机构：[1]National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China,[2]State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China,[3]University of Chinese Academy of Sciences, Beijing, China,[4]Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Peking University, Beijing, China,[5]Biomedical Pioneering Innovation Center, Peking University, Beijing, China,[6]State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China,[7]Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China,[8]Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China,首都医科大学宣武医院衰老与再生研究中心国家老年疾病临床医学研究中心[9]Children’s Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China,[10]Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America,[11]Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America,[12]Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China,[13]Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing, China,[14]Beijing Institute for Brain Disorders, Beijing, China
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.
基金：
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, 2015CB964800,
2014CB910503), the National Natural Science
Foundation of China (91749202, 81625009,
31671429, 91749123, 81330008, 81601233,
81671377, 31601109, 31601158, 81771515,
81701388, 81870228, 81822018, 81801399,
31801010, 81801370 and 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) and the State Key Laboratory of
Membrane Biology. Work in the laboratory of J.C.I.
B. was supported by the G. Harold and Leila Y.
Mathers Charitable Foundation, the Glenn
Foundation, Fundacion Dr. Pedro Guillen and
Universidad Catolica San Antonio de Murcia
(UCAM).
第一作者机构：[1]National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China,[2]State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China,[3]University of Chinese Academy of Sciences, Beijing, China,
共同第一作者：
通讯作者：
通讯机构：[2]State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China,[3]University of Chinese Academy of Sciences, Beijing, China,[4]Beijing Advanced Innovation Center for Genomics, College of Life Sciences, Peking University, Beijing, China,[5]Biomedical Pioneering Innovation Center, Peking University, Beijing, China,[6]State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China,[7]Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China,[8]Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China,[12]Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China,[13]Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing, China,[14]Beijing Institute for Brain Disorders, Beijing, China
推荐引用方式(GB/T 7714)：
Lina Fu,Yuqiong Hu,Moshi Song,et al.Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis[J].PLOS BIOLOGY.2019,17(4):e3000201.doi:10.1371/journal.pbio.3000201.
APA：
Lina Fu,Yuqiong Hu,Moshi Song,Zunpeng Liu,Weiqi Zhang...&Guang-Hui Liu.(2019).Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis.PLOS BIOLOGY,17,(4)
MLA：
Lina Fu,et al."Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis".PLOS BIOLOGY 17..4(2019):e3000201
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