间充质干细胞来源的外泌体通过TGF-β1/Smad2/3信号通路抑制高糖诱导的成纤维细胞转分化

Mesenchymal Stem Cell-Derived Exosome Inhibits High Glucose-Induced Fibroblasts Transdifferentiation Via TGF-β1/Smad2/3 Signaling Pathway

心脏纤维化是糖尿病患者心肌功能障碍的主要原因。成纤维细胞转分化为成肌纤维细胞是心脏纤维化过程中的一个关键性事件。该研究的目的是探究高糖诱导成纤维细胞转分化的分子机制,并找寻抑制成纤维细胞转分化的方法。结果显示,经高糖处理的BJ细胞(人皮肤成纤维细胞系)与正常BJ细胞相比,α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)的表达明显上调。通过使用SB525334或转化生长因子-β1(transforming growth factor-β1,TGF-β1)si RNA抑制TGF-β1/Smad2/3信号通路的活化,发现α-SMA和胶原I的蛋白质水平及Smad2/3的磷酸化水平均降低。同时,SB525334也抑制了高糖诱导的BJ细胞增殖。大鼠骨髓间充质干细胞来源的外泌体(mesenchymal stem cell-derived exosome,MSC-Exo)通过降低Smad2/3磷酸化水平,抑制高糖诱导的α-SMA表达。综上所述,高糖通过激活TGF-β1信号通路导致BJ细胞的转分化,而MSC-Exo通过抑制该通路防止BJ细胞的转分化。

Cardiac fibrosis is the leading cause of myocardial dysfunction in patients with diabetes. Fibroblasts transdifferentiation into myofibroblasts is a key event in cardiac fibrosis. The purpose of this study was to investigate the mechanism of high glucose-induced fibroblasts transdifferentiation and to find a way to inhibit the transdifferentiation. Our results showed that the level of α-SMA（α-smooth muscle actin） was significantly up-regulated in BJ cells（human dermal fibroblasts） treated with high glucose compared with the normal BJ cells. We found that α-SMA and collagen I protein levels, and the phosphorylation level of Smad2/3 were decreased by SB525334, an inhibitor of TGF-β1（transforming growth factor-β1） pathway, or TGF-β1 siRNA to inhibit the activation of TGF-β1/Smad2/3 signaling pathway. SB525334 also inhibited the high glucose-induced BJ cells proliferation. Rat bone marrow mesenchymal stem cell-derived exosome（MSC-Exo） inhibited the high glucose-induced expression of α-SMA by decreasing the phosphorylation of Smad2/3. In summary, high glucose-induced fibroblasts transdifferentiation is mediated by TGF-β1/Smad2/3 signaling pathway, which can be inhibited by MSC-Exo.