A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases.

Autor:	Al-Thani M; Department of Clinical Neurosciences, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge and Royal Papworth Hospital, Cambridge, UK., Goodwin-Trotman M; Department of Clinical Neurosciences, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge and Royal Papworth Hospital, Cambridge, UK., Bell S; Department of Clinical Neurosciences, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge and Royal Papworth Hospital, Cambridge, UK., Patel K; Department of Clinical Neurosciences, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge and Royal Papworth Hospital, Cambridge, UK., Fleming LK; School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK., Vilain C; Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Universite Libre de Bruxelles, Bruxelles, Belgium., Abramowicz M; Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Universite Libre de Bruxelles, Bruxelles, Belgium., Allan SM; Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK., Wang T; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust, The University of Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK., Cader MZ; Nuffield Department of Clinical Neurosciences, Kavli Institute of Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, Sherrington Road, University of Oxford, Oxford, UK., Horsburgh K; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Van Agtmael T; School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK., Sinha S; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK., Markus HS; Department of Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Granata A; Department of Clinical Neurosciences, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge and Royal Papworth Hospital, Cambridge, UK. Electronic address: ag686@cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2023 Dec 12; Vol. 18 (12), pp. 2386-2399. Date of Electronic Publication: 2023 Nov 16.
DOI:	10.1016/j.stemcr.2023.10.014
Abstrakt:	Cerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology, but this remains poorly characterized. To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients with COL4A1/A2 SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodeling, and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cell tight junctions through paracrine actions. COL4A1/A2 models also express high levels of matrix metalloproteinases (MMPs), and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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