我校西南医院杨柳教授团队在Biomaterials杂志发表研究成果——髌下脂肪垫干细胞来源的外泌体通过抑制mTOR发挥关节软骨保护作用
发布人:wuph 发布时间:10/24/2019 5:11:24 PM  浏览次数:735次
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髌下脂肪垫干细胞来源的外泌体通过抑制mTOR发挥关节软骨保护作用

                      吴江怡  杨柳

骨性关节炎(Osteoarthritis,OA)是一种最常见的退行性关节疾病,其主要特征为关节软骨的退化、滑膜炎症以及软骨下骨重建,是导致患者出现疼痛症状甚至致残的重要原因。目前临床上对骨关节炎的治疗仍缺乏较好的措施。近年来研究表明,MSCs通过其分泌的外泌体发挥软骨保护作用,提示MSCs来源的外泌体可能是治疗OA的潜在策略。

我们分离和鉴定了髌下脂肪垫 (Infrapatellar fat pad, IPFP) 干细胞(MSCsIPFP)来源的外泌体(MSCIPFP-Exos),并发现MSCIPFP-Exos可抑制OA软骨细胞的凋亡,增强其基质合成能力并减少基质降解。在OA小鼠模型中,MSCIPFP-Exos可以显著减轻其病理表型,并部分缓解小鼠的步态异常。MSCIPFP-Exos可以上调软骨细胞的自噬水平,其机制与其抑制mTOR信号通路有关。外泌体miRNA测序显示MSCIPFP-Exos中富含miR-100-5p,而antagomiR-100-5p显著抑制外泌体调节的mTOR荧光素酶报告基因活性,并且也可以部分削弱MSCIPFP-Exos所介导的关节软骨保护作用,提示MSCIPFP-Exos主要通过miR-100-5p影响软骨细胞中mTOR信号。综上所述,MSCIPFP-Exos可能通过miR-100-5p抑制mTOR信号通路,激活细胞自噬来维持软骨细胞稳态,从而保护OA小鼠的关节软骨。该研究表明MSCIPFP-Exos在OA的临床治疗方面具有潜在的应用前景。该成果发表在Biomaterials杂志(IF 10.273)。

 附:英文摘要

miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis

Jiangyi Wu*, Liang Kuang*, Cheng Chen, Junjun Yang, Wei-Nan Zeng, Tao Li, Hao Chen, Shu Huang, Zhenlan Fu, Jiamiao Li, Renfeng Liu, Zhenhong Ni#, Lin Chen#, Liu Yang#

Osteoarthritis (OA) is the most common disabling joint disease throughout the world and its therapeutic effect is still not satisfactory in clinic nowadays. Recent studies showed that the exosomes derived from several types of mesenchymal stem cells (MSCs) could maintain chondrocyte homeostasis and ameliorate the pathological severity of OA in animal models, indicating that MSCs-derived exosomes could be a novel promising strategy for treating OA. In this study, we investigated the role and underlying mechanisms of infrapatellar fat pad (IPFP) MSCs-derived exosomes (MSCIPFP-Exos) on OA in vitro and in vivo. Our data revealed that MSCIPFP could produce amounts of MSCIPFP-Exos, which exhibited the typical morphological features of exosomes. The MSCIPFP-Exos ameliorated the OA severity in vivo and inhibited cell apoptosis, enhanced matrix synthesis and reduced the expression of catabolic factor in vitro. Moreover, MSCIPFP-Exos could significantly enhance autophagy level in chondrocytes partially via mTOR inhibition. Exosomal RNA-seq showed that the level of miR-100-5p that could bind to the 3′-untranslated region (3′UTR) of mTOR was the highest among microRNAs. MSCIPFP-Exos decreased the luciferase activity of mTOR 3′UTR, while inhibition of miR-100-5p could reverse the MSCIPFP-Exos-decreased mTOR signaling pathway. Intra-articular injection of antagomir-miR-100-5p dramatically attenuated MSCIPFP-Exos-mediated protective effect on articular cartilage in vivo. In brief, MSCIPFP-derived exosomes protect articular cartilage from damage and ameliorate gait abnormality in OA mice by maintaining cartilage homeostasis, the mechanism of which may be related to miR100-5p-regulated inhibition of mTOR-autophagy pathway. As it is relatively feasible to obtain human IPFP from OA patients by arthroscopic operation in clinic, MSCIPFP-derived exosomes may be a potential therapy for OA in the future.

Keywords: Exosomes; Infrapatellar fat pad; mTOR; Autophagy; Osteoarthritis

全文链接:https://www.sciencedirect.com/science/article/pii/S0142961219301668?via%3Dihub


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