Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium
Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium
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DOI：
10.1016/j.yjmcc.2007.11.010
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发表时间：
2008-02-01
影响因子：
5
通讯作者：
Wang, Yigang
中科院分区：
文献类型：
--
作者：
Zhang, Dongsheng;Fan, Guo-Chang;Wang, Yigang
骨髓间充质干细胞参与心肌梗死后心肌修复。然而，由于它们在梗死心肌中缺乏存活，它们的体内修复能力是有限的。为了克服这一局限性，我们基因工程的雄性大鼠骨髓间充质干细胞过度表达CXCR 4，以最大限度地发挥作用的基质细胞衍生因子-la（SDF-1 α）的细胞迁移和再生。从成年雄性大鼠中分离并培养MSC。进行腺病毒转导以过表达CXCR 4/绿色荧光蛋白（Ad-CXCR 4/GFP）或单独的Ad-null/GFP（对照）。流式细胞术用于鉴定和分离GFP/CXCR 4过表达的MSC用于移植。雌性大鼠被分配到四个组中的一个（每种n = 8）在结扎左前降支（LAD）冠状动脉后3天通过尾静脉注射接受GFP转导的雄性MSC（2 × 106）：GFP转导的MSC（Ad-null/GFP-MSC，组1）或过表达CXCR 4/GFP的MSC（Ad-CXCR 4/GFP-MSC，组2）或Ad-CXCR 4/GFP-MSC加SDF-1 α（50 ng/μ l）（Ad-CXCR 4/GFP-MSC/SDF-1 α，组3）或靶向CXCR 4的Ad-miRNA加SDF-1 α（Ad-miRNA/GFP-MSC +SDF-1 α处理，组4）。在诱导局部心肌梗死（MI）后4周，使用超声心动图获得血流动力学数据，然后收获心脏进行免疫组织化学研究。与对照组（p < 0.05）或miRNA-CXCR 4组（p < 0.01）相比，组2和组3的脑梗死和梗死区域中GFP和Y染色体阳性细胞的迁移显著增加。第2、3组CXCR 4阳性细胞数与血管生成和肌生成密切相关。通过用miRNA预处理来阻断MSC植入（组4）。在接受单独或与SDF-1 α一起过表达CXCR 4的MSC的大鼠中，心脏功能显著改善。CXCR 4过表达的MSC上调基质金属蛋白酶（MMPs）可能有助于其在梗死区胶原组织中的植入。CXCR 4的过表达增强了骨髓间充质干细胞的体内动员和移植到缺血区域，这些细胞促进了新心肌血管生成并减轻了左心室重构的早期迹象。(c)2007爱思唯尔公司All rights reserved.
Bone marrow mesenchymal stem cells (MSCs) participate in myocardial repair following myocardial infarction. However, their in vivo reparative capability is limited due to lack of their survival in the infarcted myocardium. To overcome this limitation, we genetically engineered male rat MSCs overexpressing CXCR4 in order to maximize the effect of stromal cell-derived factor-la (SDF-1 alpha) for cell migration and regeneration. MSCs were isolated from adult male rats and cultured. Adenoviral transduction was carried out to over-express either CXCR4/green fluorescent protein (Ad-CXCR4/GFP) or Ad-null/GFP alone (control). Flow cytometry was used to identify and isolate GFP/CXCR4 overexpressing MSCs for transplantation. Female rats were assigned to one of four groups (n = 8 each) to receive GFP-transduced male MSCs (2 x 106) via tail vein injection 3 days after ligation of the left anterior descending (LAD) coronary artery: GFP-transduced MSCs (Ad-null/GFP-MSCs, group 1) or MSCs over-expressing CXCR4/GFP (Ad-CXCR4/GFP-MSCs, group 2), or Ad-CXCR4/GFP-MSCs plus SDF-1 alpha (50 ng/mu l) (Ad-CXCR4/GFP-MSCs/SDF-1 alpha, group 3), or Ad-miRNA targeting CXCR4 plus SDF-1 alpha (Ad-miRNA/GFP-MSCs+SDF-1 alpha treatment, group 4). Cardiodynamic data were obtained 4 weeks after induction of regional myocardial infarction (MI) using echocardiography after which hearts were harvested for immunohistochemical studies. The migration of GFP and Y-chromosome positive cells increased significantly in the peri- and infarct areas of groups 2 and 3 compared to control group (p < 0.05), or miRNA-CXCR4 group (p < 0.01). The number of CXCR4 positive cells in groups 2, 3 was intimately associated with angiogenesis and myogenesis. MSCs engraftment was blocked by pretreatment with miRNA (group 4). Cardiac function was significantly improved in rats receiving MSCs over-expressing CXCR4 alone or with SDF-1 alpha. The up-regulation of matrix metalloproteinases (MMPs) by CXCR4 overexpressing MSCs perhaps facilitated their engraftment in the collagenous tissue of the infarcted area. CXCR4 over-expression led to enhance in vivo mobilization and engraftment of MSCs into ischemic area where these cells promoted neomyoangiogenesis and alleviated early signs of left ventricular remodeling. (c) 2007 Elsevier Inc. All rights reserved.