Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling

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外文摘要：The synovium,a thin layer of tissue that is adjacent to the joints and secretes synovial fluid,undergoes changes in aging that contribute to intense shoulder pain and other joint diseases.However,the mechanism underlying human synovial aging remains poorly characterized.Here,we generated a comprehensive transcriptomic profile of synovial cells present in the subacromial synovium from young and aged individuals.By delineating aging-related transcriptomic changes across different cell types and their associated regulatory networks,we identified two sub-sets of mesenchymal stromal cells(MSCs)in human synovium,which are lining and sublining MSCs,and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated in aged MSCs.Moreover,the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling,including vascular hyperplasia and tissue fibrosis.In particular,we identified forkhead box O1(FOXO1)as one of the major regulons for aging differen-tially expressed genes(DEGs)in synovial MSCs,and validated its downregulation in both lining and sublining MSC populations of the aged synovium.In human FOXO1-depleted MSCs derived from human embryonic stem cells,we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors.These data indicate an important role of FOXO1 in the regulation of human synovial aging.Overall,our study improves our understand-ing of synovial aging during joint degeneration,thereby informing the development of novel intervention strategies aimed at rejuvenating the aged joint.

外文关键词：

agingsingle-nucleus RNA sequencingsynoviumFOXO1senescence

作者：

Feifei Liu、Yi Lu、Xuebao Wang、Shuhui Sun、Huize Pan、Min Wang、Zehua Wang、Weiqi Zhang、Shuai Ma、Guoqiang Sun、Qun Chu、Si Wang、Jing Qu、Guang-Hui Liu

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作者单位：

State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China

Sports Medicine Department,Beijing Jishuitan Hospital,Capital Medical University,Beijing 100035,China

State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China

University of Chinese Academy of Sciences,Beijing 100049,China

Institute for Stem Cell and Regeneration,Chinese Academy of Sciences,Beijing 100101,China

Beijing Institute for Stem Cell and Regenerative Medicine,Beijing 100101,China

National Laboratory of Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China

Division of Life Sciences and Medicine,School of Life Sciences,University of Science and Technology of China,Hefei 230001,China

CAS Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics,Chinese Academy of Sciences and China National Center for Bioinformation,Beijing 100101,China

The Fifth People's Hospital of Chongqing,Chongqing 400062,China

Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders,Xuanwu Hospital Capital Medical University,Beijing 100053,China

Aging Translational Medicine Center,International Center for Aging and Cancer,Beijing Municipal Geriatric Medical Research Center,Xuanwu Hospital,Capital Medical University,Beijing 100053,China

Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders,Xuanwu Hospital Capital Medical University,Beijing 10

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key Research and DevelopmentProgram of ChinaNational Key Research and DevelopmentProgram of ChinaNational Key Research and DevelopmentProgram of ChinaNational Key Research and DevelopmentProgram of ChinaNational Key Research and DevelopmentProgram of ChinaSTI2030-Major ProjectsNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaCAS Project for Young Scientists in Basic ResearchCAS Project for Young Scientists in Basic ResearchProject for Technology Development of Beijingaffiliated Medical Research InstitutesYouth Innovation Promotion Association of CASYouth Innovation Promotion Association of CASYouth Innovation Promotion Association of CASInformatization Plan of Chinese Academy of SciencesInformatization Plan of Chinese Academy of SciencesInformatization Plan of Chinese Academy of SciencesNew Cornerstone Science Foundation through the XPLORER PRIZEExcellent Young Talents Program of Capital Medical UniversityExcellent Young Talents Training Program for the Construction of Beijing Municipal University Teacher TeamYoung Elite Scientists Sponsorship Program by CAST

项目编号：

9214930181921006821250112022YFA11037002022YFA11038002020YFA08040002020YFA01122002021YFF12010002021ZD020240092168201919492099204930492049116321210018219286382122024820715883200050082271600YSBR-076YSBR-01211000023T000002036310E1CAZW040120230922022083CAS-WX2021SF-0301CAS-WX2022SDC-XK14CAS-WX2021SF-01012021-104512300927BPHR2022031052021QNRC001

出版年：

2024

DOI：

10.1093/procel/pwad060

蛋白质与细胞

CSTPCD

影响因子：0.645

ISSN：

年,卷(期)：2024.15(6)