Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats
Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats
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DOI：
10.1016/j.ejcts.2009.04.052
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发表时间：
2009-10-01
影响因子：
3.4
通讯作者：
Huang, Yongzhang
中科院分区：
文献类型：
--
作者：
Tang, Junming;Wang, Jianing;Huang, Yongzhang
背景：间充质干细胞（MSC）除了具有多能性外，还能分泌和供应大量的血管内皮生长因子（VEGF）。基质衍生因子-1 α (SDF-1 α)在干细胞向心脏损伤组织的归巢中起重要作用。因此，过表达SDF-1 α的MSCs可以增强血管生成途径。方法：采用10%胎牛血清和50 ng ml(-1) SDF-1 α或内皮氧化亚氮合成酶（eNOS）特异性抑制剂培养MSCs，诱导其向内皮样细胞分化。在体内，通过阻断左冠状动脉前降支建立大鼠心肌梗死模型。手术后7天，将5.0 × 10(9) pfu Ad-SDF-1 α（在rous肉瘤病毒（RSV）启动子控制下含有人SDF-1 α基因的腺病毒载体）、5.0 × 10(6) Ad-LacZ-MSC或5.0 × 10(6) Ad-SDF-MSC悬液在0.2 ml无血清培养基中注射到梗死区域的四个部位（每个部位0.05 ml）。接受Ad-SDF-MSC治疗的大鼠还在饮用水中给予一氧化氮（NO）合成抑制剂n - g -硝基- l -精氨酸甲酯（L-NAME） （1 mg kg(-1)）。对照组给予相同体积的无细胞培养液。移植后4周，评估心脏功能，并进行组织学和分子分析。结果：骨髓间充质干细胞在SDF-1 α存在下可向内皮细胞分化，且L-NAME可抑制该作用。Western Blotting显示VEGF、Akt和eNOS表达增加。移植后4周，Ad-SDF-MSC组梗死面积和纤维化减小，血管密度增大，左室瓦特变厚。血流动力学参数测量显示，与其他组相比，Ad-SDF-MSC组左心室功能有所改善。结论：过表达SDF-1 α的MSCs可产生有效的血管生成，从而预防心肌梗死后进行性心功能障碍。(C) 2009欧洲心胸外科协会。Elsevier B.V.版权所有。
Background: In addition to its multipotent capability, the mesenchymal stem cell (MSC) can secrete and supply a large amount of vascular endothelial growth factor (VEGF). The stromal-derived factor-1 alpha (SDF-1 alpha) plays an important role in the homing of stem cells to the injured tissues of the heart. Therefore, the MSCs over-expressing SDF-1 alpha could augment the angiogenesis pathway. Methods: In vitro, the differentiation of the MSCs into endothelial-like cells was induced by cultivation of cells in 10% foetal calf serum and 50 ng ml(-1) SDF-1 alpha or in specific inhibitors for endothelial nitrous oxide synthase (eNOS). In vivo, the rat model of myocardial infarction was established by occlusion of the left anterior descending coronary artery. Seven days following surgery, 5.0 x 10(9) pfu Ad-SDF-1 alpha (adenoviral vector containing human SDF-1 alpha gene under the control of the rous sarcoma virus (RSV) promoter), 5.0 x 10(6) Ad-LacZ-MSC or 5.0 x 10(6) Ad-SDF-MSC suspension in a 0.2-ml serum-free medium was injected into four sites in infarcted areas (0.05 ml per site). The rats receiving Ad-SDF-MSC also received the nitrous oxide (NO) synthesis inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) in drinking water (1 mg kg(-1)). The rats in the control group received the same volume of cell-free medium. Four weeks following transplantation, the heart function was assessed, and histological and molecular analyses were conducted. Results: The MSCs could differentiate into endothelial cells in the presence of SDF-1 alpha, and the effect could be inhibited by L-NAME in vitro and in vivo. Western Blotting revealed an increased expression of VEGF, Akt and eNOS. Four weeks following transplantation, a reduced infarct size and fibrosis, greater vascular density and thicker left ventricular watt were observed in the Ad-SDF-MSC group. The measurement of haemodynamic parameters showed an improvement in the left ventricular performance in the Ad-SDF-MSC group as compared with other groups. Conclusion: The MSCs over-expressing the SDF-1 alpha can produce effective angiogenesis, resulting in the prevention of progressive heart dysfunction after a myocardial infarction. (C) 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.