Zunpeng Liu
Moshi Song
Weiqi Zhang
Si Wang
Xiaoqian Liu
Shuai Ma
Shuhui Sun
Lina Fu
Qun Chu
Juan Carlos Izpisua Belmonte
Zhaoxia Wang
Jing Qu
Yun Yuan
Guang-Hui Liu
1 Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China;
2 Department of Neurology, Peking University First Hospital, Beijing 100034, China;
3 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
4 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
5 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
6 University of Chinese Academy of Sciences, Beijing 100049, China;
7 Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA;
8 Institute for Stem cell and Regeneration, CAS, Beijing 100101, China;
9 Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China;
10 Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
Funds: This work was supported by the National Key Research and Development Program of China (2018YFC2000100), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key Research and Development Program of China (2017YFA0103304, 2017YFA0102802, 2018YFA0107203, 2016YFC1300605, 2015CB964800 and 2014CB910503), the National Natural Science Foundation of China (81625009, 81330008, 91749202, 91749123, 31671429, 81671377, 81771515, 31601109, 31601158, 81701388, 81601233, 81471414, 81870228, 81822018, 81801399, 31801010, 81801370, 81861168034 and 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), and the State Key Laboratory of Membrane Biology.
Received Date: 2018-12-02
Abstract
Abstract
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 of a 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-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 iPSCs. 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 iPSCbased disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.Keywords: CADASIL,
iPSC,
NOTCH,
NF-κB,
vascular smooth muscle
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