral cavernous malformation

Postzygotic mosaicism in cerebral cavernous malformation

Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution

Abortive Intussusceptive Angiogenesis Causes Multi-Cavernous Vascular Malformations

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