Long-term improvement in postinfarct left ventricular global and regional contractile function is mediated by embryonic stem cell-derived cardiomyocytes

Abstract

Background-Pluripotent stem cells represent one promising source for cellular cardiomyoplasty. In this study, we used cardiac magnetic resonance to examine the ability of highly enriched cardiomyocytes (CMs) derived from murine embryonic stem cells (ESC) to form grafts and improve contractile function of infarcted rat hearts. Methods and Results-Highly enriched ESC-CMs were obtained by inducing cardiac differentiation of ESCs stably expressing a cardiac-restricted puromycin resistance gene. At the time of transplantation, enriched ESC-CMs expressed cardiac-specific markers and markers of developing CMs, but only 6% of them were proliferating. A growth factor- containing vehicle solution or ESC-CMs (5 to 10 million) suspended in the same solution was injected into athymic rat hearts 1 week after myocardial infarction. Initial infarct size was measured by cardiac magnetic resonance 1 day after myocardial infarction. Compared with vehicle treatment, treatment with ESC-CMs improved global systolic function 1 and 2 months after injection and significantly increased contractile function in initially infarcted areas and border zones. Immunohistochemistry confirmed successful engraftment and the persistence of α-actinin-positive ESC-CMs that also expressed α-smooth muscle actin. Connexin-43-positive sites were observed between grafted ESC-CMs but only rarely between grafted and host CMs. No teratomas were observed in any of the animals. Conclusions-Highly enriched and early-stage ESC-CMs were safe, formed stable grafts, and mediated a long-term recovery of global and regional myocardial contractile function after infarction. © 2011 American Heart Association, Inc.