Metformin Augments Anti-Inflammatory and Chondroprotective Properties of Mesenchymal Stem Cells in Experimental Osteoarthritis
Metformin Augments Anti-Inflammatory and Chondroprotective Properties of Mesenchymal Stem Cells in Experimental Osteoarthritis
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DOI：
10.4049/jimmunol.1800006
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发表时间：
2019-07-01
影响因子：
4.4
通讯作者：
Cho, Mi-La
中科院分区：
文献类型：
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作者：
Park, Min-Jung;Moon, Su-Jin;Cho, Mi-La
骨髓间充质干细胞（MSCs）可以通过其免疫调节能力防止骨关节炎（OA）中的软骨破坏。然而，使用MSC的优化策略仍然具有挑战性。本研究的目的是确定二甲双胍刺激的脂肪组织来源的人间充质干细胞（Ad-hMSCs）在OA中的体内作用。采用大鼠关节内注射碘乙酸单钠的方法建立OA动物模型。将OA大鼠分为对照组和两个治疗组（Ad-hMSCs治疗组和二甲双胍刺激的Ad-hMSCs治疗组）。通过测量缩爪潜伏期和阈值来评估肢体伤害感受。我们的数据显示二甲双胍增加了Ad-hMSCs中IL-10和IDO的表达，并降低了高迁移率族蛋白1蛋白、IL-1 β和IL-6的表达。二甲双胍可增加Ad-hMSCs的迁移能力，并上调趋化因子的表达。在共培养中，二甲双胍刺激的Ad-hMSCs抑制IL-1 β刺激的OA软骨细胞中RUNX 2、COL X、VEGF、MMP 1、MMP 3和MMP 13的mRNA表达，并增加TIMP 1和TIMP 3的表达。二甲双胍刺激的Ad-hMSCs治疗OA大鼠的抗伤害活性和软骨保护作用大于未刺激的Ad-hMSCs治疗的OA大鼠。TGF-β在OA关节软骨下骨的表达减弱更多的二甲双胍刺激的Ad-hMSCs治疗的OA大鼠。我们的研究结果表明，二甲双胍为Ad-hMSCs作为OA细胞治疗的临床应用提供了一个有前途的选择。
Mesenchymal stem cells (MSCs) can protect against cartilage breakdown in osteoarthritis (OA) via their immunomodulatory capacities. However, the optimization strategy for using MSCs remains challenging. This study's objective was to identify the in vivo effects of metformin-stimulated adipose tissue-derived human MSCs (Ad-hMSCs) in OA. An animal model of OA was established by intra-articular injection of monosodium iodoacetate into rats. OA rats were divided into a control group and two therapy groups (treated with Ad-hMSCs or metformin-stimulated Ad-hMSCs). Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Our data show that metformin increased IL-10 and IDO expression in Ad-hMSCs and decreased high-mobility group box 1 protein, IL-1 beta, and IL-6 expression. Metformin increased the migration capacity of Ad-hMSCs with upregulation of chemokine expression. In cocultures, metformin-stimulated Ad-hMSCs inhibited the mRNA expression of RUNX2, COL X, VEGF, MMP1, MMP3, and MMP13 in IL-1 beta-stimulated OA chondrocytes and increased the expression of TIMP1 and TIMP3. The antinociceptive activity and chondroprotective effects were greater in OA rats treated with metformin-stimulated Ad-hMSCs than in those treated with unstimulated Ad-hMSCs. TGF-beta expression in subchondral bone of OA joints was attenuated more in OA rats treated with metformin-stimulated Ad-hMSCs. Our findings suggest that metformin offers a promising option for the clinical application of Ad-hMSCs as a cell therapy for OA.