Mobilizing of haematopoietic stem cells to ischemic myocardium by plasmid mediated stromal-cell-derived factor-1α (SDF-1α) treatment
Mobilizing of haematopoietic stem cells to ischemic myocardium by plasmid mediated stromal-cell-derived factor-1α (SDF-1α) treatment
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DOI：
10.1016/j.regpep.2004.10.014
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发表时间：
2005-02-15
影响因子：
--
通讯作者：
Phillips, MI
中科院分区：
文献类型：
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作者：
Tang, YL;Qian, KP;Phillips, MI
基质细胞衍生因子-1 α（SDF-1 α）的浓度梯度是造血干细胞（HSC）在骨髓中归巢的主要机制。我们测试了一个假设，即使用SDF-1 α的基因治疗可以增强心肌梗死（MI）后HSC向心脏的募集。在心肌梗塞后2周，将50穆尔体积的盐水（n=12）或SDF-1 α质粒（n=12）注射到患有手术诱导的心肌缺血的成年小鼠的梗塞心脏的缺血边缘区。收获来自同基因BalB/c小鼠的供体Lin-c-kit+ HSC，通过磁性细胞分选（MACS）分选并用PKH 26 Red标记。质粒或盐水注射后三天，将I X 10（5）个标记的细胞静脉内（i. v.）生理盐水小鼠（n=4）和SDF-1 α质粒小鼠（n=4）。质粒或盐水处理后2周，取出心脏和其他组织进行Western印迹分析。免疫荧光染色鉴定标记的Lin-c-kit+细胞，免疫组化染色鉴定内源性c-kit+细胞。在梗死后1个月处死的小鼠中，Western blot显示SDF-1 α治疗的小鼠缺血心脏中SDF-1 α表达水平高于盐水治疗的心脏和其他组织。在SDF-1 α质粒处理的心脏中，SDF-1 α在梗死周围区过表达。标记的干细胞移植到心肌中SDF-1 α阳性部位。也有证据表明内源性干细胞募集。在SDF-1 α或生理盐水治疗后2周，SDF-1 α治疗组的边缘区c-kit+细胞密度（内源性干细胞动员的指标）显著高于生理盐水组（14.63 +/- 1.068个细胞/hpf vs. 11.31 +/- 0.65个细胞/hpf，P=0.013）。心肌梗死后，SDF-1 α治疗可将干细胞招募到受损的心脏，在那里它们可能在修复和再生中发挥作用。SDF-1 α载体的基因治疗为动员干细胞到缺血心肌提供了一种有前途的治疗策略。(C)2004年由Elsevier B. V.出版
A concentration gradient of stromal-cell-derived factor-1alpha (SDF-1alpha) is the major mechanism for homing of haematopoietic stem cells (HSCs) in bone marrow. We tested the hypothesis that a gene therapy using SDF-1alpha can enhance HSCs recruiting to the heart upon myocardial infarction (MI). Adult mice with surgically induced myocardial ischemia were injected intramyocardially with either saline (n=12) or SDF-1alpha plasmid (n=12) in 50 mul volume in the ischemic border zone of the infarcted heart 2 weeks after myocardial infarction. Donor Lin-c-kit+ HSCs from isogenic BalB/c mice were harvested, sorted through magnetic cell sorting (MACS) and labeled with PKH26 Red. Three days after plasmid or saline injection, 1 x 10(5) labeled cells were injected intravenously (i.v.) into saline mice (n=4) and SDF-1alpha plasmid mice (n=4). The hearts and other tissue were removed for Western blot assay 2 weeks after plasmid or saline treatment. The labeled Lin-c-kit+ cells were identified with immunofluoresent staining and endogenous c-kit+ cells were identified by immunohistochemical staining. In mice killed at 1 month postinfarct, Western blot showed higher levels of SDF-1alpha expression in SDF-1alpha-treated mouse ischemic hearts compared to saline-treated hearts and other tissues. In the SDF-1alpha plasmid-treated hearts, SDF-1alpha is overexpressed in the periinfarct zone. The labeled stem cells engrafted to the SDF-1alpha positive site in the myocardium. There was also evidence for endogenous stem cell recruiting. The density of c-kit+ cells in border zone, an index of endogenous stem cell mobilization, was significantly higher in the SDF-1alpha-treated group than in the saline group (14.63 +/- 1.068 cells/hpf vs. 11.31 +/- 0.65 cells/hpf, P=0.013) at 2 weeks after SDF-1alpha or saline treatment. Following myocardial infarction, treatment with SDF-1alpha recruits stem cells to damaged heart where they may have a role in repairing and regeneration. The gene therapy with an SDF-1alpha vector offers a promising therapeutic strategy for mobilizing stem cells to the ischemic myocardium. (C) 2004 Published by Elsevier B.V.