Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin-1-Primed Mesenchymal Stem Cells Against Sepsis

Improving the immunomodulatory efficacy of mesenchymal stem cells (MSCs) through pretreatment with pro-inflammatory cytokines is an evolving field of investigation. However, the underlying mechanisms have not been fully clarified. Here, we pretreated human umbilical cord-derived MSCs with interleukin-1 (IL-1) and evaluated their therapeutic effects in a cecal ligation and puncture-induced sepsis model. We found that systemic administration of IL-1-pretreated MSCs (MSCs) ameliorated the symptoms of murine sepsis more effectively and increased the survival rate compared with naive MSCs. Furthermore, MSCs could more effectively induce macrophage polarization toward an anti-inflammatory M2 phenotype through the paracrine activity. Mechanistically, we demonstrated that MSC-derived exosomes contributed to the enhanced immunomodulatory properties of MSCs both in vitro and in vivo. Importantly, we found that miR-146a, a well-known anti-inflammatory microRNA, was strongly upregulated by IL-1 stimulation and selectively packaged into exosomes. This exosomal miR-146a was transferred to macrophages, resulted in M2 polarization, and finally led to increased survival in septic mice. In contrast, inhibition of miR-146a through transfection with miR-146a inhibitors partially negated the immunomodulatory properties of MSC-derived exosomes. Taken together, IL-1 pretreatment effectively enhanced the immunomodulatory properties of MSCs partially through exosome-mediated transfer of miR-146a. Therefore, we believe that IL-1 pretreatment may provide a new modality for better therapeutic application of MSCs in inflammatory disorders. Stem Cells2017;35:1208-1221