Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Shock. 2010 Sep;34(3):236-42. doi: 10.1097/SHK.0b013e3181d75ae3.
Mesenchymal stem cell (MSC) infusion may reduce myocardial ischemic injury. TNF-alpha is a proinflammatory cytokine produced in large quantities during myocardial ischemia that can exert beneficial or detrimental effects on MSC function by binding to a 55-kd receptor (TNFR1) or a 75-kd receptor (TNFR2) on MSCs. We investigated whether genetic modification with ablation of TNFR1 and/or TNFR2 affects MSC-mediated protection against myocardial ischemic injury. The MSCs were harvested from wild-type mice (WT-MSCs) and knockout mice with ablation of TNFR1 and/or TNFR2 (TNFR1KO, TNFR2KO, and TNFR1/R2KO MSCs). After anesthesia was initiated via inhalation of isoflurane, myocardial ischemia was induced in rats via coronary artery ligation. Hearts were then injected with vehicle or MSCs (1 x 10 cells/mL). Myocardial function was assessed 28 days postsurgery with 2-dimensional echocardiograms and isolated heart perfusion. Myocardial tissue was collected for cytokine analysis and infarct measurements. We found that MSC treatment offered significant protection against myocardial ischemia, namely by decreasing infarct size, improving heart function, and decreasing ventricular remodeling compared with vehicle. Compared with WT-MSCs, TNFR1KO MSCs conferred increased cardiac protection, although TNFR2KO and TNFR1/R2KO MSCs conferred less cardiac protection. In addition, treatment with TNFR1KO MSCs was associated with decreased levels of proinflammatory cytokines and an increased level of vascular endothelial growth factor in the myocardium, whereas treatment with TNFR2KO or TNFR1/R2KO MSCs was associated with increased levels of proinflammatory cytokines and a decreased level of vascular endothelial growth factor compared with treatment with WT-MSCs. We conclude that MSC TNFR1 and TNFR2 play important roles in MSC-mediated cardiac protection after myocardial ischemia.
间充质干细胞（MSC）输注可能减轻心肌缺血损伤。TNF-α是心肌缺血时大量产生的促炎细胞因子，通过与 MSC 上的 55-kd 受体（TNFR1）或 75-kd 受体（TNFR2）结合，对 MSC 功能产生有益或有害的影响。我们研究了通过消融 TNFR1 和/或 TNFR2 的基因修饰是否影响 MSC 介导的对心肌缺血损伤的保护作用。MSC 从野生型小鼠（WT-MSCs）和 TNFR1 和/或 TNFR2 消融的敲除小鼠（TNFR1KO、TNFR2KO 和 TNFR1/R2KO MSCs）中分离出来。在通过吸入异氟烷开始麻醉后，通过冠状动脉结扎诱导大鼠心肌缺血。然后用载体或 MSC（1 x 10 个细胞/mL）注射心脏。手术后 28 天通过二维超声心动图和离体心脏灌注评估心肌功能。收集心肌组织进行细胞因子分析和梗塞测量。我们发现，与载体相比，MSC 治疗对心肌缺血具有显著的保护作用，即通过减少梗塞面积、改善心脏功能和减少心室重构。与 WT-MSCs 相比，TNFR1KO MSCs 提供了更高的心脏保护作用，尽管 TNFR2KO 和 TNFR1/R2KO MSCs 提供的心脏保护作用较低。此外，与 WT-MSCs 相比，TNFR1KO MSC 治疗与心肌中促炎细胞因子水平降低和血管内皮生长因子水平升高相关，而 TNFR2KO 或 TNFR1/R2KO MSC 治疗与心肌中促炎细胞因子水平升高和血管内皮生长因子水平降低相关。我们得出结论，MSC TNFR1 和 TNFR2 在心肌缺血后 MSC 介导的心脏保护中发挥重要作用。
