Extracellular vesicles deliver thioredoxin to rescue stem cells from senescence and intervertebral disc degeneration via a feed-forward circuit of the NRF2/AP-1 composite pathway  

作　　者：Xuanzuo Chen Sheng Liu Huiwen Wang Yiran Liu Yan Xiao Kanglu Li Feifei Ni Wei Wu Hui Lin Xiangcheng Qing Feifei Pu Baichuan Wang Zengwu Shao Yizhong Peng 

机构地区：[1]Department of Orthopaedics,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [2]The First School of Clinical Medicine,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [3]Department of Radiology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [4]Department of Orthopedics,Traditional Chinese and Western Medicine Hospital of Wuhan,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第2期1007-1022,共16页药学学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(82202764 and 81974352);the China Postdoctoral Science Foundation(2021M701331);Natural Science Foundation of Hubei Province(2020CFB778,China);the Scientific Research Training Program for Young Talents from Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China.

摘　　要：Intervertebral disc degeneration(IDD)is largely attributed to impaired endogenous repair.Nucleus pulposus-derived stem cells(NPSCs)senescence leads to endogenous repair failure.Small extracellular vesicles/exosomes derived from mesenchymal stem cells(mExo)have shown great therapeutic potential in IDD,while whether mExo could alleviate NPSCs senescence and its mechanisms remained unknown.We established a compression-induced NPSCs senescence model and rat IDD models to evaluate the therapeutic efficiency of mExo and investigate the mechanisms.We found that mExo significantly alleviated NPSCs senescence and promoted disc regeneration while knocking down thioredoxin(TXN)impaired the protective effects of mExo.TXN was bound to various endosomal sorting complex required for transport(ESCRT)proteins.Autocrine motility factor receptor(AMFR)mediated TXN K63 ubiquitination to promote the binding of TXN on ESCRT proteins and sorting of TXN into mExo.Knocking down exosomal TXN inhibited the transcriptional activity of nuclear factor erythroid 2-related factor 2(NRF2)and activator protein 1(AP-1).NRF2 and AP-1 inhibition reduced endogenous TXN production that was promoted by exosomal TXN.Inhibition of NRF2 in vivo diminished the anti-senescence and regenerative effects of mExo.Conclusively,AMFR-mediated TXN ubiquitination promoted the sorting of TXN into mExo,allowing exosomal TXN to promote endogenous TXN production in NPSCs via TXN/NRF2/AP-1 feed-forward circuit to alleviate NPSCs senescence and disc degeneration.

关 键 词：TXN NRF2 AP-1 Exosomes SENESCENCE Intervertebral disc degeneration NPSCs ESCRT 

分 类 号：R681.5[医药卫生—骨科学]