Dataset Information

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

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.

SUBMITTER: Orsenigo F

PROVIDER: S-EPMC7609066 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Orsenigo Fabrizio F Conze Lei Liu LL Jauhiainen Suvi S Corada Monica M Lazzaroni Francesca F Malinverno Matteo M Sundell Veronica V Cunha Sara Isabel SI Brännström Johan J Globisch Maria Ascención MA Maderna Claudio C Lampugnani Maria Grazia MG Magnusson Peetra Ulrica PU Dejana Elisabetta E

eLife 20201103

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 bra ...[more]

PMID: 33138917

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Project description: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 ?m diameter) CCMs consisted, almost exclusively, of the clonally dominant mutant ECs labeled with the same confetti color, whereas the large (>100 ?m 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.

Dataset Information

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

Publications

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

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