Toll-like receptor 2 mediates mesenchymal stem cell-associated myocardial recovery and VEGF production following acute ischemia-reperfusion injury
Toll-like receptor 2 mediates mesenchymal stem cell-associated myocardial recovery and VEGF production following acute ischemia-reperfusion injury
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DOI：
10.1152/ajpheart.01087.2009
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发表时间：
2010-05-01
影响因子：
4.8
通讯作者：
Meldrum, Daniel R.
中科院分区：
文献类型：
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作者：
Abarbanell, Aaron M.;Wang, Yue;Meldrum, Daniel R.
Abarbanell AM、Wang Y、Herrmann JL、Weil BR、Poynter JA、Manukyan MC、Meldrum DR。 Toll 样受体 2 介导急性缺血再灌注损伤后间充质干细胞相关的心肌恢复和 VEGF 产生。 Am J Physiol Heart Circ Physiol 298：H1529-H1536，2010。首次发表于 2010 年 2 月 19 日； doi: 10.1152/ajpheart.01087.2009.-Toll 样受体 2 (TLR2) 是先天免疫系统的关键组成部分，与缺血再灌注损伤 (I/R) 后的炎症和心肌功能障碍有关。众所周知，用间充质干细胞 (MSC) 治疗心脏可改善 I/R 后的心肌恢复，部分原因是 VEGF 等旁分泌因子。然而，尚不清楚 MSC 上的 TLR2 激活是否会影响 MSC 介导的心肌恢复和 VEGF 产生。我们假设敲除 MSC 上的 TLR2 (TLR2KO MSC) 将 1) 改善 MSC 介导的心肌恢复，2) 增加心肌和 MSC VEGF 释放。使用离体心脏灌注系统，对 Sprague-Dawley 大鼠心脏进行 I/R 处理，并接受三种冠状动脉内治疗之一：载体、雄性野生型 MSC (MWT MSC) 或 TL2KO MSC。所有治疗均在缺血前立即进行，并连续测量心脏功能。再灌注后，分析心脏匀浆的心肌 VEGF 产生。与我们的假设相反，仅MWT MSC治疗显着改善了左心室发展压的恢复以及压力一阶导数的最大正值和负值。此外，用 MWT MSC 处理的心脏中 VEGF 的产生量最大。为了研究 MSC 产生 VEGF，在体外用 TNF 激活 MSC，并收集上清液用于 ELISA。 MSC VEGF 产生的体外基础水平相似。然而，随着TNF的激活，MWT MSC产生显着更多的VEGF，而激活的TLR2KO MSC产生的VEGF却没有变化。最后，我们观察到 MWT MSC 比 TLR2KO MSC 增殖更快。这些数据表明 TLR2 可能对于 MSC 介导的心肌恢复和 VEGF 产生至关重要。
Abarbanell AM, Wang Y, Herrmann JL, Weil BR, Poynter JA, Manukyan MC, Meldrum DR. Toll-like receptor 2 mediates mesenchymal stem cell-associated myocardial recovery and VEGF production following acute ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 298: H1529-H1536, 2010. First published February 19, 2010; doi: 10.1152/ajpheart.01087.2009.-Toll-like receptor 2 (TLR2), a key component of the innate immune system, is linked to inflammation and myocardial dysfunction after ischemia-reperfusion injury (I/R). Treatment of the heart with mesenchymal stem cells (MSCs) is known to improve myocardial recovery after I/R in part by paracrine factors such as VEGF. However, it is unknown whether TLR2 activation on the MSCs affects MSC-mediated myocardial recovery and VEGF production. We hypothesized that the knockout of TLR2 on the MSCs (TLR2KO MSCs) would 1) improve MSC-mediated myocardial recovery and 2) increase myocardial and MSC VEGF release. With the isolated heart perfusion system, Sprague-Dawley rat hearts were subjected to I/R and received one of three intracoronary treatments: vehicle, male wild-type MSCs (MWT MSCs), or TL2KO MSCs. All treatments were performed immediately before ischemia, and heart function was measured continuously. Postreperfusion, heart homogenates were analyzed for myocardial VEGF production. Contrary to our hypothesis, only MWT MSC treatment significantly improved the recovery of left ventricular developed pressure and the maximal positive and negative values of the first derivative of pressure. In addition, VEGF production was greatest in hearts treated with MWT MSCs. To investigate MSC production of VEGF, MSCs were activated with TNF in vitro and the supernatants collected for ELISA. In vitro basal levels of MSC VEGF production were similar. However, with TNF activation, MWT MSCs produced significantly more VEGF, whereas activated TLR2KO MSC production of VEGF was unchanged. Finally, we observed that MWT MSCs proliferated more rapidly than TLR2KO MSCs. These data indicate that TLR2 may be essential to MSC-mediated myocardial recovery and VEGF production.