Preservation of left ventricular function and attenuation of remodeling after transplantation of human epicardium-derived cells into the infarcted mouse heart
Preservation of left ventricular function and attenuation of remodeling after transplantation of human epicardium-derived cells into the infarcted mouse heart
复制标题
DOI：
10.1161/circulationaha.106.668178
复制
发表时间：
2007-08-21
期刊：
影响因子：
37.8
通讯作者：
Gittenberger-de Groot, A. C.
中科院分区：
文献类型：
--
作者：
Winter, E. M.;Grauss, R. W.;Gittenberger-de Groot, A. C.
背景-致密心肌、冠状动脉和浦肯野纤维的正常发育取决于胚胎心肌中是否存在心外膜衍生细胞(EPDCs)。我们推测，成人EPDCs移植到缺血心肌后，可能会部分恢复其胚胎程序，改善心肌梗死后的心功能。方法和结果-从成人心房组织中分离EPDCs。建立免疫缺陷小鼠心肌梗死模型，心肌内注射4x10(5)增强型绿色荧光蛋白标记的EPDCs(2周存活22只，6周存活15只)或培养基组(24只和18只)。用9.4T动物磁共振装置评价左心功能。两组在第2天的射血分数相似，但EPDC注射组在2周(短期)以及长期存活6周后显著高于对照组。在所有被评估的年龄段中，EPDC注射组的收缩末期和舒张期末容量明显小于中等注射组。在2周时，EPDC治疗组的血管形成显著增加，壁厚也显著增加，这一发展可能是由于梗死区DNA损伤修复活性的增强所致。免疫组织化学分析显示，注射的EPDCs在2周后大量植入，表达α-平滑肌肌动蛋白、von Willebrand因子、肌浆网钙-ATPase和电压门控性钠通道(α-亚单位；SCN5A)。EPDCs的心肌细胞标志均为阴性。在存活6周时，EPDCs的壁厚仍有所增加，但仅可检测到少量EPDCs。结论：成人EPDCs移植到缺血心肌后，可保护心功能，减轻心室重构。自体人内皮细胞是临床应用于心肌梗死的有希望的候选细胞。
Background - Proper development of compact myocardium, coronary vessels, and Purkinje fibers depends on the presence of epicardium-derived cells (EPDCs) in embryonic myocardium. We hypothesized that adult human EPDCs might partly reactivate their embryonic program when transplanted into ischemic myocardium and improve cardiac performance after myocardial infarction.Methods and Results - EPDCs were isolated from human adult atrial tissue. Myocardial infarction was created in immunodeficient mice, followed by intramyocardial injection of 4x10(5) enhanced green fluorescent protein - labeled EPDCs (2-week survival, n=22; 6-week survival, n=15) or culture medium (n=24 and n=18, respectively). Left ventricular function was assessed with a 9.4T animal MRI unit. Ejection fraction was similar between groups on day 2 but was significantly higher in the EPDC-injected group at 2 weeks ( short term), as well as after long-term survival at 6 weeks. End-systolic and end-diastolic volumes were significantly smaller in the EPDC-injected group than in the medium-injected group at all ages evaluated. At 2 weeks, vascularization was significantly increased in the EPDC-treated group, as was wall thickness, a development that might be explained by augmented DNA-damage repair activity in the infarcted area. Immunohistochemical analysis showed massive engraftment of injected EPDCs at 2 weeks, with expression of alpha-smooth muscle actin, von Willebrand factor, sarcoplasmic reticulum Ca2+-ATPase, and voltage-gated sodium channel (alpha-subunit; SCN5a). EPDCs were negative for cardiomyocyte markers. At 6-weeks survival, wall thickness was still increased, but only a few EPDCs could be detected.Conclusions - After transplantation into ischemic myocardium, adult human EPDCs preserve cardiac function and attenuate ventricular remodeling. Autologous human EPDCs are promising candidates for clinical application in infarcted hearts.