Peroxisome Proliferator-Activated Receptor Gamma Negatively Regulates the Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells Toward Myofibroblasts in Liver Fibrogenesis

Abstract

BACKGROUND/AIMS: Bone marrow-derived mesenchymal stem cells (BMSCs) have been confirmed to have capacity to differentiate toward hepatic myofibroblasts, which contribute to fibrogenesis in chronic liver diseases. Peroxisome proliferator-activated receptor gamma (PPARx03B3;), a ligand-activated transcription factor, has gained a great deal of recent attention as it is involved in fibrosis and cell differentiation. However, whether it regulates the differentiation of BMSCs toward myofibroblasts remains to be defined. METHODS: Carbon tetrachloride or bile duct ligation was used to induce mouse liver fibrosis. Expressions of PPARx03B3;, α-smooth muscle actin, collagen α1 (I) and collagen α1 (III) were detected by real-time RT-PCR and Western blot or immunofluorescence assay. RESULTS: PPARx03B3; expression was decreased in mouse fibrotic liver. In addition, PPARx03B3; was declined during the differentiation of BMSCs toward myofibroblasts induced by transforming growth factor β1. Activation of PPARx03B3; stimulated by natural or synthetic ligands suppressed the differentiation of BMSCs. Additionally, knock down of PPARx03B3; by siRNA contributed to BMSC differentiation toward myofibroblasts. Furthermore, PPARx03B3; activation by natural ligand significantly inhibited the differentiation of BMSCs toward myofibroblasts in liver fibrogenesis and alleviated liver fibrosis. CONCLUSIONS: PPARx03B3; negatively regulates the differentiation of BMSCs toward myofibroblasts, which highlights a further mechanism implicated in the BMSC differentiation.