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

Abstract

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 stem 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 autoimmune response genes and their protein products including retinoic acid-related orphan receptor (ROR)-γt, tumor necrosis factor (TNF)-α, interleukin (IL)-17, -6, -10, and transforming growth factor (TGF)-β in the Splenocytes were determined using both quantitative real-time PCR and ELISA. Results: 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. miR-146a-transduced MSC-derived exosomes also increased forkhead box P3 (FoxP3), TGFβ and IL-10 gene expression in the CIA mice; miR-155 further increased the gene expressions of RORγt, IL-17, and IL-6 in these mice. Conclusion: 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. Ultimately, such modulation may promote the recovery of appropriate T-cell responses in inflammatory situations such as RA.

RETRACTED ARTICLE: Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders

“…Rendering the findings by Dey et al that interaction between RAC2 and inducible nitric oxide synthase (iNOS) may provoke NO upregulation and consequently initiate chronic inflammation in the RA synovium, application of therapeutic strategies focusing on RAC2 inhibition can exert beneficial effects in RA patients [219]. Another preclinical study suggested that MSC-derived exosomes with overexpressed miR-146a, a well-known miRNA involved in regulation of immune response, improved FoxP3, TGF-β, and IL-10 gene expression in murine CIA models, proposing their potential for treating RA through enhancing Treg cell populations and anti-inflammatory cytokine levels [220]. According to the promising results based on MSC therapy for RA in animal models, several clinical trials have been accomplished to report the safety and efficacy of these cell transplantation in human models.…”

miR-155 Contributes to the Immunoregulatory Function of Human Mesenchymal Stem Cells

“…By contrast, miR-146a was the most significantly up-regulated in TNFastimulated human umbilical cord MSCs even though no functional assay confirmed a possible immunosuppressive role (15). Recently, exosomes from MSCs over-expressing miR-146a were demonstrated to increase Treg cell populations and improve collagen-induced arthritis (16). In the present study, we did not observe any effect on the proliferation of T lymphocytes.…”

Expedition into Exosome Biology: A Perspective of Progress from Discovery to Therapeutic Development

“…Exosomes release into the extracellular milieu influences cellular morphology by interfering with cell signaling components and by modulating recipient gene expressions and functions and the cell differentiation program. Exosomes have been reported to influence infections [ 91 , 92 , 93 ], tumor development and metastasis [ 94 , 95 , 96 , 97 , 98 ], neurodegenerative diseases [ 99 , 100 , 101 , 102 ], inflammation, and autoimmune disorders [ 103 , 104 , 105 , 106 ]. In addition, they play crucial role in intracellular communication and in the pathogenesis of several diseases as they can transfer signals (cytokines, proteins, lipids, nucleic acids, and infectious agents) from cells to nearby or distant locations [ 91 , 107 , 108 ].…”

“…Mesenchymal stem cells (MSCs) are multipotent stromal cells sourced from bone marrow, adipose tissues, placenta, or umbilical cord ( Table 2 ). Their regenerative capacities underlie their importance in immune modulation [ 106 , 119 , 120 , 121 , 122 ]. The immunomodulatory effects of MSC-derived exosomes on peripheral blood mononuclear cells (PBMCs) have been well established.…”

“…Furthermore, an increase in the regulatory T-cells (Tregs) was also observed in the interaction between Th-cells and exosomes. Together, studies have revealed that MSC-derived exosomes have favorable immunomodulatory properties [ 106 , 120 , 121 , 122 , 123 , 124 , 125 , 126 ], and thus, they are considered as potential therapeutic candidates in many pathological contexts and as a convenient means of delivering therapeutics, enzymes, and genes to targeted cells [ 127 ]. Interestingly, recent evidence suggests that MSC-derived exosomes offer a potentially safe means of treating graft-versus-host disease (GvHD) [ 128 ].…”