PRECONDITIONING MESENCHYMAL STEM CELLS WITH TRANSFORMING GROWTH FACTOR-ALPHA IMPROVES MESENCHYMAL STEM CELL-MEDIATED CARDIOPROTECTION
PRECONDITIONING MESENCHYMAL STEM CELLS WITH TRANSFORMING GROWTH FACTOR-ALPHA IMPROVES MESENCHYMAL STEM CELL-MEDIATED CARDIOPROTECTION
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DOI：
10.1097/shk.0b013e3181b7d137
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发表时间：
2010-01-01
期刊：
影响因子：
3.1
通讯作者：
Meldrum, Daniel R.
中科院分区：
文献类型：
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作者：
Herrmann, Jeremy L.;Wang, Yue;Meldrum, Daniel R.
间充质干细胞（MSC）是一种有前途的治疗急性器官缺血的部分原因是由于他们的旁分泌生产的生长因子。然而，移植的细胞会遇到减轻其功能和存活的炎性环境，并且在移植前的离体扩增期间用外源性试剂处理细胞是通过增强旁分泌功能来克服这种限制的一种策略。我们假设，在大鼠急性心肌I/R损伤模型中，用TGF-α预处理骨髓MSC将1）通过p38丝裂原活化蛋白激酶（MAPK）依赖性机制增加MSC关键旁分泌因子血管内皮生长因子（VEGF）的产生，2）促进心肌功能恢复。为了研究这一点，从成年雄性小鼠（C57 BL/6 J）收获骨髓MSC，并根据以下组在体外处理24小时：1）对照，2）TGF-α（250 ng mL（-1）），3）TNF-α（50 ng mL（-1）），4）TGF-α + TNF-α，5）缺氧，和6）TGF-α +缺氧。对于离体心脏灌注实验，分离成年雄性Sprague-Dawley大鼠心脏，通过Langendorff模型灌注，并进行I/R。在缺血前立即输注具有或不具有TGF-α预处理的媒介物或MSC。间充质干细胞也用单独的TGF-α或与p38 MAPK抑制剂（SB 202190）组合处理。在体外，TGF-α单独增加MSC VEGF的产生，（157.9 +/- 1.11 - 291.0 +/- 3.74 pg 10（-5）; P < 0.05），并且在更大程度上，与TNF-α或缺氧联合（分别为364.5 +/- 0.868和342.0 +/- 7.92 pg 10（-5）细胞; P < 0.05，与单独的TGF-α相比）。与未处理的MSC或媒介物相比，灌注TGF-α预处理的MSC的心脏的缺血后心肌功能恢复更大。心肌IL-1 β和TNF-α的产生和caspase 3的活化在两个细胞组输注后显著降低。p38 MAPK抑制抑制TGF-α刺激的MSC VEGF产生和缺血后心肌恢复。这些结果表明，TGF-α刺激MSC VEGF的生产部分通过p38 MAPK依赖的机制，和预处理MSC与TGF-α可能会提高他们的能力，以保护心肌在I/R损伤。
Mesenchymal stem cells (MSCs) are a promising therapy for acute organ ischemia in part due to their paracrine production of growth factors. However, transplanted cells encounter an inflammatory environment that mitigates their function and survival, and treating the cells with exogenous agents during ex vivo expansion before transplantation is one strategy for overcoming this limitation by enhancing paracrine function. We hypothesized that preconditioning bone marrow MSCs with TGF-alpha would 1) increase MSC production of the critical paracrine factor, vascular endothelial growth factor (VEGF), via a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism and 2) enhance myocardial functional recovery in a rat model of acute myocardial I/R injury. To study this, bone marrow MSCs were harvested from adult male mice (C57BL/6J) and treated in vitro for 24 h according to the following groups: 1) control, 2) TGF-alpha (250 ng mL(-1)), 3) TNF-alpha (50 ng mL(-1)), 4) TGF-alpha + TNF-alpha, 5) hypoxia, and 6) TGF-alpha + hypoxia. For the isolated heart perfusion experiments, adult male Sprague-Dawley rat hearts were isolated, perfused via the Langendorff model, and subjected to I/R. Vehicle or MSCs with or without TGF-alpha preconditioning were infused immediately before ischemia. Mesenchymal stem cells were also treated with TGF-alpha alone or in combination with a p38 MAPK inhibitor (SB202190). In vitro, TGF-alpha increased MSC VEGF production alone (157.9 +/- 1.11 - 291.0 +/- 3.74 pg 10(-5); P < 0.05) and, to a greater extent, in combination with TNF-alpha or hypoxia (364.5 +/- 0.868 and 342.0 +/- 7.92 pg 10(-5) cells, respectively; P < 0.05 vs. TGF-alpha alone). Postischemic myocardial functional recovery was greater in hearts infused with TGF-alpha-preconditioned MSCs compared with untreated MSCs or vehicle. Myocardial IL-1 beta and TNF-alpha production and activation of caspase 3 were significantly decreased after infusion of both cell groups. p38 MAPK inhibition suppressed TGF-alpha-stimulated MSC VEGF production and postischemic myocardial recovery. These results suggest that TGF-alpha stimulates MSC VEGF production in part via a p38 MAPK-dependent mechanism, and preconditioning MSCs with TGF-alpha may enhance their ability to protect myocardium during I/R injury.