Lee JuHyeok, Lee Jiyoung, Choi Byung Hyune
Department of Biomedical Sciences, Inha University College of Medicine, 100 Inha-ro, Michuhol-gu, Incheon, 22212, Republic of Korea.
Tissue Eng Regen Med. 2025 May 15. doi: 10.1007/s13770-025-00720-1.
This study investigated anti-inflammatory effects of exosomes derived from human fetal cartilage progenitor cells (hFCPC-Exo) and their microRNAs (miRNAs) on the osteoarthritis (OA) phenotype in vitro in comparison with exosomes from bone marrow mesenchymal stem cells (MSC-Exo).
SW982 cells (synoviocytes) or hFCPCs (chondrocytes) were stimulated with 10 ng/mL IL-1β to mimic OA phenotypes. The effects of hFCPC-Exo and MSC-Exo were compared by measuring the expression of inflammatory cytokines and an anti-inflammatory protein. miRNA profiles of hFCPC-Exo and MSC-Exo were analyzed using a 2588 human miRNA dataset, and miRNAs potentially involved in the anti-inflammatory effect of hFCPC-Exo were selected. miRNA mimics and antisense inhibitors were used to investigate the role of selected miRNAs in the IL-1β signaling pathways.
Both hFCPC-Exo and MSC-Exo significantly decreased the expression of inflammatory cytokines (IL-1β, IL-6, and MCP-1), while slightly increased an anti-inflammatory protein (SOCS1) in IL-1β-treated SW982 cells. miRNA sequencing revealed anti-inflammatory miRNAs present in large amounts in both hFCPC-Exo and MSC-Exo. Among them, miR-125b-5p mimic significantly suppressed the expression of inflammatory cytokines induced by IL-1β, while anti-sense inhibitor of miR-125b-5p efficiently blocked anti-inflammatory effects of hFCPC-Exo. Both hFCPC-Exo and miR-125b-5p inhibited IκBα down-regulation and -NF-κB stabilization in IL-1β-treated SW982 cells. Additionally, hFCPC-Exo and miR-125b-5p showed similar effects on IL-1β-treated hFCPCs as an OA model in chondrocytes by down-regulating the expression of IL-1β, MMP13, and ADAMTS-5 and up-regulating the expression of aggrecan (ACAN) and type II collagen (COL2A1).
This study demonstrated that hFCPC-Exo exhibits anti-inflammatory effects on IL-1β-treated synoviocytes and chondrocytes in vitro possibly by down-regulating the IL-1β-TRAF6-NF-κB pathway via anti-inflammatory miRNAs such as miR-125b-5p.
本研究调查了人胎儿软骨祖细胞来源的外泌体（hFCPC-Exo）及其微小RNA（miRNA）与骨髓间充质干细胞来源的外泌体（MSC-Exo）相比，在体外对骨关节炎（OA）表型的抗炎作用。
用10 ng/mL白细胞介素-1β（IL-1β）刺激SW982细胞（滑膜细胞）或hFCPCs（软骨细胞）以模拟OA表型。通过测量炎性细胞因子和一种抗炎蛋白的表达来比较hFCPC-Exo和MSC-Exo的作用。使用2588个人类miRNA数据集分析hFCPC-Exo和MSC-Exo的miRNA谱，并选择可能参与hFCPC-Exo抗炎作用的miRNA。使用miRNA模拟物和反义抑制剂研究所选miRNA在IL-1β信号通路中的作用。
hFCPC-Exo和MSC-Exo均显著降低了炎性细胞因子（IL-1β、IL-6和单核细胞趋化蛋白-1）的表达，同时在IL-1β处理的SW982细胞中轻微增加了一种抗炎蛋白（SOCS1）的表达。miRNA测序显示hFCPC-Exo和MSC-Exo中均大量存在抗炎miRNA。其中，miR-125b-5p模拟物显著抑制了IL-1β诱导的炎性细胞因子的表达，而miR-125b-5p的反义抑制剂有效阻断了hFCPC-Exo的抗炎作用。hFCPC-Exo和miR-125b-5p均抑制了IL-1β处理的SW982细胞中IκBα的下调和NF-κB的稳定。此外，hFCPC-Exo和miR-125b-5p通过下调IL-1β、基质金属蛋白酶13（MMP13）和含血小板反应蛋白基序的解聚素样金属蛋白酶5（ADAMTS-5）的表达以及上调聚集蛋白聚糖（ACAN）和II型胶原（COL2A1）的表达，对作为软骨细胞OA模型的IL-1β处理的hFCPCs表现出相似的作用。
本研究表明，hFCPC-Exo可能通过miR-125b-5p等抗炎miRNA下调IL-1β-肿瘤坏死因子受体相关因子6（TRAF6）-核因子κB（NF-κB）途径，从而在体外对IL-1β处理的滑膜细胞和软骨细胞发挥抗炎作用。
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