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

Abstract

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-1β (IL-1β) and evaluated their therapeutic effects in a cecal ligation and puncture-induced sepsis model. We found that systemic administration of IL-1β-pretreated MSCs (βMSCs) ameliorated the symptoms of murine sepsis more effectively and increased the survival rate compared with naïve MSCs. Furthermore, βMSCs could more effectively induce macrophage polarization toward an anti-inflammatory M2 phenotype through the paracrine activity. Mechanistically, we demonstrated that βMSC-derived exosomes contributed to the enhanced immunomodulatory properties of βMSCs both in vitro and in vivo. Importantly, we found that miR-146a, a well-known anti-inflammatory microRNA, was strongly upregulated by IL-1β 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 βMSC-derived exosomes. Taken together, IL-1β pretreatment effectively enhanced the immunomodulatory properties of MSCs partially through exosome-mediated transfer of miR-146a. Therefore, we believe that IL-1β pretreatment may provide a new modality for better therapeutic application of MSCs in inflammatory disorders. Stem Cells 2017;35:1208-1221.

Stem cell‐derived extracellular vesicles attenuate the early inflammatory response after tendon injury and repair

“…These findings are supported by several independent reports indicating that inflammation‐stimulated stem cell EVs possess enhanced immunosuppressive functions, and improved therapeutic efficacy in treating inflammation‐related conditions . The priming effect has been reported to be associated with selective enrichment of certain regulatory miRNA cargos in primed EVs, such as let‐7b and miR‐146a, which are capable of modulating the macrophage inflammatory response . It remains to be determined if a similar mechanism contributes to the iEV effects discovered in this study.…”

Exosomes derived from pro‐inflammatory bone marrow‐derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization

“…Evidence showed that LPS‐pre‐conditioned MSC‐derived exosomes reduced inflammation and promoted wound healing through modulating the M2 macrophage activation by shuttling let‐7b . Similarly, IL‐1β‐primed human umbilical cord MSC‐derived exosomes effectively induced macrophage polarization towards an anti‐inflammatory M2 phenotype partially through the transfer of exosomal miR‐146a . In addition, LPS pre‐conditioning could activate BMSCs, producing several other factors, such as fibroblast growth factor 2 (FGF2), vascular endothelial growth factors (VEGF), hepatocyte growth factor (HGF), insulin‐like growth factor 1 (IGF‐1) and TGF‐β, which may be packed in exosomes to exert cardioprotection after MI .…”

Concise Review: Mesenchymal Stromal/Stem Cells: A New Treatment for Sepsis and Septic Shock?

“…In vivo, using the CLP murine model, they observed a significant reduction in plasma levels of IL6, TNFa, and murine homolog of human showed recently that pretreatment of MSC with IL1b induces an increase in the level of anti-inflammatory miR146 contained in MSC exosomes. Transferred into the macrophages, miR146 induces their polarization into anti-inflammatory M2 macrophages, by blocking the pro-inflammatory signaling pathways IL-1R-associated kinase (IRAK1), TNF receptor-associated factor 6 (TRAF6), and Interferon regulatory factor 5 (IRF5) [48].…”