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

Abstract

Summary: 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. : Wang, Kimber and colleagues established an iPSC model for the most common genetic stroke and vascular dementia syndrome CADASIL, and identified primary defects of iPSC-derived mural cells in stabilizing vascular capillary structures with reduced PDGFRβ expression and VEGF secretion. Supplementation of VEGF significantly rescued the capillary destabilization, suggesting a therapeutic target. siRNA knockdown of NOTCH3 suggests a gain-of-function mechanism. Keywords: iPSC, iPSC disease model, small vessel disease, vascular dementia, CADASIL, NOTCH3, angiogenesis, pericytes, genetic stroke, notch signaling