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

• Published in: eLife Vol. 9
• Main Authors: Orsenigo, Fabrizio, Conze, Lei Liu, Jauhiainen, Suvi, Corada, Monica, Lazzaroni, Francesca, Malinverno, Matteo, Sundell, Veronica, Cunha, Sara Isabel, Brännström, Johan, Globisch, Maria Ascención, Maderna, Claudio, Lampugnani, Maria Grazia, Magnusson, Peetra Ulrica, Dejana, Elisabetta
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 03.11.2020; eLife Sciences Publications, Ltd; eLife Sciences Publications Ltd
• Subjects: Analysis; Animals; Apoptosis Regulatory Proteins - metabolism; Arteries - pathology; blood brain barrier; Brain; Brain - blood supply; Brain - pathology; Cell Biology; Cell Differentiation; cerebral cavernous malformation; Disease Models, Animal; Endothelial Cells - cytology; Endothelium; Gene Deletion; Genetics and Genomics; Hemangioma, Cavernous, Central Nervous System - physiopathology; Immunohistochemistry; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Mitosis; Neovascularization, Pathologic; Phenotype; RNA sequencing; RNA-Seq; Sequence Analysis, RNA; Signal Transduction - genetics; single cell RNA sequencing; Single-Cell Analysis; spatial transcriptomics; Tamoxifen - pharmacology; Transcriptome; vascular biology; vascular disease; blood brain barrier; cerebral cavernous malformation; mouse; cell biology; genetics; vascular disease; single cell RNA sequencing; spatial transcriptomics; genomics; vascular biology
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.61413

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, , , and . 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 ( 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.