miRNA-146a Improves Immunomodulatory Effects of MSC-derived Exosomes in Rheumatoid Arthritis

被引:106
作者
Tavasolian, Fataneh [1 ]
Hosseini, Ahmad Zavaran [1 ]
Soudi, Sara [1 ]
Naderi, Mahmood [2 ]
机构
[1] Tarbiat Modares Univ, Fac Med Sci, Dept Immunol, POB 14155-4838, Tehran, Iran
[2] Digest Dis Res Inst, Cell Based Therapies Res Ctr, Sci, Tehran, Iran
基金
美国国家科学基金会;
关键词
Mesenchymal stem cell; microRNA; exosomes; rheumatoid arthritis; autoimmune diseases; joints and bones; MESENCHYMAL STEM-CELLS; REGULATORY T-CELLS; BONE DESTRUCTION; B-CELLS; EXPRESSION; MIR-146A; THERAPY; MICRORNA-146A; CONTRIBUTES; STRATEGIES;
D O I
10.2174/1566523220666200916120708
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Background: Rheumatoid arthritis (RA) is a severe inflammatory joint disorder, and several studies have taken note of the probability that microRNAs (miRNAs) play an important role in RA pathogenesis. MiR-146 and miR-155 arose as primary immune response regulators. Mesenchymal stein cells (MSCs) immunomodulatory function is primarily regulated by paracrine factors, such as exosomes. Exosomes, which serve as carriers of genetic information in cell-to-cell communication, transmit miRNAs between cells and have been studied as vehicles for the delivery of therapeutic molecules. Aims: The current research aimed to investigate the therapeutic effect of miR-146a/miR-155 transduced mesenchymal stem cells (MSC)-derived exosomes on the immune response. Methods: Here, exosomes were extracted from normal MSCs with over-expressed miR-146a/miR-155; Splenocytes were isolated from collagen-induced arthritis (CIA) and control mice. Expression levels miR-146a and miR-155 were then monitored. Flow cytometry was performed to assess the impact of the exosomes on regulatory T-cell (Treg) levels. Expression of some key autoinunune response genes and their protein products, including retinoic acid-related orphan receptor (ROR)-gamma t, tumor necrosis factor (TNF)-alpha, interleukin (IL)-17, -6, -10, and transforming growth factor (TGF)-beta in the Splenocytes was determined using both quantitative real-time PCR and ELISA. The results showed that miR-146a was mainly down-regulated in CIA mice. Treatment with MSC-derived exosomes and miR-146a/miR-155-transduced MSC-derived exosomes significantly altered the CIA mice Treg cell levels compared to in control mice. Results: Ultimately, such modulation may promote the recovery of appropriate T-cell responses in inflammatory situations such as RA. Conclusion: miR-146a-transduced MSC-derived exosomes also increased forkhead box P3 (Fox-P3), TOFfi and IL-10 gene expression in the CIA mice; miR-155 further increased the gene expressions of ROR gamma t, IL-17, and IL-6 in these mice. Based on the findings here, Exosomes appears to promote the direct intracellular transfer of miRNAs between cells and to represent a possible therapeutic strategy for RA. The manipulation of MSC-derived exosomes with anti-inflammatory miRNA may increase Treg cell populations and anti-inflammatory cytokines.
引用
收藏
页码:297 / 312
页数:16
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