Exosomes Derived from IDO1-Overexpressing Rat Bone Marrow Mesenchymal Stem Cells Promote Immunotolerance of Cardiac Allografts

Abstract

Background:The immunosuppressive activity of mesenchymal stem cells (MSCs) has been exploited to induce tolerance after organ transplantation. The indoleamine 2,3-dioxygenase (IDO) may have beneficial effects in the immunoregulatory properties of MSCs. It was recently revealed that exosomes derived from MSCs play important roles in mediating the biological functions of MSCs. This study aimed to explore the roles of exosomes derived from MSCs in the induction of immune tolerance.Methods:Dendritic cells (DCs) and T-cells were cultured with exosomes derived from rat bone marrow MSCs (BMSCs) overexpressing IDO1 or controls. For the in-vivo study, rats received heart transplants and were treated with exosomes from IDO-BMSCs and heart function was evaluated. Flow cytometry was used to detect expression of cell surface markers. Cytokine levels were detected in culture supernatants or serum samples. Protein and microRNA expressions in exosomes were investigated by chips.Results:Exosomes from IDO-BMSCs cultured with DCs and T-cells (1) downregulated CD40, CD86, CD80, MHC-II, CD45RA, CD45RA+CD45RB, OX62, and upregulated CD274 expression, (2) increased the number of regulatory T-cells (Tregs) and decreased the number of CD8+ T-cells, and (3) decreased the levels of pro-inflammatory cytokines, but increased the levels of anti-inflammatory cytokines compared with the other groups. Transplanted rats, which were injected with exosomes from IDO-BMSCs, had reduced allograft-targeting immune responses and improved cardiac allograft function. Exosomes secreted by IDO-BMSCs exhibited significant upregulations of the immunoregulatory protein FHL-1, miR-540-3p, and a downregulation of miR-338-5p.Conclusion:Exosomes derived from IDO-BMSCs can be used to promote immunotolerance and prolong the survival of cardiac allografts.

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

“…A large number of experimental and clinical studies demonstrated beneficial effects of MSC-Exos in the suppression of autoimmune and chronic inflammatory eye diseases [88][89][90][91][92][93][94][95]. Intravenous as well as periocular administration of MSC-Exos efficiently attenuated experimental autoimmune uveitis (EAU) [89,90].…”

“…MSC-Exos contain a growth related oncogene (GRO), which suppresses production of Th17-inducing cytokines (IL-1β, IL-6 and IL-23) in DCs and prevent Th17 cell-driven inflammation [91,92]. In addition to GRO, MSC-sourced Indoleamine 2-3 dioxygenase (IDO) was responsible for MSC-Exo-based suppression of DC-dependent generation of Th17 cells [93,94]. Exos obtained from IDO-overexpressing MSCs down-regulated expression of co-stimulatory molecules and suppressed production of Th17-inducing cytokines in DCs, attenuating their capacity for activation of naïve T cells and generation of inflammatory Th17 cells [93,94].…”

Mesenchymal stem cell-derived secretomes for therapeutic potential of premature infant diseases

“…These biomolecules can be divided into the following categories, and have protective functions in different tissues: (1) angiogenesis factors, such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1), and hepatocyte growth factor (HGF); (2) anti-apoptotic factors, such as basic fibroblast growth factor (bFGF), transforming growth factor (TGF), and granulocyte macrophage-colony stimulating factor (GM-CSF); (3) anti-inflammatory factors, such as TNF-a-stimulated gene/protein (TSG), interleukin (IL-10), and heme oxygenase (HO) [41,42]. Additionally, soluble factors such as immunoregulatory protein produced by cells can be found to be sealed in vesicles [43]. These secretomes can mediate diverse functions via a cross-talk between different cell types, and are easily affected by organism environment in vivo [44][45][46].…”

“…Bartosh et al [58] observed that the secretion of anti-inflammatory molecules, namely TNF-α-stimulated gene-6 (TSG-6) and STC-1, by MSCs was increased after three-dimensional spheroid culturing, which decreased inflammation in vivo and macrophage activation in vitro. In addition, TGF-β and interferon-γ (IFN-γ) stimulation [30], the overexpression of angiopoietin-1 [59], HO-1 or other genes [43], and neutralizing antibodies can also change the secretory composition of MSCs and affect their functions.…”

“…The proteins contained in exosomes also have crucial functions in alleviating organ damage. Wang et al demonstrated that exosomes secreted by indoleamine 2, 3-dioxygenase (IDO)-overexpressing BM-MSCs (IDO-BM-MSCs) up-regulated the immunoregulatory protein four-and-a-half LIM domain 1 (FHL-1), and that these exosomes reduced the immunoreaction after transplantation and improved cardiac allograft function in rats that received transplants [43]. Yan et al demonstrated that human umbilical cord MSC (hUC-MSC) exosomes promoted hepatocyte recovery from oxidative stress via the antioxidant and antiapoptotic effects of exosomal glutathione peroxidase1 (GPX1) both in vitro and in vivo, however, GPX1 knockdown was found to delay this hepatoprotective effect [72].…”