Macrophage-derived extracellular vesicles regulate skeletal stem/progenitor Cell lineage fate and bone deterioration in obesity  

作　　者：Chen He Chen Hu Wen-Zhen He Yu-Chen Sun Yangzi Jiang Ling Liu Jing Hou Kai-Xuan Chen Yu-Rui Jiao Mei Huang Min Huang Mi Yang Qiong Lu Jie Wei Chao Zeng Guang-Hua Lei Chang-Jun Li 

机构地区：[1]Department of Endocrinology,Endocrinology Research Center,Xiangya Hospital of Central South University,Changsha,Hunan,410008,China [2]School of Biomedical Sciences,Institute for Tissue Engineering and Regenerative Medicine,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong SAR,China [3]Center for Neuromusculoskeletal Restorative Medicine(CNRM),The Chinese University of Hong Kong,Hong Kong SAR,China [4]Key Laboratory for Regenerative Medicine,Ministry of Education,School of Biomedical Sciences,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong SAR,China [5]Department of Pharmacy,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China [6]Department of Orthopaedics,Xiangya Hospital of Central South University,Changsha,Hunan,410008,China [7]Department of Epidemiology and Health Statistics,Xiangya School of Public Health,Central South University,Changsha,Hunan,410008,China [8]Hunan Key Laboratory of Joint Degeneration and Injury,Changsha,Hunan,410008,China [9]National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha,Hunan,410008,China [10]Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment,Ministry of Education,Xiangya Hospital,Central South University,Changsha,China

出　　处：《Bioactive Materials》2024年第6期508-523,共16页生物活性材料（英文）

基　　金：supported by the National Key R&D Program of China(Grant 2022YFC3601900 to G.H.L.,2022YFC3601903,and 2022YFC3601905 to C.J.L.,2019YFA0111900 to Y.J.);the National Natural Science Foundation of China(Grant Nos.82261160397,82272560,81922017 to C.J.L.);the Hunan Provincial Science and Technology Department(2023JJ30896 to C.J.L.,2023JJ40965 to L.L.);the Key Research and Development Program of Hunan Province(2022SK2023 to C.J.L.);Science and Technology Innovation Program of Hunan Province(2023RC1027 to C.J.L.,2022RC1009 to J.W.,and 2022RC3075 to C.Z.);The NSFC/RGC Joint Research Scheme,the Research Grants Council(UGC)of the Hong Kong Special Administrative Region and the National Natural Science Foundation of China(NSFC/RGC Project No.N_CUHK483/22 to Y.J.);the Center for Neuromusculoskeletal Restorative Medicine[CNRM at InnoHK,to Y.J.]by Innovation and Technology Commission(ITC)of Hong Kong SAR,China.

摘　　要：Obesity-induced chronic inflammation exacerbates multiple types of tissue/organ deterioration and stem cell dysfunction;however,the effects on skeletal tissue and the underlying mechanisms are still unclear.Here,we show that obesity triggers changes in the microRNA profile of macrophage-secreted extracellular vesicles,leading to a switch in skeletal stem/progenitor cell(SSPC)differentiation between osteoblasts and adipocytes and bone deterioration.Bone marrow macrophage(BMM)-secreted extracellular vesicles(BMM-EVs)from obese mice induced bone deterioration(decreased bone volume,bone microstructural deterioration,and increased adipocyte numbers)when administered to lean mice.Conversely,BMM-EVs from lean mice rejuvenated bone deterioration in obese recipients.We further screened the differentially expressed microRNAs in obese BMM-EVs and found that among the candidates,miR-140(with the function of promoting adipogenesis)and miR-378a(with the function of enhancing osteogenesis)coordinately determine SSPC fate of osteogenic and adipogenic differentiation by targeting the Pparα-Abca1 axis.BMM miR-140 conditional knockout mice showed resistance to obesity-induced bone deterioration,while miR-140 overexpression in SSPCs led to low bone mass and marrow adiposity in lean mice.BMM miR-378a conditional depletion in mice led to obesity-like bone deterioration.More importantly,we used an SSPC-specific targeting aptamer to precisely deliver miR-378a-3p-overloaded BMM-EVs to SSPCs via an aptamer-engineered extracellular vesicle delivery system,and this approach rescued bone deterioration in obese mice.Thus,our study reveals the critical role of BMMs in mediating obesity-induced bone deterioration by transporting selective extracellular-vesicle microRNAs into SSPCs and controlling SSPC fate.

关 键 词：Obesity-induced bone deterioration Macrophage-derived extracellular vesicles Skeletal stem/progenitor cells Cell fate Aptamer Cell-specific targeting 

分 类 号：R392[医药卫生—免疫学]