Endothelial cell clonal expansion in the development of cerebral cavernous malformations
| Autor: | Fabrizio Orsenigo, Maria Grazia Lampugnani, Matteo Malinverno, Federica Pisati, Abdallah Abu Taha, Peetra U. Magnusson, Monica Corada, Monica Giannotta, Yi Arial Zeng, Claudio Maderna, Carmela Fusco, Mariaelena Valentino, Qing Cissy Yu, Paolo Graziano, Elisabetta Dejana |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Hemangioma Cavernous Central Nervous System Cerebrovascular disorders Cell- och molekylärbiologi General Physics and Astronomy 02 engineering and technology Stem cell marker Benign tumor Central Nervous System Neoplasms Gene Knockout Techniques Mice Loss of Function Mutation lcsh:Science Mice Knockout Multidisciplinary Intracellular Signaling Peptides and Proteins Brain Cell Differentiation 021001 nanoscience & nanotechnology Endothelial stem cell Mechanisms of disease medicine.anatomical_structure Female 0210 nano-technology Endothelium Science Biology Article General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Proto-Oncogene Proteins medicine Animals Humans Progenitor cell Vascular disease Mesenchymal stem cell Endothelial Cells Membrane Proteins Mesenchymal Stem Cells General Chemistry medicine.disease Disease Models Animal 030104 developmental biology Cell culture Cancer research lcsh:Q Endothelium Vascular Apoptosis Regulatory Proteins Biomarkers Cell and Molecular Biology |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-16 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics. Cerebral cavernous malformation is a vascular disease characterized by capillary-venous cavernomas in the central nervous system. Here the authors show that cavernomas display benign tumor characteristics and originate from the clonal expansion of mutated endothelial progenitors which can attract surrounding wild-type cells, inducing their mesenchymal transition and leading to growth of the cavernoma. |
| Databáze: | OpenAIRE |
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