Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis

Lina Fu; Yuqiong Hu; Moshi Song; Zunpeng Liu; Weiqi Zhang; Fa-Xing Yu; Jun Wu; Si Wang; Juan Carlos Izpisua Belmonte; Piu Chan; Jing Qu; Fuchou Tang; Guang-Hui Liu

doi:10.1371/journal.pbio.3000201

Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis

PLoS Biol. 2019 Apr 1;17(4):e3000201. doi: 10.1371/journal.pbio.3000201. eCollection 2019 Apr.

Authors

Lina Fu^{1

2

3}, Yuqiong Hu^{4

5}, Moshi Song^{3

6

7}, Zunpeng Liu^{2

3}, Weiqi Zhang^{1

3

7

8}, Fa-Xing Yu⁹, Jun Wu¹⁰, Si Wang^{1

8}, Juan Carlos Izpisua Belmonte¹¹, Piu Chan⁸, Jing Qu^{2

3

7}, Fuchou Tang^{4

5

12

13}, Guang-Hui Liu^{1

3

6

7

8

14}

Affiliations

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.
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.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Cell Proliferation / genetics
Cellular Senescence / physiology
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism*
Heterografts
Humans
Male
Mesenchymal Stem Cells / metabolism
Mesenchymal Stem Cells / pathology
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
Osteoarthritis / genetics
Osteoarthritis / metabolism*
Osteoarthritis / pathology*
Signal Transduction
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcriptional Activation
Up-Regulation
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
FOXD1 protein, human
Forkhead Transcription Factors
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human

Grants and funding

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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.