Division of Immunotherapy, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Circ Res. 2012 Oct 26;111(10):1286-96. doi: 10.1161/CIRCRESAHA.111.262584. Epub 2012 Aug 22.
Various types of viable stem cells have been reported to result in modest improvement in cardiac function after acute myocardial infarction. The mechanisms for improvement from different stem cell populations remain unknown.
To determine whether irradiated (nonviable) embryonic stem cells (iESCs) improve postischemic cardiac function without adverse consequences.
After coronary artery ligation-induced cardiac infarction, either conditioned media or male murine or male human iESCs were injected into the penumbra of ischemic myocardial tissue of female mice or female rhesus macaque monkeys, respectively. Murine and human iESCs, despite irradiation doses that prevented proliferation and induced cell death, significantly improved cardiac function and decreased infarct size compared with untreated or media-treated controls. Fluorescent in situ hybridization of the Y chromosome revealed disappearance of iESCs within the myocardium, whereas 5-bromo-2'-deoxyuridine assays revealed de novo in vivo cardiomyocyte DNA synthesis. Microarray gene expression profiling demonstrated an early increase in metabolism, DNA proliferation, and chromatin remodeling pathways, and a decrease in fibrosis and inflammatory gene expression compared with media-treated controls.
As a result of irradiation before injection, ex vivo and in vivo iESC existence is transient, yet iESCs provide a significant improvement in cardiac function after acute myocardial infarction. The mechanism(s) of action of iESCs seems to be related to cell-cell exchange, paracrine factors, and a scaffolding effect between iESCs and neighboring host cardiomyocytes.
已有多种类型的有活力干细胞被报道能在急性心肌梗死后使心功能得到一定程度的改善。但不同干细胞群改善心功能的机制尚不清楚。
旨在确定辐照（无活力）胚胎干细胞（iESCs）是否能在不产生不良反应的情况下改善缺血性心脏病的心功能。
结扎冠状动脉诱导心肌梗死发生后，将条件培养基或雄性小鼠或雄性人 iESCs 分别注射到雌性小鼠或雌性恒河猴缺血性心肌组织的半影区。尽管辐照剂量能阻止增殖并诱导细胞死亡，但与未处理或培养基处理对照组相比，小鼠和人 iESCs 能显著改善心功能和减小梗死面积。Y 染色体荧光原位杂交显示 iESCs 在心肌内消失，而 5-溴-2'-脱氧尿苷检测显示体内新的心肌细胞 DNA 合成。微阵列基因表达谱分析显示与培养基处理对照组相比，早期代谢、DNA 增殖和染色质重塑途径增加，纤维化和炎症基因表达减少。
由于在注射前进行了辐照，体外和体内的 iESC 存在是短暂的，但 iESCs 能显著改善急性心肌梗死后的心功能。iESCs 的作用机制似乎与细胞-细胞交换、旁分泌因子以及 iESCs 与邻近宿主心肌细胞之间的支架效应有关。
