1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
2 Department of Pharmacology, Harbin Medical University, Harbin, China.
Stem Cells Dev. 2019 May 1;28(9):620-631. doi: 10.1089/scd.2018.0213. Epub 2019 Apr 11.
Bone marrow-derived mesenchymal stem cells (MSCs) improve cardiac function after ischemia/reperfusion injury, in part, due to the release of cytoprotective paracrine factors. Toll-like receptor 4 (TLR4) is expressed in MSCs and regulates the expression of cytoprotective factors, cytokines, and chemokines. Lipopolysaccharide (LPS) stimulation of TLR4 activates two distinct signaling pathways that are either MyD88 dependent or MyD88 independent/TIR-domain-containing adapter-inducing interferon-β (TRIF) dependent. While it was reported previously that LPS treatment improved MSC-mediated cardioprotection, the mechanism underlying such improved effect remains unknown. To study the role of MyD88 signaling in MSC cardioprotective activity, wild type (WT) and MyD88 MSCs were treated with LPS (200 ng/mL) for 24 h. WT and MyD88 MSCs with or without LPS pretreatment were infused into the coronary circulation of isolated mouse hearts (Langendorff model) and then subjected to ischemia (25 min) and reperfusion (50 min). Saline served as a negative control. Both untreated and LPS-pretreated WT MSCs significantly improved postischemic recovery of myocardial function of isolated mouse hearts, as evidenced by improved left ventricular developed pressure and ventricular contractility assessment (ie, the rate of left ventricle pressure change over time, ± dp/dt). LPS-pretreated WT MSCs conferred better cardiac function recovery than untreated MSCs; however, such effect of LPS was abolished when using MyD88 MSCs. In addition, LPS stimulated stat3 activity in WT MSCs, but not MyD88 MSCs. stat3 small interfering RNA abolished the effect of LPS in improving the cardioprotection of WT MSCs. In conclusion, this study demonstrates that LPS improves MSC-mediated cardioprotection by MyD88-dependent activation of stat3.
骨髓间充质干细胞（MSCs）通过释放细胞保护的旁分泌因子，改善缺血/再灌注损伤后的心脏功能。Toll 样受体 4（TLR4）在 MSCs 中表达，并调节细胞保护因子、细胞因子和趋化因子的表达。脂多糖（LPS）刺激 TLR4 激活两条不同的信号通路，一条是 MyD88 依赖的，另一条是 MyD88 非依赖/TIR 结构域包含衔接子诱导干扰素-β（TRIF）依赖的。虽然先前有报道称 LPS 处理可改善 MSC 介导的心脏保护作用，但改善这种作用的机制尚不清楚。为了研究 MyD88 信号在 MSC 心脏保护活性中的作用，用 LPS（200ng/mL）处理野生型（WT）和 MyD88 MSC 24 小时。用或不用 LPS 预处理的 WT 和 MyD88 MSC 注入分离的小鼠心脏冠状动脉循环（Langendorff 模型），然后进行缺血（25 分钟）和再灌注（50 分钟）。盐水作为阴性对照。未经处理和 LPS 预处理的 WT MSC 均显著改善分离的小鼠心脏缺血后心肌功能的恢复，表现为左心室发展压和心室收缩性评估的改善（即左心室压力随时间的变化率，±dp/dt）。LPS 预处理的 WT MSC 比未经处理的 MSC 具有更好的心脏功能恢复效果；然而，当使用 MyD88 MSC 时，LPS 的这种作用被消除。此外，LPS 刺激 WT MSC 中的 stat3 活性，但不刺激 MyD88 MSC。stat3 小干扰 RNA 消除了 LPS 改善 WT MSC 心脏保护作用。总之，这项研究表明，LPS 通过 MyD88 依赖性激活 stat3 来改善 MSC 介导的心脏保护作用。
