Title:miRNA-146a Improves Immunomodulatory Effects of MSC-derived Exosomes in Rheumatoid Arthritis
Volume: 20
Issue: 4
Author(s): Fataneh Tavasolian, Ahmad Zavaran Hosseini*, Sara Soudi and Mahmood Naderi
Affiliation:
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran,Iran
Keywords:
Mesenchymal stem cell, microRNA, exosomes, rheumatoid arthritis, autoimmune diseases, joints and bones.
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 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), 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. 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.
