期刊
PLOS BIOLOGY
卷 17, 期 4, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.3000201
关键词
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资金
- National Key Research and Development Program of China [2018YFC2000100, 2017YFA0103304, 2017YFA0102802, 2018YFA0107203, 2015CB964800, 2014CB910503]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16010100]
- National Natural Science Foundation of China [91749202, 81625009, 31671429, 91749123, 81330008, 81601233, 81671377, 31601109, 31601158, 81771515, 81701388, 81870228, 81822018, 81801399, 31801010, 81801370, 81861168034]
- Program of Beijing Municipal Science and Technology Commission [Z151100003915072]
- Beijing Municipal Commission of Health and Family Planning [PXM2018_026283_000002]
- Advanced Innovation Center for Human Brain Protection [3500-1192012]
- State Key Laboratory of Membrane Biology
- G. Harold and Leila Y. Mathers Charitable Foundation
- Glenn Foundation
- Fundacion Dr. Pedro Guillen
- Universidad Catolica San Antonio de Murcia (UCAM)
Cellular senescence is a driver of various aging-associated disorders, including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (hMSCs) and ameliorating osteoarthritis in mice. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 nuclease (Cas9)-mediated knockout (KO) of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP cooperated with TEA domain transcriptional factor (TEAD) to activate the expression of forkhead box D1 (FOXD1), a geroprotective protein. YAP deficiency led to the down-regulation of FOXD1. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vector encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential target for gene therapy to alleviate osteoarthritis.
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