1. Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution
- Author
-
Francesca Lazzaroni, Matteo Malinverno, Peetra U. Magnusson, Monica Corada, Sara I. Cunha, Maria Ascención Globisch, Claudio Maderna, Lei Liu Conze, Suvi Jauhiainen, Maria Grazia Lampugnani, Veronica Sundell, Johan Brännström, Fabrizio Orsenigo, and Elisabetta Dejana
- Subjects
0301 basic medicine ,Pathology ,Hemangioma, Cavernous, Central Nervous System ,Mouse ,Cell- och molekylärbiologi ,Cell ,blood brain barrier ,Transcriptome ,Mice ,0302 clinical medicine ,RNA-Seq ,Biology (General) ,Microscopy, Confocal ,Neovascularization, Pathologic ,spatial transcriptomics ,General Neuroscience ,Brain ,vascular disease ,Cell Differentiation ,General Medicine ,cerebral cavernous malformation ,Arteries ,Immunohistochemistry ,3. Good health ,Endothelial stem cell ,medicine.anatomical_structure ,Phenotype ,Medicine ,Single-Cell Analysis ,Research Article ,Signal Transduction ,medicine.medical_specialty ,QH301-705.5 ,Science ,Mitosis ,Biology ,Blood–brain barrier ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,single cell RNA sequencing ,medicine ,Animals ,Progenitor cell ,Gene ,General Immunology and Microbiology ,Vascular disease ,Sequence Analysis, RNA ,Endothelial Cells ,Genetics and Genomics ,vascular biology ,Cell Biology ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Tamoxifen ,030104 developmental biology ,Apoptosis Regulatory Proteins ,030217 neurology & neurosurgery ,Cell and Molecular Biology ,Gene Deletion - 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.
- Published
- 2020