Patient-specific iPSC model of a genetic vascular dementia syndrome reveals failure of mural cells to stabilize capillary structures

Kelleher, J. et al. (2019) Patient-specific iPSC model of a genetic vascular dementia syndrome reveals failure of mural cells to stabilize capillary structures. Stem Cell Reports, 13(5), pp. 817-831. (doi: 10.1016/j.stemcr.2019.10.004) (PMID:31680059) (PMCID:PMC6893064)

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Abstract

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor β, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets.

Item Type:Articles
Additional Information:The study is mainly funded by British Heart Foundation (BHF) (PG/12/31/2952) and the National Centre for the Replacement, Reduction and Refinement of Animals in Research (NC3Rs, NC/K001744/1). The work is also supported by MRC UK Regenerative Medicine Platform funding (MR/K026666/1), the Stroke Association and a MRC Confidence in Concept grant. We thank Dr Helen Murphy and Iris Trender-Gerhard from Manchester Centre for Genomic Medicine (MCGM) for helping recruiting and biopsy CADASIL patients, and Meenakshi Minnis and Stephen Trueman in MCGM for helping growing HDFs and karyotyping iPSCs. We also thank Drs Karla Neves and Augusto Montezano, Institute of Cardiovascular and Medical Sciences, Glasgow, for helping with the CADASIL cell culture and Dr Paul Rocchicciolli, Golden Jubilee National Hospital, Glasgow, for helping with the biopsies from CADASIL patients.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Moreton, Dr Fiona and Harvey, Dr Adam and Muir, Professor Keith and Touyz, Professor Rhian
Authors: Kelleher, J., Dickinson, A., Cain, S., Hu, Y., Bates, N., Harvey, A., Ren, J., Zhang, W., Moreton, F. C., Muir, K. W., Ward, C., Touyz, R. M., Sharma, P., Xu, Q., Kimber, S. J., and Wang, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Stem Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2213-6711
ISSN (Online):2213-6711
Published Online:31 October 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Stem Cell Reports 13(5): 817-831
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
300689Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762CAMS - Cardiovascular Science
190814BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177Institute of Cardiovascular & Medical Sciences