Jia Shuangshuang, Liu Xin, Li Weiyang, Xie Jieshi, Yang Le, Li Liying
Cell Physiol Biochem. 2015;37(6):2085-100. doi: 10.1159/000438567. Epub 2015 Nov 25.
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.
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.
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.
PPARx03B3; negatively regulates the differentiation of BMSCs toward myofibroblasts, which highlights a further mechanism implicated in the BMSC differentiation.
背景/目的：骨髓间充质干细胞（BMSCs）已被证实具有向肝肌成纤维细胞分化的能力，这在慢性肝病的纤维化过程中发挥作用。过氧化物酶体增殖物激活受体γ（PPARγ）是一种配体激活的转录因子，因其参与纤维化和细胞分化而受到广泛关注。然而，它是否调节BMSCs向肌成纤维细胞的分化仍有待确定。
采用四氯化碳或胆管结扎诱导小鼠肝纤维化。通过实时RT-PCR、Western印迹或免疫荧光分析检测PPARγ、α-平滑肌肌动蛋白、胶原蛋白α1（I）和胶原蛋白α1（III）的表达。
小鼠纤维化肝脏中PPARγ表达降低。此外，在转化生长因子β1诱导的BMSCs向肌成纤维细胞分化过程中，PPARγ表达下降。天然或合成配体刺激PPARγ激活可抑制BMSCs分化。此外，siRNA敲低PPARγ促进BMSCs向肌成纤维细胞分化。此外，天然配体激活PPARγ可显著抑制肝纤维化过程中BMSCs向肌成纤维细胞的分化，并减轻肝纤维化。
PPARγ负向调节BMSCs向肌成纤维细胞的分化，这揭示了BMSCs分化的另一种机制。
