Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling

摘要: Tissue inhibitor of metalloproteinases 1 (TIMP-1) is a matrix metalloproteinase (MMP)-independent regulator growth and apoptosis in various cell types. The receptors signaling pathways that are involved the factor activities TIMP-1, however, remain controversial. RNA interference TIMP-1 has revealed endogenous suppresses proliferation, metabolic activity, osteogenic differentiation capacity human mesenchymal stem cells (hMSCs). knockdown hMSCs activated Wnt/β-catenin pathway as indicated by increased stability nuclear localization β-catenin TIMP-1–deficient hMSCs. Moreover, exhibited enhanced transcriptional determined target gene expression analysis luciferase-based β-catenin–activated reporter assay. An mutant form cannot inhibit MMP effect on independent. Furthermore, binding CD63 to surface essential for TIMP-1–mediated effects signaling. array microRNAs (miRNAs) transfection studies with specific miRNA inhibitors mimics showed let-7f crucial regulation activity TIMP-1. Let-7f was up-regulated TIMP-1–depleted demonstrably reduced axin 2, an antagonist stability. Our results demonstrate direct hMSC functions reveal regulatory network which modulates activity.