Hypoxia Preconditioned Mesenchymal Stem Cells Prevent Cardiac Fibroblast Activation and Collagen Production via Leptin (Retracted Article)
Hypoxia Preconditioned Mesenchymal Stem Cells Prevent Cardiac Fibroblast Activation and Collagen Production via Leptin (Retracted Article)
复制标题
缺氧预处理间充质干细胞通过瘦素阻止心脏成纤维细胞活化和胶原蛋白产生
DOI：
10.1371/journal.pone.0103587
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发表时间：
2014-08-12
期刊：
影响因子：
3.7
通讯作者：
Hu, Xinyang
中科院分区：
文献类型：
--
作者：
Chen, Panpan;Wu, Rongrong;Hu, Xinyang
目的 由于间质纤维化，心脏成纤维细胞活化为肌成纤维细胞是心肌梗死 (MI) 后心脏重塑的关键步骤。间充质干细胞 (MSC) 已被证明可以改善心肌梗死后重塑，缺氧预处理 (HPC) 可以增强这种效果。瘦素已被证明可以促进心脏纤维化。 HPC 后 MSC 中瘦素的表达显着增加，但尚不清楚瘦素是否有助于 MSC 治疗或纤维化过程。本研究的目的是确定间充质干细胞分泌的瘦素是否调节心脏纤维化。方法 缺氧（0.5% O2）诱导心脏成纤维细胞（CF）活化。通过将MSC与CF共培养，通过Western blot、免疫荧光和天狼星红染色检测CF中α-SMA、SM22α和胶原蛋白IαI的表达，分析MSC对成纤维细胞活化的影响。使用涉及永久结扎左冠状动脉前降支的急性心肌梗死模型研究了体内 MSC 对左心室重构的抗纤维化作用。结果共培养的 MSC 降低了成纤维细胞的活化，而 HPC 则增强了这一效果。来自 Ob/Ob 小鼠的瘦素缺陷 MSC 不会降低成纤维细胞活化。与此一致的是，H-MSC 显着抑制 MI 后的心脏纤维化，并介导 CF 中 TGF-β/Smad2 和 MRTF-A 表达降低。这些效应在瘦素缺陷的 MSC 中再次不存在。结论 我们的数据表明，间充质干细胞以瘦素依赖性方式抑制心脏成纤维细胞的活化。其机制可能涉及阻断 TGF-β/Smad2 和 MRTF-A 信号通路。
Aims Activation of cardiac fibroblasts into myofibroblasts constitutes a key step in cardiac remodeling after myocardial infarction (MI), due to interstitial fibrosis. Mesenchymal stem cells (MSCs) have been shown to improve post-MI remodeling an effect that is enhanced by hypoxia preconditioning (HPC). Leptin has been shown to promote cardiac fibrosis. The expression of leptin is significantly increased in MSCs after HPC but it is unknown whether leptin contributes to MSC therapy or the fibrosis process. The objective of this study was to determine whether leptin secreted from MSCs modulates cardiac fibrosis. Methods Cardiac fibroblast (CF) activation was induced by hypoxia (0.5% O2). The effects of MSCs on fibroblast activation were analyzed by co-culturing MSCs with CFs, and detecting the expression of α-SMA, SM22α, and collagen IαI in CFs by western blot, immunofluorescence and Sirius red staining. In vivo MSCs antifibrotic effects on left ventricular remodeling were investigated using an acute MI model involving permanent ligation of the left anterior descending coronary artery. Results Co-cultured MSCs decreased fibroblast activation and HPC enhanced the effects. Leptin deficit MSCs from Ob/Ob mice did not decrease fibroblast activation. Consistent with this, H-MSCs significantly inhibited cardiac fibrosis after MI and mediated decreased expression of TGF-β/Smad2 and MRTF-A in CFs. These effects were again absent in leptin-deficient MSCs. Conclusion Our data demonstrate that activation of cardiac fibroblast was inhibited by MSCs in a manner that was leptin-dependent. The mechanism may involve blocking TGF-β/Smad2 and MRTF-A signal pathways.