Exosomal MicroRNA-320a Derived From Mesenchymal Stem Cells Regulates Rheumatoid Arthritis Fibroblast-Like Synoviocyte Activation by Suppressing CXCL9 Expression
Exosomal MicroRNA-320a Derived From Mesenchymal Stem Cells Regulates Rheumatoid Arthritis Fibroblast-Like Synoviocyte Activation by Suppressing CXCL9 Expression
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来自间充质干细胞的外泌体MicroRNA-320a通过抑制CXCL9的表达调节类风湿关节炎成纤维细胞样滑膜细胞的激活
DOI：
10.3389/fphys.2020.00441
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发表时间：
2020-05-26
影响因子：
4
通讯作者：
Qiu, Bing
中科院分区：
文献类型：
--
作者：
Meng, Qing;Qiu, Bing
类风湿性关节炎（RA）是一种慢性全身炎症性疾病，是全世界残疾的主要原因。成纤维细胞样滑膜细胞（FLS）在 RA 发病机制调节中的作用已被强调。间充质干细胞（MSC）是许多炎症性自身免疫性疾病细胞治疗的重要候选者。在此，我们确定了装载有 microRNA-320a (miR-320a) 的 MSC 衍生的外泌体是否调节 RA-FLS。收集了 22 名 RA 患者和 9 名骨关节炎患者的滑膜组织。 RA-FLS 取自 RA 患者，通过测定白细胞介素 1 β (IL-1 β)、IL-6 和 IL-8 的水平以及 Transwell 迁移和侵袭测定来评估其功能。采用双荧光素酶报告基因测定来鉴定 miR-320a 和 CXC 趋化因子配体 9 (CXCL9) 之间的相互作用。进行了 MSC 衍生的外泌体和 RA-FLS 的共培养系统。开发了具有关节炎和骨损伤的胶原诱导关节炎（CIA）小鼠模型。我们的结果揭示了 RA 患者滑膜组织中存在 miR-320a 和 CXCL9 的相互表达。 CXCL9 敲低或 miR-320a 上调抑制 RA-FLS 的激活、迁移和侵袭。 CXCL9 被证实是 miR-320a 的靶标，并且 CXCL9 过表达在 miR-320a 存在的情况下恢复了 RA-FLS 功能。含有 miR-320a 模拟物的 MSC 衍生的外泌体在体外显着抑制 RA-FLS 激活、迁移和侵袭，并在体内减轻 CIA 小鼠的关节炎和骨损伤。我们的研究发现，MSC 衍生的外泌体参与 miR-320a 的细胞间转移，并随后抑制 RA 的进展。这些结果通过增加外泌体中的 miR-320a 为 RA 治疗提供了一种新的潜在治疗方法。
Rheumatoid arthritis (RA), a chronic systemic inflammatory disease, is a primary cause of disability worldwide. The involvement of fibroblast-like synoviocytes (FLSs) in the regulation of the pathogenesis of RA has been highlighted. Mesenchymal stem cells (MSCs) are important candidates for cell-based treatment in many inflammatory autoimmune diseases. Herein, we identify whether MSC-derived exosomes loaded with microRNA-320a (miR-320a) regulate RA-FLSs. Synovial tissues from 22 patients with RA and 9 patients with osteoarthritis were collected. RA-FLSs were obtained from patients with RA, and their functions were evaluated by determining levels of interleukin-1 beta (IL-1 beta), IL-6, and IL-8 and by transwell migration and invasion assays. Dual luciferase reporter gene assays were employed to identify interaction between miR-320a and CXC chemokine ligand 9 (CXCL9). A co-culture system of MSC-derived exosomes and RA-FLSs were performed. The collagen-induced arthritis (CIA) mouse models with arthritis and bone damage were developed. Our results revealed the existence of reciprocal expression of miR-320a and CXCL9 in the synovial tissues obtained from patients with RA. CXCL9 knockdown or miR-320a upregulation suppressed the activation, migration, and invasion of RA-FLSs. CXCL9 was confirmed to be a target of miR-320a, and CXCL9 overexpression restored RA-FLS function in the presence of miR-320a. MSC-derived exosomes containing miR-320a mimic significantly suppressed RA-FLS activation, migration, and invasion in vitro and attenuated arthritis and bone damage in mice with CIA in vivo. Our study uncovers that MSC-derived exosomes participate in the intercellular transfer of miR-320a and subsequently inhibit the progression of RA. These results provide a novel potential therapeutic approach for RA treatment by increasing miR-320a in exosomes.