Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate the Infarcted Pig Heart but Induce Ventricular Tachyarrhythmias

Abstract

Summary Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) show considerable promise for regenerating injured hearts, and we therefore tested their capacity to stably engraft in a translationally relevant preclinical model, the infarcted pig heart. Transplantation of immature hESC-CMs resulted in substantial myocardial implants within the infarct scar that matured over time, formed vascular networks with the host, and evoked minimal cellular rejection. While arrhythmias were rare in infarcted pigs receiving vehicle alone, hESC-CM recipients experienced frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. Electroanatomical mapping and pacing studies implicated focal mechanisms, rather than macro-reentry, for these graft-related tachyarrhythmias as evidenced by an abnormal centrifugal pattern with earliest electrical activation in histologically confirmed graft tissue. These findings demonstrate the suitability of the pig model for the preclinical development of a hESC-based cardiac therapy and provide new insights into the mechanistic basis of electrical instability following hESC-CM transplantation.

Cardiopharyngeal Progenitor Specification: Multiple Roads to the Heart and Head Muscles

“…The identification of multipotent CPCs has brought significant hope to the field of heart repair and further research into the early steps of CPC specification will undoubtedly lead to the design of strategies to specify multipotent CPCs into a specific mature cardiac cell type, that could then be used for cell therapy. As a recent example, hPSC-derived CMs have recently been grafted into infarcted pig hearts and showed significant engraftment, although accompanied by ventricular tachyarrhythmia (Romagnuolo et al 2019). Further improvements are thus required to successfully repair infarcted hearts in patients.…”

Function Follows Form ― A Review of Cardiac Cell Therapy ―

“…Although the graft-induced ventricular arrhythmias are asymptomatic up to <10 kg non-human primates, they were not tolerated in a recent study of hESC transplantation in 20-30-kg pigs, with 2/7 pigs succumbing to an arrhythmic death. 93 In that report, 1 billion hESC-CMs were surgically transplanted into pigs 3 weeks after MI, and all recipients experienced graft-induced ventricular tachyarrhythmias of worse severity than observed in non-human primates. As in previous studies, the graft-induced arrhythmias were transient and self-resolved within 1 month of transplantation.…”

Toward the realization of cardiac regenerative medicine using pluripotent stem cells

“…Additionally, it has been shown that transplanted cardiomyocytes demonstrated electrical coupling with the host heart after hESC-derived cardiomyocytes were engrafted to guinea pig hearts [28]. However, several studies have also reported the development of ventricular arrhythmia within the first 2 weeks to 1 month after transplantation into a recipient's heart, which however disappeared a month after cell transplantation [31,46]. These data suggest that the arrhythmogenicity of hPSC-derived cardiomyocytes in vivo remains controversial and that it is necessary to closely monitor the heart for arrhythmias after cell transplantation in humans.…”