Format

Send to

Choose Destination
Protein Cell. 2019 Apr;10(4):249-271. doi: 10.1007/s13238-019-0608-1. Epub 2019 Feb 18.

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

Ling C1,2,3, Liu Z4,5, Song M6,5,7, Zhang W1,3,5,7, Wang S1,3,5,7, Liu X4,5, Ma S3,5,7, Sun S3,5, Fu L3,5, Chu Q4,5, Belmonte JCI8, Wang Z2, Qu J9,10,11, Yuan Y12, Liu GH13,14,15,16,17,18.

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
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
University of Chinese Academy of Sciences, Beijing, 100049, China.
6
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
7
Institute for Stem cell and Regeneration, CAS, Beijing, 100101, China.
8
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
9
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. qujing@ioz.ac.cn.
10
University of Chinese Academy of Sciences, Beijing, 100049, China. qujing@ioz.ac.cn.
11
Institute for Stem cell and Regeneration, CAS, Beijing, 100101, China. qujing@ioz.ac.cn.
12
Department of Neurology, Peking University First Hospital, Beijing, 100034, China. yuanyun2002@126.com.
13
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.
14
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. ghliu@ibp.ac.cn.
15
University of Chinese Academy of Sciences, Beijing, 100049, China. ghliu@ibp.ac.cn.
16
Institute for Stem cell and Regeneration, CAS, Beijing, 100101, China. ghliu@ibp.ac.cn.
17
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China. ghliu@ibp.ac.cn.
18
Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100069, China. ghliu@ibp.ac.cn.

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.

KEYWORDS:

CADASIL; NF-κB; NOTCH; iPSC; vascular smooth muscle

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center