Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells(i PSCs) from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation(c.3226C>T, p.R1076C). Vascular smooth muscle cells(VSMCs) differentiated from CADASIL-specific i PSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-κB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison,these abnormalities were not observed in vascular endothelial cells(VECs) derived from the patient's i PSCs. Importantly, the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this i PSCbased disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.