Winter E M, Grauss R W, Hogers B, van Tuyn J, van der Geest R, Lie-Venema H, Steijn R Vicente, Maas S, DeRuiter M C, deVries A A F, Steendijk P, Doevendans P A, van der Laarse A, Poelmann R E, Schalij M J, Atsma D E, Gittenberger-de Groot A C
Leiden University Medical Center, Department of Anatomy and Embryology, Einthovenweg 20, PO Box 9600, 2300 RC Leiden, The Netherlands.
Circulation. 2007 Aug 21;116(8):917-27. doi: 10.1161/CIRCULATIONAHA.106.668178. Epub 2007 Aug 7.
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.
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.
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.
致密心肌、冠状血管和浦肯野纤维的正常发育依赖于胚胎心肌中的心外膜衍生细胞（EPDC）。我们推测，成人EPDC移植到缺血心肌后可能会部分重新激活其胚胎程序，并改善心肌梗死后的心脏功能。
从成人心房组织中分离出EPDC。在免疫缺陷小鼠中制造心肌梗死，随后心肌内注射4×10⁵个增强型绿色荧光蛋白标记的EPDC（2周存活，n = 22；6周存活，n = 15）或培养基（分别为n = 24和n = 18）。使用9.4T动物MRI装置评估左心室功能。第2天时，各组间射血分数相似，但在2周（短期）以及6周长期存活后，EPDC注射组的射血分数显著更高。在所有评估年龄时，EPDC注射组的收缩末期和舒张末期容积均显著小于培养基注射组。在2周时，EPDC治疗组的血管生成显著增加，壁厚也增加，这种变化可能是由于梗死区域DNA损伤修复活性增强所致。免疫组织化学分析显示，注射的EPDC在2周时大量植入，表达α-平滑肌肌动蛋白、血管性血友病因子、肌浆网Ca²⁺-ATP酶和电压门控钠通道（α亚基；SCN5a）。EPDC对心肌细胞标志物呈阴性。在6周存活时，壁厚仍增加，但仅能检测到少数EPDC。
移植到缺血心肌后，成人EPDC可保留心脏功能并减轻心室重构。自体成人EPDC有望成为梗死心脏临床应用的候选细胞。
