Metformin enhances the immunomodulatory potential of adipose-derived mesenchymal stem cells through STAT1 in an animal model of lupus

Abstract

Abstract Mesenchymal stem cells (MSCs) are considered potential therapeutic agents for treating autoimmune disease because of their immunomodulatory capacities and anti-inflammatory effects. However, several studies have shown that there is no consistency in the effectiveness of the MSCs to treat for autoimmune disease. In this study, we investigated whether metformin could enhance the immunoregulatory function of MSCs, what mechanism is relevant, and whether metformin-treated MSCs could be effective in an animal lupus model. To examine the effects of metformin, adipose-derived (Ad)-MSCs were cultured for 72 h in the presence of metformin. Immunoregulatory factors expression was analyzed by real-time PCR and ELISA. MRL/lpr mice weekly injected 1×106 metformin-treated Ad-MSCs for 8 weeks. Proteinuria, serum anti-dsDNA antibody, lupus nephritis, immune complex, cellular subset were analyzed in each group. Metformin enhanced the immunomodulatory functions of Ad-MSCs including IDO, IL-10, and TGF-β. Metformin upregulated the expression of p-AMPK, p-STAT1, and inhibited the expression of p-STAT3, p-mTOR in Ad-MSCs. STAT1 inhibition by siRNA strongly diminished IDO, IL-10, TGF-β in metformin-treated Ad-MSCs. As a result, metformin promoted the immunoregulatory effect of Ad-MSCs by enhancing STAT1 expression, which was dependent on the AMPK/mTOR pathway. Administration of metformin-treated Ad-MSCs resulted in significant disease activity improvement in MRL/lpr mice. Moreover, metformin-treated Ad-MSCs inhibited CD4−CD8− T cell expansion and Th17/Treg cell ratio. These finding suggest that metformin optimized the immunoregulatory properties of Ad-MSCs and may be a novel therapeutic agent for the treatment of lupus.