Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells.
10.1007/s13238-019-0608-1
- Author:
Chen LING
1
;
Zunpeng LIU
2
;
Moshi SONG
3
;
Weiqi ZHANG
1
;
Si WANG
1
;
Xiaoqian LIU
2
;
Shuai MA
4
;
Shuhui SUN
4
;
Lina FU
4
;
Qun CHU
2
;
Juan Carlos Izpisua BELMONTE
5
;
Zhaoxia WANG
6
;
Jing QU
7
;
Yun YUAN
8
;
Guang-Hui LIU
9
Author Information
1. Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
2. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
3. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
4. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
5. Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
6. Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
7. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. qujing@ioz.ac.cn.
8. Department of Neurology, Peking University First Hospital, Beijing, 100034, China. yuanyun2002@126.com.
9. Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. ghliu@ibp.ac.cn.
- Publication Type:Journal Article
- Keywords:
CADASIL;
NF-κB;
NOTCH;
iPSC;
vascular smooth muscle
- From:
Protein & Cell
2019;10(4):249-271
- CountryChina
- Language:English
-
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 iPSC-based disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.
