滑膜间充质干细胞来源的BMP-7修饰外泌体通过巨噬细胞的M2极化减轻骨关节炎
BMP-7 modified exosomes derived from synovial mesenchymal stem cells attenuate osteoarthritis by M2 polarization of macrophages.
作者信息
Sun Weixue, Qu Shaozheng, Ji Mingxia, Sun Yanli, Hu Baiqiang
机构信息
Joint Surgery and Sports Medicine Department, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264000, Shandong, China.
Spinal Surgery Department, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264000, Shandong, China.
出版信息
Heliyon. 2023 Sep 10;9(9):e19934. doi: 10.1016/j.heliyon.2023.e19934. eCollection 2023 Sep.
BACKGROUND
Although the exosomes derived from mesenchymal stem cells (MSCs) display a therapeutic effect on inflammatory diseases, its application on OA has great limitations due to lack of specificity and targeting. The current study aimed to elucidate the potential therapeutic role of bone morphogenetic proteins-7(BMP-7) modified synovial mesenchymal stem cells-derived exosomes (SMSCs-exo) on OA and mechanism.
METHODS
For in vitro experiments, LPS-treated macrophages RAW264.7 were treated with SMSCs-exo (exo) or BMP-7 modified SMSCs-exos (BMP-7-exo). The levels of inflammatory factors were assessed by ELISA. Also, the proportion of iNOS and CD206 positive cells were quantified by flow cytometry. Chondrocytes and RAW264.7 were co-culture to evaluate the effects of macrophage polarization on chondrocytes cellular behaviors. This effect on KOA was verified by an experiment in vivo. HE staining and Safranin fast green staining were used to observe the damage of articular cartilage. Immunohistochemistry was used to determine the expression of collagen II and aggrecan in articular cartilage, as well as the expression of iNOS and CD206 in synovial tissues.
RESULTS
Our in vitro results showed that BMP-7-exo treatment promoted LPS-induced proliferation of macrophages and chondrocytes, and showed a better ability to reduce inflammation by promoting macrophages M2 polarization. After co-culture with LPS treated macrophages, the proliferation rate and migration of chondrocytes were significantly decreased, while the apoptosis was significantly increased. The macrophages treated with BMP-7-exo and exo partially reversed these changes. The chondrocytes in BMP-7-exo group had higher proliferation rate and migration, as well as lower apoptosis compared with the exo group. Also, the in vivo results showed BMP-7-exo treatment improved the pathological changes of KOA and promoted synovial macrophages M2 polarization.
CONCLUSIONS
Our results demonstrated that BMP-7-exo attenuated KOA inflammation and cartilage injury by synovial macrophages M2 polarization, suggesting that BMP-7-exo carry much therapeutic potential for OA.
背景
尽管间充质干细胞（MSCs）来源的外泌体对炎症性疾病具有治疗作用，但由于缺乏特异性和靶向性，其在骨关节炎（OA）中的应用存在很大局限性。本研究旨在阐明骨形态发生蛋白-7（BMP-7）修饰的滑膜间充质干细胞来源的外泌体（SMSCs-exo）对OA的潜在治疗作用及机制。
方法
在体外实验中，用SMSCs-exo（exo）或BMP-7修饰的SMSCs-exos（BMP-7-exo）处理经脂多糖（LPS）处理的巨噬细胞RAW264.7。通过酶联免疫吸附测定（ELISA）评估炎症因子水平。此外，通过流式细胞术定量诱导型一氧化氮合酶（iNOS）和CD206阳性细胞的比例。将软骨细胞与RAW264.7共培养，以评估巨噬细胞极化对软骨细胞行为的影响。通过体内实验验证了这对膝骨关节炎（KOA）的作用。采用苏木精-伊红（HE）染色和番红固绿染色观察关节软骨损伤情况。免疫组织化学法检测关节软骨中Ⅱ型胶原蛋白和聚集蛋白聚糖的表达，以及滑膜组织中iNOS和CD206的表达。
结果
我们的体外实验结果表明，BMP-7-exo处理促进了LPS诱导的巨噬细胞和软骨细胞增殖，并通过促进巨噬细胞M2极化显示出更好的抗炎能力。与经LPS处理的巨噬细胞共培养后，软骨细胞的增殖率和迁移能力显著降低，而凋亡显著增加。用BMP-7-exo和exo处理的巨噬细胞部分逆转了这些变化。与exo组相比，BMP-7-exo组的软骨细胞具有更高的增殖率和迁移能力，以及更低的凋亡率。此外，体内实验结果表明，BMP-7-exo处理改善了KOA的病理变化，并促进了滑膜巨噬细胞M2极化。
结论
我们的结果表明，BMP-7-exo通过滑膜巨噬细胞M2极化减轻了KOA炎症和软骨损伤，表明BMP-7-exo对OA具有很大的治疗潜力。
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