Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
PLoS One. 2010 Dec 3;5(12):e14206. doi: 10.1371/journal.pone.0014206.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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-deficiency 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.
CONCLUSIONS/SIGNIFICANCE: This study indicates that TLR4 exerts deleterious effects on MSC-derived cardioprotection following I/R by a STAT3 inhibitory mechanism.
骨髓间充质干细胞（MSC）可改善缺血/再灌注（I/R）损伤后的心肌恢复。这些作用部分是通过旁分泌血管生成和组织生长促进因子来介导的。Toll 样受体 4（TLR4）在 MSC 中表达，并诱导神经元祖细胞以及许多其他细胞类型的凋亡和抑制增殖。尚不清楚 TLR4 的敲除（KO）是否会改变 MSC 的旁分泌特性，并进而改善与 MSC 相关的心肌保护作用。
方法/主要发现：本研究通过 ELISA 和细胞因子阵列检测，探讨了 MSC TLR4 对体外血管生成因子和趋化因子分泌的影响，并在离体大鼠心脏模型中研究了 TLR4 在 MSC 介导的 I/R 损伤后心肌恢复中的作用。我们观察到，来自 TLR4 KO 小鼠的 MSC 在大鼠心肌 I/R 损伤模型中表现出更高程度的心肌保护作用。这种增强的保护作用与血管生成因子产生、增殖和分化的增加有关。TLR4 缺失也与 PI-3K 和 AKT 的磷酸化减少有关，但 STAT3 的激活增加。STAT3 的 siRNA 靶向导致 TLR4 缺陷型 MSC 增强的心脏保护作用减弱。
结论/意义：这项研究表明，TLR4 通过 STAT3 抑制机制对 I/R 后 MSC 来源的心脏保护作用产生有害影响。
