TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection.
TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection.
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DOI：
10.1371/journal.pone.0014206
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发表时间：
2010-12-03
期刊：
影响因子：
3.7
通讯作者：
Meldrum DR
中科院分区：
文献类型：
--
作者：
Wang Y;Abarbanell AM;Herrmann JL;Weil BR;Manukyan MC;Poynter JA;Meldrum DR
骨髓间充质干细胞(MSC)可促进缺血再灌注(I/R)损伤后的心肌恢复。这些作用部分是由血管生成和组织生长促进因子的旁分泌介导的。Toll样受体4(Toll-like Receptor 4，TLR4)由骨髓间充质干细胞表达，可诱导神经前体细胞的凋亡和抑制其增殖。目前尚不清楚TLR4基因敲除(KO)是否会改变MSC的旁分泌特性，从而改善MSC相关的心肌保护。本研究采用体外培养的大鼠心脏I/R损伤模型，采用ELISA法和细胞因子阵列检测方法，探讨MSC TLR4对血管生成因子和趋化因子分泌的影响，并探讨TLR4在MSC介导的心肌缺血再灌注损伤后心肌恢复中的作用。我们观察到，从TLR4KO小鼠分离的MSC在大鼠心肌I/R损伤模型中显示出更大程度的心脏保护作用。这种增强的保护与血管生成因子的产生、增殖和分化的增加有关。TLR4缺陷还与PI-3K和AKT的磷酸化降低，但STAT3的激活增加有关。靶向STAT3的siRNA导致TLR4缺陷的MSC增强的心肌保护作用减弱。本研究表明，TLR4通过抑制STAT3的作用机制，对MSC诱导的I/R心肌保护产生不利影响。
Bone marrow-derived mesenchymal stem cells (MSC) improve myocardial recovery after ischemia/reperfusion (I/R) injury. These effects are mediated in part by the paracrine secretion of angiogenic and tissue growth-promoting factors. Toll-like receptor 4 (TLR4) is expressed by MSC and induces apoptosis and inhibits proliferation in neuronal progenitors as well as many other cell types. It is unknown whether knock-out (KO) of TLR4 will change the paracrine properties of MSC and in turn improve MSC-associated myocardial protection. This study explored the effect of MSC TLR4 on the secretion of angiogenic factors and chemokines in vitro by using ELISA and cytokine array assays and investigated the role of TLR4 on MSC-mediated myocardial recovery after I/R injury in an isolated rat heart model. We observed that MSC isolated from TLR4 KO mice exhibited a greater degree of cardioprotection in a rat model of myocardial I/R injury. This enhanced protection was associated with increased angiogenic factor production, proliferation and differentiation. TLR4-dificiency was also associated with decreased phosphorylation of PI-3K and AKT, but increased activation of STAT3. siRNA targeting of STAT3 resulted in attenuation of the enhanced cardioprotection of TLR4-deficient MSC. This study indicates that TLR4 exerts deleterious effects on MSC-derived cardioprotection following I/R by a STAT3 inhibitory mechanism.
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间充质干细胞和心脏修复。
影响因子：
5.3
作者：
Nesselmann C;Ma N;Bieback K;Wagner W;Ho A;Konttinen YT;Zhang H;Hinescu ME;Steinhoff G
通讯作者：
Steinhoff G
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6.2
作者：
Filipovic, Radmiia;Zecevic, Nada
通讯作者：
Zecevic, Nada
影响因子：
4.4
作者：
Jung, DY;Lee, H;Suk, K
通讯作者：
Suk, K
影响因子：
4.8
作者：
Loberg, Robert D.;Ying, Chi;Pienta, Kenneth J.
通讯作者：
Pienta, Kenneth J.
影响因子：
3.7
作者：
Edman, Linda C.;Mira, Helena;Arenas, Ernest
通讯作者：
Arenas, Ernest