Epidermal Growth Factor Stimulates Exosomal microRNA-21 Derived from Mesenchymal Stem Cells to Ameliorate aGVHD By Modulating Regulatory T Cells

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.