Hypoxic pretreatment of small extracellular vesicles mediates cartilage repair in osteoarthritis by delivering miR-216a-5p

Osteoarthritis (OA) is a regressive joint disease that mainly affects the cartilage and surrounding tissues. Mounting studies have confirmed that the paracrine effect is related to the potential mechanism of mesenchymal stem cell (MSC) transplantation and that small extracellular vesicles (sEVs) play an imperative role in this paracrine signaling. In fact, hypoxia can significantly improve the effectiveness of MSC transplantation in various disease models. However, it remains unknown whether MSCs in the state of a hypoxic environment can enhance OA cartilage repair and whether this enhancement is mediated by sEV signaling. The primary aim of the present study was to determine whether sEVs from MSCs in the state of hypoxia (Hypo-sEVs) have a superior effect on OA cartilage repair relative to sEVs from MSCs in the normoxia (Nor-sEVs) state. By using an OA model and performing in vitro studies, we verified that Hypo-sEV treatment facilitated the proliferation, migration, and apoptosis suppression of chondrocytes to a greater extent than Nor-sEV treatment. Furthermore, we verified the functional role of sEV miR-216a5p in the OA cartilage repair process. We also identified JAK2 as the target gene of sEV miR-216a-5p through a series of experiments. Our findings indicated that HIF-1 alpha induces hypoxic BMSCs to release sEVs, which promote the proliferation, migration, and apoptosis inhibition of chondrocytes through the miR-216a-5p/JAK2/STAT3 signaling pathway. Therefore, hypoxic pretreatment is a prospective and effective method to maximize the therapeutic effect of MSC-derived sEVs on OA. Statement of significance Osteoarthritis (OA) is a regressive joint disease mainly affecting the cartilage and surrounding tissues. Our study demonstrates for the first time that hypoxic pretreatment of small extracellular vesicles (Hypo-sEVs) effectively protected cartilage from degeneration and slowed down the progression of OA. In short, this study showed that HIF-1 alpha induces hypoxic BMSCs to release sEVs, which promote chondrocyte proliferation, migration and apoptosis inhibition through miR-216a-5p/JAK2/STAT3 pathway. Therefore, hypoxic pretreatment is a promising and effective method for optimizing the therapeutic effects of BMSCs-derived sEVs. The combination of miRNA and BMSC-derived sEVs could be a promising therapeutic method for OA.(C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

The study demonstrated that hypoxic pretreatment of small extracellular vesicles effectively protected cartilage from degeneration and slowed down the progression of OA. Through the miR-216a-5p/JAK2/STAT3 pathway, hypoxic pretreatment is promising for optimizing the therapeutic effects of BMSC-derived sEVs.