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

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Bioactive Materials 2023年第9期27卷 98-112页

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 Department of Orthopaedic Surgery Yong Loo Lin School of MedicineNational University of SingaporeSingapore NUS Tissue Engineering Program Life Sciences InstituteNational University of SingaporeSingapore Critical Analytics for Manufacturing Personalised-Medicine Singapore-MIT Alliance for Research and TechnologySingapore

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.

关键词： Hypoxia preconditioned MSCs Secretome Extracellular vesicles Cartilage regeneration Joint inflammation

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