Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes

Abstract

We conclude that electrically active, hESC-derived CMs are capable of actively pacing quiescent, recipient, ventricular CMs in vitro and ventricular myocardium in vivo. Our results may lead to an alternative or a supplemental method for correcting defects in cardiac impulse generation, such as cell-based pacemakers.

Formation of Human Myocardium in the Rat Heart from Human Embryonic Stem Cells

“…While this manuscript was under review, two groups also reported the successful formation of stable graft of hESC-derived cardiomyocytes in pharmacologically immunosuppressed pigs 56 and guinea pigs. 57 Importantly, these independent studies by the Gepstein and Li groups unambiguously demonstrated electromechanical integration of the cardiac implants with the host myocardium, and they provide exciting proof-of-concept for this cell type for applications as a biological pacemaker. Their cell preparation differed from our own in that they physically dissected spontaneous beating foci from differentiated embryoid body outgrowths, an approach not readily scalable to human cell therapeutic applications.…”

Gene Therapy for Cardiac Arrhythmias

“…Since ESCs have the potential to differentiate into cardiomyocytes, 34,35 transplantation of ESC-derived pacemaker cells induced spontaneous ectopic beats. 36,37 …”

Adhesion Proteins, Stem Cells, and Arrhythmogenesis

“…Different methods have been used in an attempt to do so. A number of studies have used GFP-or CFP-expression to label the injected cells [78][79][80][81][82], but in only a few studies do ESC-derived cardiomyocytes (ESC-CM) appear to be structurally integrated [79,82]. Immunohistochemistry is another common tool used to distinguish between the host cells and engrafted ESC-CM.…”

“…1f). In most cases, however, the connexin-43 staining is very blurred or absent between the islands of transplanted stem cells and the rest of the myocardium [55,80,81,83]. One can also try to discern electrical connectivity between the host and engrafted cells by using a dye transfer technique [84,85].…”

“…One can also try to discern electrical connectivity between the host and engrafted cells by using a dye transfer technique [84,85]. While demonstration of electrical coupling in vivo remains a challenge, several in vitro studies clearly show that it does occur [81,83]. Documented evidence of electrical coupling in vivo, albeit at a macroscopic level, is presented in two studies in which ESC injected into the left ventricle successfully paced the hearts of animals in which the atrioventricular node was disabled [81,83].…”