IFN-alpha and vitamin B6-primed human clonal mesenchymal stem cells enhanced therapeutic efficacy by regulating the balance between Treg and Th17 cells.

초록

Mesenchymal stem cell (MSC) therapy has garnered significant interest in the treatment of immune diseases due to its anti-inflammatory and immunomodulatory properties. In recent years, numerous researchers have been attempting to enhance the therapeutic effectiveness of MSCs through priming techniques using IL-1? or IFN-?. We conducted a screening of various soluble factors and discovered that IFN-? and vitamin B6 showed promising results. We then compared their therapeutic efficacy in treating atopic dermatitis in combination with either IL-1? or TNF-? and IFN-? (T/I). This combination is referred to as pcMSC1 and pcMSC2, respectively. pcMSC2 increased numerous immunomodulatory factors compared to pcMSC1. In particular, the expression of IL-1Ra, PD-L1, and galectin-9 (Gal-9) was significantly increased by pcMSC2 compared to pcMSC1. pcMSC2 significantly decreased T-cell proliferation. Using murine models of ovalbumin-induced atopic dermatitis, we observed a significant increase in the therapeutic efficacy of pcMSC2 compared to pcMSC1 and cMSCs. In the mechanism study, we observed an increase in the expression of Foxp3+ Treg, IL-10, and Gal-9 in the regulatory T-cell conditions. When we neutralized IL-1Ra, PD-L1, and Gal-9 using antibodies, only the anti-Gal-9 antibodies decreased the population of Foxp3+ Treg, while the other two antibodies did not affect it. It suggests that Gal-9, induced by pcMSC2, may be responsible for the induction of Tregs. In the IL-17A differentiation condition, pcMSC2 significantly decreased the expression of IL-17A and increased the expression of IL-2. Probably, pcMSC2 can induce IL-2, which may increase the differentiation of Treg cells and decrease the differentiation of Th17 cells. Thus, the new priming approaches might help improve the clinical therapeutic efficacy of cMSCs by regulating the balance between Treg and Th17 cells.