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Mesenchymal Stromal Cell-Derived Microvesicles Regulate An Internal Pro-Inflammatory Program In Activated M1 Macrophages.

Abstract

Mesenchymal stromal cells (MSCs) are multipotent cells with abilities to exert immunosuppressive response promoting tissue repair. Studies have shown that MSCs can secrete extracellular vesicles (MVs-MSCs) with similar regulatory functions to the parental cells. Furthermore, strong evidence suggesting that MVs-MSCs can modulate several immune cells (i.e. Th1, Th17 and Foxp3+ T cells). However, their precise effect on macrophages (Mxs) remains unexplored. We investigated the immunoregulatory effect of MVs-MSCs on activated M1-Mxs in vitro and in vivo using differentiated bone marrow Mxs and an acute experimental model of thioglycollate-induced peritonitis, respectively. We observed that MVs-MSCs shared surface molecules with MSCs (CD44, CD105, CD90, CD73) and expressed classical microvesicle markers (Annexin V and CD9). The in vitro treatment with MVs-MSCs exerted a regulatory-like phenotype in M1-Mxs, which showed higher CD206 level and reduced CCR7 expression. This was associated with decreased levels of inflammatory molecules (IL-1², IL-6, NO) and increased immunoregulatory markers (IL-10 and Arginase) in M1-Mxs. In addition, we detected that MVs-MSCs promoted the down-regulation of inflammatory miRNAs (miR-155 and miR-21), as well as its predicted target gene SOCS3 in activated M1-Mxs. In vivo MVs-MSCs treatment reduced the Mxs infiltrate in the peritoneal cavity inducing a M2-like regulatory phenotype in peritoneal Mxs (higher arginase activity and reduced expression of CD86, iNOS, IFN-³, IL-1², TNF-±, IL-1± and IL-6 molecules). This in vivo immunomodulatory effect of MVs-MSCs on M1-Mxs was partially associated with the up-regulation of CX3CR1 in F4/80+/Ly6C+/CCR2+ Mxs subsets. In summary, our findings indicate that MVs-MSCs can modulate an internal program in activated Mxs establishing an alternative regulatory-like phenotype. (AU)