Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures.

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.

• Authors: Joseph Kelleher, Adam Dickinson, Stuart Cain, Yanhua Hu, Nicola Bates, Adam Harvey, Jianzhen Ren, Wenjun Zhang, Fiona C Moreton, Keith W Muir, Christopher Ward, Rhian M Touyz, Pankaj Sharma, Qingbo Xu, Susan J Kimber, Tao Wang
• Journal: Stem cell reports (Stem Cell Reports) Vol. 13 Issue 5 Pg. 817-831 (Nov 12 2019) ISSN: 2213-6711 [Electronic] United States
• PMID: 31680059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• NOTCH3 protein, human
• Receptor, Notch3
• Receptor, Platelet-Derived Growth Factor beta

Topics

• CADASIL (genetics, pathology)
• Cells, Cultured
• Dementia, Vascular (genetics, pathology)
• Down-Regulation
• Endothelial Cells (metabolism, pathology)
• Humans
• Induced Pluripotent Stem Cells (metabolism, pathology)
• Mutation
• Neovascularization, Pathologic (genetics, pathology)
• Receptor, Notch3 (genetics)
• Receptor, Platelet-Derived Growth Factor beta (analysis, genetics)