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Endothelial cell clonal expansion in the development of cerebral cavernous malformations

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, whi...

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Autores principales: Malinverno, Matteo, Maderna, Claudio, Abu Taha, Abdallah, Corada, Monica, Orsenigo, Fabrizio, Valentino, Mariaelena, Pisati, Federica, Fusco, Carmela, Graziano, Paolo, Giannotta, Monica, Yu, Qing Cissy, Zeng, Yi Arial, Lampugnani, Maria Grazia, Magnusson, Peetra U., Dejana, Elisabetta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591323/
https://www.ncbi.nlm.nih.gov/pubmed/31235698
http://dx.doi.org/10.1038/s41467-019-10707-x
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author Malinverno, Matteo
Maderna, Claudio
Abu Taha, Abdallah
Corada, Monica
Orsenigo, Fabrizio
Valentino, Mariaelena
Pisati, Federica
Fusco, Carmela
Graziano, Paolo
Giannotta, Monica
Yu, Qing Cissy
Zeng, Yi Arial
Lampugnani, Maria Grazia
Magnusson, Peetra U.
Dejana, Elisabetta
author_facet Malinverno, Matteo
Maderna, Claudio
Abu Taha, Abdallah
Corada, Monica
Orsenigo, Fabrizio
Valentino, Mariaelena
Pisati, Federica
Fusco, Carmela
Graziano, Paolo
Giannotta, Monica
Yu, Qing Cissy
Zeng, Yi Arial
Lampugnani, Maria Grazia
Magnusson, Peetra U.
Dejana, Elisabetta
author_sort Malinverno, Matteo
collection PubMed
description 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.
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spelling pubmed-65913232019-06-26 Endothelial cell clonal expansion in the development of cerebral cavernous malformations Malinverno, Matteo Maderna, Claudio Abu Taha, Abdallah Corada, Monica Orsenigo, Fabrizio Valentino, Mariaelena Pisati, Federica Fusco, Carmela Graziano, Paolo Giannotta, Monica Yu, Qing Cissy Zeng, Yi Arial Lampugnani, Maria Grazia Magnusson, Peetra U. Dejana, Elisabetta Nat Commun Article 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. Nature Publishing Group UK 2019-06-24 /pmc/articles/PMC6591323/ /pubmed/31235698 http://dx.doi.org/10.1038/s41467-019-10707-x Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Malinverno, Matteo
Maderna, Claudio
Abu Taha, Abdallah
Corada, Monica
Orsenigo, Fabrizio
Valentino, Mariaelena
Pisati, Federica
Fusco, Carmela
Graziano, Paolo
Giannotta, Monica
Yu, Qing Cissy
Zeng, Yi Arial
Lampugnani, Maria Grazia
Magnusson, Peetra U.
Dejana, Elisabetta
Endothelial cell clonal expansion in the development of cerebral cavernous malformations
title Endothelial cell clonal expansion in the development of cerebral cavernous malformations
title_full Endothelial cell clonal expansion in the development of cerebral cavernous malformations
title_fullStr Endothelial cell clonal expansion in the development of cerebral cavernous malformations
title_full_unstemmed Endothelial cell clonal expansion in the development of cerebral cavernous malformations
title_short Endothelial cell clonal expansion in the development of cerebral cavernous malformations
title_sort endothelial cell clonal expansion in the development of cerebral cavernous malformations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591323/
https://www.ncbi.nlm.nih.gov/pubmed/31235698
http://dx.doi.org/10.1038/s41467-019-10707-x
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