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Stem Cell Reports. 2019 May 14;12(5):967-981. doi: 10.1016/j.stemcr.2019.04.005. Epub 2019 May 2.

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

Author information

1
McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
2
Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 2N2, Canada.
3
Schulich Heart Research Program, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada.
4
Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
5
Centre for Commercialization of Regenerative Medicine, Toronto, ON M5G 1M1, Canada.
6
Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 2N2, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; University of Toronto, Toronto, ON M5G 1L7, Canada.
7
Centre for Commercialization of Regenerative Medicine, Toronto, ON M5G 1M1, Canada; University of Toronto, Toronto, ON M5G 1L7, Canada.
8
Schulich Heart Research Program, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada; University of Toronto, Toronto, ON M5G 1L7, Canada.
9
Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 2N2, Canada; University of Toronto, Toronto, ON M5G 1L7, Canada.
10
McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; University of Toronto, Toronto, ON M5G 1L7, Canada.
11
McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 2N2, Canada; University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: michael.laflamme@uhnresearch.ca.

Abstract

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.

KEYWORDS:

MRI; electroanatomical mapping; human embryonic stem cell-derived cardiomyocytes; myocardial infarction; pluripotent stem cells; ventricular tachyarrhythmias

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