Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector
Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector
复制标题
DOI：
10.1016/j.jacc.2005.05.079
复制
发表时间：
2005-10-04
影响因子：
24
通讯作者：
Phillips, I
中科院分区：
文献类型：
--
作者：
Tang, YL;Tang, Y;Phillips, I
目的：本研究的目的是用缺氧调节的血红素加氧酶-1（HO-1）质粒修饰间充质干细胞（MSC）细胞，以增强间充质干细胞（MSC）在急性心肌梗死（MI）心脏中的存活率。背景：虽然干细胞正在临床测试用于心脏修复，但由于缺氧/复氧、炎症细胞因子和促凋亡因子的影响，移植细胞在缺血心脏中死亡。血红素加氧酶-1 是抑制大多数这些因子的关键成分。方法：用HO-1 或LacZ 质粒转染来自骨髓的间充质干细胞。缺氧-复氧处理后体外检测细胞凋亡。在体内，MI 后 1 小时将 1 X 10(6) 雄性 MSCHO-1、MSCLacZ、MSCS 或培养基注射到小鼠心脏中（n = 16/组）。在性别不匹配的移植模型中评估细胞存活率。在性别匹配的模型中检测细胞凋亡、左心室重构和心功能。结果：在缺血心肌中，与MSCLacZ组相比，MSCHO-1组HO-1表达较高，末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸原位缺口末端标记阳性细胞数量减少2倍。植入后 7 天，MSCHO-1 的存活率是 MSCLacZ 组的五倍； MSCHO-1还可以减弱左心室重构，增强心肌梗塞后两周的心脏功能恢复。结论：MSCs的缺氧调节HO-1载体修饰增强了移植的MSC对体外缺氧-复氧损伤的耐受性，并提高了它们在缺血心脏中的活力。该演示首次表明表达 HO-1 基因的生理诱导型载体可改善心肌缺血中干细胞的存活率。
Objectives: The goal of this study was to modify mesenchymal stem cells (MSCs) cells with a hypoxia-regulated heme oxygenase-1 (HO-1) plasmid to enhance the survival of MSCs in acute myocardial infarction (MI) heart.Background: Although stem cells are being tested clinically for cardiac repair, graft cells die in the ischemic heart because of the effects of hypoxia/reoxygenation, inflammatory cytokines, and proapoptotic factors. Heme oxygenase-1 is a key component in inhibiting most of these factors.Methods: Mesenchymal stem cells from bone marrow were transfected with either HO-1 or LacZ Plasmids. Cell apoptosis was assayed in vitro after hypoxia-reoxygen treatment. In vivo, 1 X 10(6) of male MSCHO-1, MSCLacZ, MSCS, or medium was injected into mouse hearts 1 h after MI (n = 16/group). Cell survival was assessed in a gender-mismatched transplantation model. Apoptosis, left ventricular remodeling, and cardiac function were tested in a gender-matched model.Results: In the ischemic myocardium, the MSCHO-1 group had greater expression of HO-1 and a 2-fold reduction in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling-positive cells compared with the MSCLacZ group. At seven days after implantation, the survival MSCHO-1 was five-fold greater than the MSCLacZ group; MSCHO-1 also attenuated left ventricular remodeling and enhanced the functional recovery of infarcted hearts two weeks after MI.Conclusions: A hypoxia-regulated HO-1 vector modification of MSCs enhances the tolerance of engrafted MSCs to hypoxia-reoxygen injury in vitro and improves their viability in ischemic hearts. This demonstration is the first showing that a physiologically inducible vector expressing of HO-1 genes improves the survival of stem cells in myocardial ischemia.