Abstract
Mesenchymal stromal cells (MSCs) are adult, multipotent cells of mesodermal origin representing the progenitors of all stromal tissues. MSCs possess significant and broad immunomodulatory functions affecting both adaptive and innate immune responses once MSCs are primed by the inflammatory microenvironment. Recently, the role of extracellular vesicles (EVs) in mediating the therapeutic effects of MSCs has been recognized. Nevertheless, the molecular mechanisms responsible for the immunomodulatory properties of MSC-derived EVs (MSC-EVs) are still poorly characterized. Therefore, we carried out a molecular characterization of MSC-EV content by high-throughput approaches. We analyzed miRNA and protein expression profile in cellular and vesicular compartments both in normal and inflammatory conditions. We found several proteins and miRNAs involved in immunological processes, such as MOES, LG3BP, PTX3, and S10A6 proteins, miR-155-5p, and miR-497-5p. Different in silico approaches were also performed to correlate miRNA and protein expression profile and then to evaluate the putative molecules or pathways involved in immunoregulatory properties mediated by MSC-EVs. PI3K-AKT signaling pathway and the regulation of actin cytoskeleton were identified and functionally validated in vitro as key mediators of MSC/B cell communication mediated by MSC-EVs. In conclusion, we identified different molecules and pathways responsible for immunoregulatory properties mediated by MSC-EVs, thus identifying novel therapeutic targets as safer and more useful alternatives to cell or EV-based therapeutic approaches.
Highlights
Intercellular communication amongst neighboring cells usually occurs either through cell-to-cell contact or exchange of soluble factors
We functionally validated the modulated molecules and we focused our analysis on those involved in the crosstalk between Mesenchymal stromal cells (MSCs) and B cells for the following reasons: (i) we and other groups have previously demonstrated that B cell activity is strongly modulated by extracellular vesicles (EVs) released by MSCs [20, 44]; (ii) the characterization of the EV-mediated interactions between normal B cells and MSCs represents the basis for studying the same crosstalk in inflammatory and autoimmune diseases as well as in hematological malignancies [45,46,47]
We found a significant expression of CD146 (Figure 1F), a typical molecule characterizing a specific subpopulation of MSCs with a higher therapeutic potential [49]
Summary
Intercellular communication amongst neighboring cells usually occurs either through cell-to-cell contact or exchange of soluble factors. Microvesicles result from plasmatic membrane gemmation and contain specific cytoplasmatic proteins of the cells of origin, such as GTPbinding protein, ADP-ribosylation factor 6 (ARF6), matrix metalloproteinases (MMPs), glycoproteins (e.g., GPIb, GPIIbIIIa), integrins, receptors (e.g., EGFRvIII), and cytoskeletal components (e.g., β-actin and α-actinin-4) [5, 6]. Both exosomes and microvesicles contain a large number of molecules, whose functions are still under investigation [8]. Apoptotic bodies act as a powerful signaling pathway for the microenvironment surrounding dying cells [1,2,3,4]
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