Min Jiang-Yong, Huang Xuling, Xiang Meixiang, Meissner Achim, Chen Yu, Ke Qingen, Kaplan Emel, Rana Jamal S, Oettgen Peter, Morgan James P
Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass, USA.
J Thorac Cardiovasc Surg. 2006 Apr;131(4):889-97. doi: 10.1016/j.jtcvs.2005.12.022.
The present study was designed to test whether intravenously infused embryonic stem cell-derived cells could translocate to injured myocardium after myocardial infarction and improve cardiac function.
Cultured embryonic stem cell-derived cells were transfected with green fluorescent protein. Embryonic stem cell-derived cells were administered through the tail vein (approximately 10(7) cells in 1 mL of medium for each rat) every other day for 6 days in 45 rats after myocardial infarction. Six weeks after myocardial infarction and cell infusion, cardiac function, blood flow, and the numeric density of arterioles were measured to test the benefits of cell therapy. An in vitro Transwell assay was performed to evaluate the embryonic stem cell migration.
Ventricular function, regional blood flow, and arteriole density were significantly increased in rats receiving intravenously infused embryonic stem cell-derived cells compared with control rats after myocardial infarction. Histologic analysis demonstrated that infused embryonic stem cell-derived cells formed green fluorescent protein-positive grafts in infarcted myocardium. Additionally, positive immunostaining for cardiac troponin I was found in hearts after myocardial infarction receiving embryonic stem cell-derived cell infusion that corresponded to the green fluorescent protein-positive staining. The Transwell migration assay indicated that cultured neonatal rat cardiomyocytes with overexpression of tumor necrosis factor alpha induced greater migration of embryonic stem cells compared with cardiomyocytes without tumor necrosis factor alpha expression.
Our data demonstrate that intravenously infused embryonic stem cell-derived cells homed to the infarcted heart, improved cardiac function, and enhanced regional blood flow at 6 weeks after myocardial infarction. The in vitro migration assay suggested that such a homing mechanism could be associated with locally released cytokines, such as tumor necrosis factor alpha, that are upregulated in the setting of acute myocardial infarction and heart failure.
本研究旨在测试静脉输注胚胎干细胞来源的细胞在心肌梗死后能否迁移至受损心肌并改善心脏功能。
将培养的胚胎干细胞来源的细胞转染绿色荧光蛋白。在45只大鼠心肌梗死后，每隔一天经尾静脉给予胚胎干细胞来源的细胞（每只大鼠在1 mL培养基中给予约10⁷个细胞），共给药6天。在心肌梗死和细胞输注6周后，测量心脏功能、血流量和小动脉的数值密度，以测试细胞治疗的益处。进行体外Transwell试验以评估胚胎干细胞的迁移。
与心肌梗死后的对照大鼠相比，接受静脉输注胚胎干细胞来源细胞的大鼠的心室功能、局部血流量和小动脉密度显著增加。组织学分析表明，输注的胚胎干细胞来源的细胞在梗死心肌中形成了绿色荧光蛋白阳性移植物。此外，在接受胚胎干细胞来源细胞输注的心肌梗死后心脏中发现了心肌肌钙蛋白I的阳性免疫染色，其与绿色荧光蛋白阳性染色相对应。Transwell迁移试验表明，与未表达肿瘤坏死因子α的心肌细胞相比，过表达肿瘤坏死因子α的培养新生大鼠心肌细胞诱导胚胎干细胞的迁移能力更强。
我们的数据表明，静脉输注的胚胎干细胞来源的细胞在心肌梗死后6周归巢至梗死心脏，改善了心脏功能，并增加了局部血流量。体外迁移试验表明，这种归巢机制可能与局部释放的细胞因子有关，如肿瘤坏死因子α，其在急性心肌梗死和心力衰竭时上调。
