Department of Orthopaedics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
Department of Orthopaedics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China; Department of Orthopedics, Wuhu First People's Hospital, Wuhu, China.
Acta Biomater. 2021 Mar 1;122:325-342. doi: 10.1016/j.actbio.2020.12.034. Epub 2020 Dec 18.
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-216a-5p 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-1α 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.
骨关节炎（OA）是一种退行性关节疾病，主要影响软骨和周围组织。越来越多的研究证实，旁分泌作用与间充质干细胞（MSC）移植的潜在机制有关，而小细胞外囊泡（sEVs）在这种旁分泌信号中起着至关重要的作用。事实上，缺氧可以显著提高 MSC 移植在各种疾病模型中的效果。然而，尚不清楚处于缺氧环境中的 MSC 是否可以增强 OA 软骨修复，以及这种增强是否由 sEV 信号介导。本研究的主要目的是确定缺氧状态下的 MSC 产生的 sEV（Hypo-sEVs）是否比常氧状态下的 MSC 产生的 sEV（Nor-sEVs）对 OA 软骨修复具有更好的效果。通过使用 OA 模型并进行体外研究，我们验证了 Hypo-sEV 处理在促进软骨细胞增殖、迁移和抑制凋亡方面的效果优于 Nor-sEV 处理。此外，我们还验证了 sEV miR-216a-5p 在 OA 软骨修复过程中的功能作用。我们还通过一系列实验确定了 JAK2 是 sEV miR-216a-5p 的靶基因。我们的研究结果表明，HIF-1α 诱导缺氧 BMSCs 释放 sEVs，通过 miR-216a-5p/JAK2/STAT3 信号通路促进软骨细胞的增殖、迁移和凋亡抑制。因此，缺氧预处理是最大限度提高 MSC 衍生 sEV 对 OA 治疗效果的一种有前景且有效的方法。
