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Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize
Joseph Kelleher1, Adam Dickinson2, Stuart Cain3
1School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK; Division of Evolution and Genomic Sciences, The University of Manchester, Manchester, UK.
Insights
Patient-derived stem cells reveal CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) vascular cells fail to stabilize brain capillaries. Vascular Endothelial Growth Factor (VEGF) partially restored function, suggesting new therapeutic targets for this genetic stroke condition.
Area of Science:
- Neuroscience
- Genetics
- Stem Cell Biology
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic stroke and vascular dementia syndrome caused by NOTCH3 mutations.
- Understanding the molecular basis of CADASIL is crucial for developing effective treatments.
Purpose of the Study:
- To establish a patient-specific induced pluripotent stem cell (iPSC) model for CADASIL.
- To investigate the role of vascular mural cells (iPSC-MCs) in CADASIL pathogenesis.
- To identify potential drug targets for CADASIL.
Main Methods:
- Generated patient-specific iPSCs and differentiated them into vascular mural cells (iPSC-MCs).
- Assessed iPSC-MC function in capillary stabilization assays.
- Analyzed protein expression (platelet-derived growth factor receptor β) and angiogenic factor secretion (VEGF).
- Utilized small interfering RNA (siRNA) to knock down NOTCH3 and investigate gain-of-function mechanisms.
Main Results:
- Patient iPSC-MCs demonstrated impaired ability to engage and stabilize endothelial capillary structures.
- Reduced platelet-derived growth factor receptor β and VEGF secretion were observed in patient iPSC-MCs.
- Patient iPSC-MCs induced apoptosis in adjacent endothelial cells.
- VEGF supplementation partially rescued capillary destabilization.
- NOTCH3 knockdown revealed a gain-of-function mechanism for mutant NOTCH3.
Conclusions:
- CADASIL involves a failure of vascular mural cells in stabilizing brain capillaries, likely due to mutant NOTCH3 gain-of-function.
- These cellular defects contribute to impaired brain repair, hypoperfusion, and dementia in CADASIL.
- The findings highlight VEGF and NOTCH3 pathways as potential therapeutic targets for CADASIL.
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.
