TNF receptor 2, not TNF receptor 1, enhances mesenchymal stem cell-mediated cardiac protection following acute ischemia.
TNF receptor 2, not TNF receptor 1, enhances mesenchymal stem cell-mediated cardiac protection following acute ischemia.
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DOI：
10.1097/shk.0b013e3181cc0913
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发表时间：
2010-06
期刊：
影响因子：
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通讯作者：
Meldrum DR
中科院分区：
文献类型：
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作者：
Kelly ML;Wang M;Crisostomo PR;Abarbanell AM;Herrmann JL;Weil BR;Meldrum DR
间充质干细胞（MSCs）可能通过旁分泌作用改善缺血/再灌注（I/R）损伤后的心肌功能，包括释放生长因子。骨髓间充质干细胞的基因修饰是增强骨髓间充质干细胞旁分泌作用的一种有吸引力的方法。消融TNF受体1 （TNFR1）而非TNFR2可增加MSC生长因子的产生。因此，在本研究中，我们假设：1。缺血前输注TNFR1敲除小鼠（TNFR1KO）的MSCs将进一步改善心肌功能恢复；2. TNFR2KO和TNFR1/2KO将在I/R损伤后消除骨髓间质干细胞介导的心脏保护。MSCs来源于成年小鼠C57BL/6J （WT1）、B6129SF2 （WT2）、TNFR1KO、TNFR2KO和TNFR1/2KO。3代后培养MSCs进行实验。取成年雄性Sprague-Dawley大鼠离体心脏缺血25分钟，再灌注40分钟（Langendorff模型），连续监测心肌功能。缺血前，取WT1、WT2、TNFR1KO、TNFR2KO、TNFR1/2KO各细胞1 ml或1×10^6 MSCs/ml注入心脏（n= 4-6 /组）。缺血前WT1 MSC治疗可显著提高心功能。与WT MSCs相比，TNFR1KO MSCs在I/R后表现出更强的心脏保护作用，这表现在LVDP和+/−dp/dt的改善上。然而，与WT MSC相比，输注来自TNFR2KO和TNFR1/2KO小鼠的MSCs对I/R反应没有益处或降低了MSCs介导的心功能恢复。TNFR1信号传导可能破坏MSC旁分泌作用并降低MSC介导的心脏保护作用，而TNFR2可能在MSC中介导有益作用。
Mesenchymal stem cells (MSCs) may improve myocardial function after ischemia/reperfusion (I/R) injury via paracrine effects, including the release of growth factors. Genetic modification of MSCs is an appealing method to enhance MSC paracrine action. Ablation of TNF receptor 1 (TNFR1), but not TNFR2, increases MSC growth factor production. In this study, therefore, we hypothesized that: 1. pre-ischemic infusion of MSCs derived from TNFR1 knockout (TNFR1KO) mice will further improve myocardial functional recovery; 2. TNFR2KO and TNFR1/2KO will abolish MSC-mediated protection in the heart following I/R injury. MSCs were harvested from adult C57BL/6J (WT1), B6129SF2 (WT2), TNFR1KO, TNFR2KO and TNFR1/2KO mice. MSCs were cultured and adopted for experiments after passage 3. Isolated hearts from adult male Sprague-Dawley rats were subjected to 25-minutes of ischemia and 40-minutes of reperfusion (Langendorff model), during which time myocardial function was continuously monitored. Before ischemia, 1 ml of vehicle or 1×10^6 MSCs/ml from WT1, WT2, TNFR1KO, TNFR2KO, or TNFR1/2KO was infused into the hearts (n=4–6/group). WT1 MSC treatment prior to ischemia significantly increased cardiac function. TNFR1KO MSCs demonstrated greater cardioprotection when compared to WT MSCs following I/R as exhibited by improved LVDP and +/−dp/dt. However, infusion of MSCs from TNFR2KO and TNFR1/2KO mice either offered no benefit or decreased MSC-mediated cardiac functional recovery in response to I/R when compared with WT MSC. TNFR1 signaling may damage MSC paracrine effects and decrease MSC-mediated cardioprotection, whereas TNFR2 likely mediates beneficial effects in MSCs.