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Regulatory T cells (Tregs), a subset of CD4+ T cells, may exert inhibitory effects on alloimmune responses including acute graft-versus-host disease (aGVHD), and several microRNAs are implicated in the pathophysiological process of GVHD. Therefore, we aimed in the present study to characterize the functional relevance of epidermal growth factor (EGF)-stimulated microRNA-21 (miR-21) in regulating bone marrow-derived mesenchymal stem cells (BMSCs) in a mouse model of aGVHD. We first isolated and cultured BMSCs and Tregs. Then, we examined effects of miR-21 knockdown or overexpression and EGF on cell activities of BMSCs and the expression of PTEN, Foxp3, AKT phosphorylation, and extent of c-jun phosphorylation by gain- and loss-of-function approaches. The results showed that miR-21 promoted the proliferation, invasion, and migration of BMSCs. Furthermore, miR-21 in BMSCs-derived exosomes inhibited PTEN, but enhanced AKT phosphorylation and Foxp3 expression in Tregs. In addition, EGF enhanced c-jun phosphorylation to elevate the miR-21 expression. Furthermore, EGF significantly increased the efficacy of BMSCs in a mouse model of aGVHD, manifesting in reduced IFN-γ expression and lesser organ damage. Moreover, EGF treatment promoted the Foxp3 expression of Tregs in BMSCs-treated aGVHD mice. Taken together, EGF induced the BMSCs-derived exosomal miR-21 expression, which enhanced Foxp3 expression in Tregs, thereby improving the therapeutic effect of BMSCs on aGVHD.

Objective: Several microRNAs have been revealed to be involved in the pathophysiological process of GVHD. This study aimed to characterize the functional relevance of epidermal growth factor (EGF)-stimulated microRNA-21 (miR-21) in the bone marrow-derived mesenchymal stem cells (BMSCs) in a mouse model of aGVHD. Methods: BMSCs and regulatory T cells (Tregs) were isolated and cultured. The effects of miR-21 knockdown or overexpression and EGF on cell activities of BMSCs as well as the expression of PTEN, Foxp3, AKT phosphorylation and extent of c-jun phosphorylation were examined by gain- and loss-of-function approaches. The efficacy and safety of EGF were further assessed in the mouse model of aGVHD. Results: Overexpression of miR-21 promoted the proliferation, invasion and migration of BMSCs. Besides, miR-21 in BMSCs-derived exosomes inhibited the expression of PTEN, enhanced AKT as well as GSK-3β phosphorylation and Foxp3 expression in Tregs. In addition, EGF enhanced c-jun phosphorylation to elevate the miR-21 expression. Furthermore, EGF significantly increased the effect of BMSCs in the mouse model of aGVHD, corresponding to reduced IFN-γ expression and organ damage. Moreover, the Foxp3 expression of Tregs in BMSCs-treated aGVHD mice was promoted by the treatment of EGF. Conclusion: Taken together, EGF induced the BMSCs-derived exosomal miR-21 expression to enhance the expression of Foxp3 in Tregs, thereby improving the therapeutic effect of BMSCs on aGVHD. Disclosures No relevant conflicts of interest to declare.