Journal
PROTEIN & CELL
Volume 10, Issue 4, Pages 249-271Publisher
SPRINGER
DOI: 10.1007/s13238-019-0608-1
Keywords
CADASIL; iPSC; NOTCH; NF-B; vascular smooth muscle
Categories
Funding
- National Key Research and Development Program of China [2017YFA0103304, 2017YFA0102802, 2018YFA0107203, 2016YFC1300605, 2015CB964800, 2014CB910503, 2018YFC2000100]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16010100]
- National Natural Science Foundation of China [81625009, 81330008, 91749202, 91749123, 31671429, 81671377, 81771515, 31601109, 31601158, 81701388, 81601233, 81471414, 81870228, 81822018, 81801399, 31801010, 81801370, 81861168034, 81471185]
- Program of Beijing Municipal Science and Technology Commission [Z151100003915072]
- Key Research Program of the Chinese Academy of Sciences [KJZDEWTZ-L05]
- Beijing Municipal Commission of Health and Family Planning [PXM2018_026283_000002]
- Advanced Innovation Center for Human Brain Protection [117212]
- State Key Laboratory of Membrane Biology
- UCAM
- Pedro Guillen
- Helmsley Foundation
- AFE
- Moxie Foundation
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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 (iPSCs) from fibroblasts ofa CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-B 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 iPSCs. Importantly, the abnormal upregulation of NF-B target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identifiedclues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.
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