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

• Published in: Stem cell reports Vol. 12; no. 5; pp. 967 - 981
• Main Authors: Romagnuolo, Rocco, Masoudpour, Hassan, Porta-Sánchez, Andreu, Qiang, Beiping, Barry, Jennifer, Laskary, Andrew, Qi, Xiuling, Massé, Stéphane, Magtibay, Karl, Kawajiri, Hiroyuki, Wu, Jun, Valdman Sadikov, Tamilla, Rothberg, Janet, Panchalingam, Krishna M., Titus, Emily, Li, Ren-Ke, Zandstra, Peter W., Wright, Graham A., Nanthakumar, Kumaraswamy, Ghugre, Nilesh R., Keller, Gordon, Laflamme, Michael A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.05.2019; Elsevier
• Subjects: Animals; Arrhythmias, Cardiac - diagnosis; Arrhythmias, Cardiac - etiology; Cell Differentiation - physiology; Cell Survival - physiology; electroanatomical mapping; Electroencephalography; Heterografts; human embryonic stem cell-derived cardiomyocytes; Human Embryonic Stem Cells - cytology; Humans; Magnetic Resonance Imaging; MRI; myocardial infarction; Myocardial Infarction - diagnostic imaging; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocytes, Cardiac - cytology; pluripotent stem cells; Regeneration - physiology; Stem Cell Transplantation - adverse effects; Stem Cell Transplantation - methods; Swine; Tachycardia - diagnosis; Tachycardia - etiology; ventricular tachyarrhythmias; human embryonic stem cell-derived cardiomyocytes; electroanatomical mapping; ventricular tachyarrhythmias; pluripotent stem cells; MRI; myocardial infarction
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.04.005

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. •hESC-CM transplantation partially remuscularizes the infarcted pig heart•hESC-CM recipients show frequent tachyarrhythmias at early time points•Graft-related arrhythmias arise from focal mechanisms rather than macro-reentry In this article, Laflamme and colleagues show that the transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) partially remuscularizes the scar of infarcted and appropriately immunosuppressed pigs. hESC-CM recipients exhibited frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. These graft-related tachyarrhythmias were found to be due to focal mechanisms rather than macro-reentry.