Molecular characterization of msc-derived extracellular vesicles and correlation with their immunomodulatory potential

      Mesenchymal stromal cells (MSCs) are adult, multipotent stem cells of mesodermal origin. In addition to their stem cell properties, MSCs possess broad immunosuppressive functions influencing both adaptive and innate immune effector cells (IECs). This anti-inflammatory potential is triggered by the release of inflammatory cytokines produced by immune cells in the microenvironment. Indeed, high levels of inflammatory cytokines induce MSCs to become immunosuppressive (primed-MSCs). The immunosuppressive potential of primed-MSCs results from a dynamic interaction between MSCs and IECs mediated by the release of bioactive factors, including extracellular vesicles (EVs). EVs are secreted by many cell types and influence various biological processes, both directly activating cell surface receptors through bioactive ligands and delivering transcription factors, oncogenes, mRNA, and non-coding regulatory RNAs, such as microRNAs (miRNA), into target cells. In this study, we have investigated the undisclosed molecular mechanisms regulating the immunosuppressive capabilities of EVs derived from primed-MSCs (primed-EVs), starting from a molecular characterization of their contents by high-throughput approaches. We analyzed miRNAs, mRNAs and proteins differentially expressed in primed-EVs compared to ctrl-EVs. We found miR-155-5p and miR-6723-5p significantly up-regulated in primed-EVs. Enrichment analysis on predicted target genes revealed an involvement of miR-155-5p and miR-6723-5p in different pathways regulating immunomodulatory processes. Moreover, we found IDO mRNA significantly up-regulated in primed-EVs. Furthermore, primed-EVs showed 73 proteins significantly modulated compared to ctrl-EVs. Enrichment analysis on modulated proteins revealed different pathways up and down regulated involved in immunomodulatory properties exerted by primed-EVs. This molecular characterization of MSC-EVs, and the consequent functional validation of candidate molecules, will pave the way for novel therapeutic perspectives for the treatment of inflammatory and autoimmune diseases.
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