Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

Abstract

Aims/hypothesis Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes. Methods Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation. DCs were differentiated from CD14 + cells, obtained from nine type 1 diabetic patients at disease onset, pulsed with antigen GAD65 and cultured with MSCs or EVs. Levels of DC maturation and activation markers were evaluated by flow cytometry. GAD65-pulsed DCs and autologous CD14− cell were cocultured and IFN-γ enzyme-linked immunosorbent spot responses were assayed. Secreted cytokine levels were measured and Th17 and regulatory T cells were analysed.Results MSC-and EV-conditioned DCs acquired an immature phenotype with reduced levels of activation markers and increased IL-10 and IL-6 production. Conditioned DC plus T cell co-cultures showed significantly decreased IFN-γ spots and secretion levels. Moreover, higher levels of TGF-β, IL-10 and IL-6 were detected compared with unconditioned DC plus T cell co-cultures. Conditioned DCs decreased Th17 cell numbers and IL-17 levels, and increased FOXP3 + regulatory T cell numbers. EVs were internalised by DCs and EV-conditioned DCs exhibited a similar effect. Conclusions/interpretation In type 1 diabetes, MSCs induce immature IL-10-secreting DCs in vitro, thus potentially intercepting the priming and amplification of autoreactive T cells in tissue inflammation. These DCs can contribute to the inhibition of inflammatory T cell responses to islet antigens and the promotion of the anti-inflammatory, regulatory responses exerted by MSCs.

Stem Cell-Derived Extracellular Vesicles and Immune-Modulation

“…The ability of MSC-derived EVs to mimic the effect of the cell of origin has been studied on various different effector cells of the immune system (Blazquez et al, 2014; Conforti et al, 2014; Favaro et al, 2014, 2016; Zhang, 2014; Amarnath et al, 2015; Del Fattore et al, 2015; Gouveia de Andrade et al, 2015; Di Trapani et al, 2016; see Table 2). …”

“…In addition, there was a reduction in the number of Th17 cells as reflected by the reduction in IL17 secretion and an increase in regulatory T-cells in the same setting, suggesting that T-cells switched to an anti-inflammatory phenotype in the presence of EVs (Favaro et al, 2014). Furthermore, in a later study they reported that DCs conditioned with MSC-derived EVs acquired an immature phenotype with increased IL-10 secretion, which contributed toward inhibition of inflammatory T-cell response against islet Ags (Di Nicola et al, 2002; Favaro et al, 2014, 2016). …”

Artificial Mitochondria Transfer: Current Challenges, Advances, and Future Applications

“…Viable and nonfunctional mitochondria can be shared by the cell inducing different cellular responses from cellular rescue to promoting inflammation. The first transfer mechanism is the microvesicle transport of mitochondria, it has been observed specially in MSCs in which the secreted microvesicles carrying mitochondria, once internalized by the recipient cells, induce its rescue from cellular damage and enhance the phagocytic properties of immune cells [182, 183]. The second way of transfer is by TNTs; many cells share the ability to produce them and transport mitochondria with proven effects in the rescue from cellular damage, metabolic reprogramming, and immune enhancement and it was also associated with its differentiation [65, 184].…”

Recent Developments in Cellular Immunotherapy for HSCT-Associated Complications

“…Additionally, infusion of MSC-EVs led to enhanced survival of allogeneic skin grafts in mice (100). Recently, Favaro et al demonstrated that MSC-EVs internalized by DCs impaired their in vitro maturation, with reduced expression of maturation markers CD86, CD80, and CD83, and an increase in IL-10 production by the EV-conditioned DCs (101). …”

“…A recent report on the immunosuppressive effect of BM-MSCs and their derived EVs has shown the latter were considerably less potent in suppressing T cell proliferation and preventing B cell differentiation (115). EVs were also seen to be not as effective in modulating DC maturation as their parent cells (101). In the future, it will be important to investigate the effect of MSC variability and licensing on the molecular signature of their derived vesicles.…”