Secretive derived from hypoxia preconditioned mesenchymal stem cells promote cartilage regeneration and mitigate joint inflammation via extracellular vesicles

作     者：Yanmeng Yang Yingnan Wu Dahou Yang Shu Hui Neo Nurul Dinah Kadir Doreen Goh Jian Xiong Tan Vinitha Denslin Eng Hin Lee Zheng Yang 

作者机构：Department of Orthopaedic SurgeryYong Loo Lin School of MedicineNational University of SingaporeSingapore NUS Tissue Engineering ProgramLife Sciences InstituteNational University of SingaporeSingapore Critical Analytics for Manufacturing Personalised-MedicineSingapore-MIT Alliance for Research and TechnologySingapore 

出 版 物：《Bioactive Materials》 (生物活性材料（英文）)

年 卷 期：2023年第27卷第9期

页      面：98-112页

核心收录：

学科分类：1002[医学-临床医学] 100210[医学-外科学(含：普外、骨外、泌尿外、胸心外、神外、整形、烧伤、野战外)] 10[医学] 

基　　金：supported by National Medical Research Council of Singapore(MOH-000371-00) the National Research Foundation,Prime Minister’s Office,Singapore under its Campus for Research Excellence and Technological Enterprise(CREATE)program,through Singapore-MIT Alliance for Research and Technology(SMART):Critical Analytics for Manufacturing Personalized-Medicine(CAMP)Inter-Disciplinary Research Group.YY was supported by NUS Research Scholarship 

主　　题：Hypoxia preconditioned MSCs Secretome Extracellular vesicles Cartilage regeneration Joint inflammation 

摘      要：Secretome derived from mesenchymal stem cells (MSCs) have profound effects on tissue regeneration, which could become the basis of future MSCs therapies. Hypoxia, as the physiologic environment of MSCs, has great potential to enhance MSCs paracrine therapeutic effect. In our study, the paracrine effects of secretome derived from MSCs preconditioned in normoxia and hypoxia was compared through both in vitro functional assays and an in vivo rat osteochondral defect model. Specifically, the paracrine effect of total EVs were compared to that of soluble factors to characterize the predominant active components in the hypoxic secretome. We demonstrated that hypoxia conditioned medium, as well as the corresponding EVs, at a relatively low dosage, were efficient in promoting the repair of critical-sized osteochondral defects and mitigated the joint inflammation in a rat osteochondral defect model, relative to their normoxia counterpart. In vitro functional test shows enhancement through chondrocyte proliferation, migration, and matrix deposition, while inhibit IL-1β-induced chondrocytes senescence, inflammation, matrix degradation, and pro-inflammatory macrophage activity. Multiple functional proteins, as well as a change in EVs’ size profile, with enrichment of specific EV-miRNAs were detected with hypoxia preconditioning, implicating complex molecular pathways involved in hypoxia pre-conditioned MSCs secretome generated cartilage regeneration.