Weiqi Zhang
Moshi Song
Wei Wang
Gang Wei
Wei Li
Jinghui Lei
Yu Huang
Yanmei Sang
Piu Chan
Chang Chen
Jing Qu
Keiichiro Suzuki
Juan Carlos Izpisua Belmonte
Guang-Hui Liu
1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
2 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
3 University of Chinese Academy of Sciences, Beijing 100049, China;
4 National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing 100053, China;
5 State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
6 Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
7 Department of Medical genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;
8 Department of Pediatric Endocrinology and Genetic Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China;
9 Institute for Advanced Co-Creation Studies, Osaka University, Osaka 560-8531, Japan;
10 Graduate School of Engineering Science, Osaka University, Osaka 560-8531, Japan;
11 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla 92037, USA;
12 Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
Funds: This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key R&D Program of China (2015CB964800, 2017YFA0103304, 2017YFA0102802, 2014CB910503), the National High Technology Research and Development Program of China (2015AA020307), CAS (KJZDEWTZ-L05, and CXJJ-16M271), the National Natural Science Foundation of China (Grant Nos. 81625009, 81330008, 91749202, 91749123, 81371342, 81471414, 81422017, 81401159, 31671429, 81601233, 81671377, 31601109, 31601158, 81771515 and 81701388), Program of Beijing Municipal Science and Technology Commission (Z151100003915072), the Thousand Young Talents Program of China, and the State Key Laboratory of Stem Cell and Reproductive Biology (2016SRLab-KF13).
Received Date: 2018-01-18
Rev Recd Date:2018-02-08
Abstract
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS-and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.Keywords: WRN,
lamin,
HGPS,
Werner syndrome,
stem cell,
aging
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