Reduced Let-7f in Bone Marrow-Derived Mesenchymal Stem Cells Triggers Treg/Th17 Imbalance in Patients With Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) patients exist an imbalance between regulatory T (Treg) and T helper 17 cells (Th17), which might be contributed by defective immune regulation of bone marrow derived mesenchymal stem cells (BM-MSCs) from SLE patients. Our microRNA array analysis showed markedly down-regulated expression levels of microRNA let-7f in BM-MSCs from SLE patients compared to those from normal controls (NOR). To explore the role of let-7f in the disease pathogenesis, we showed that expression levels of let-7f in SLE BM-MSCs were negatively associated with SLE disease activity, and the predicted let-7 family targeted gene expression of interlukin-6 (IL-6) was significantly higher in BM-MSCs from SLE patients compared to normal controls (NOR). Transient transfection of BM-MSCs with let-7f mimics or inhibitors showed reduced levels of let-7f impaired the proliferation rate of BM-MSCs, BM-MSC-mediated downregulation of Th17 cells and upregulation of Treg cells, increased the apoptosis rate of BM-MSCs through targeting IL-6 and activating signal transducers and activators of transcription-3 (STAT3) pathway, but had no significant effect on the differentiation of Th1 and Th2. Our findings showed a key role of let-7f in the imbalance of Treg/Th17 mediated by SLE BM-MSCs, suggesting the potential of manipulating let-7f expression in BM-MSCs for treating SLE patients.