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

• DOI: 10.1007/s13238-019-0608-1
• Publication Date: 2019-02-18T11:25:22Z
• Authors: Chen Ling; Zunpeng Liu; Moshi Song; Weiqi Zhang; Si Wang; Xiaoqian Liu; Shuai Ma; Shuhui Sun; Lina Fu; Qun Chu; Juan Carlos Izpis...; Zhaoxia Wang; Jing Qu; Yun Yuan; Guang-Hui Liu
• Keywords: CADASIL

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