Cellular heterogeneity of pluripotent stem cell-derived cardiomyocyte grafts is mechanistically linked to treatable arrhythmias

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2024年2月6日

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Dinesh Selvakumar,
Zoe E. Clayton,
Andrew Prowse,
Steve Dingwall,
Sul Ki Kim,
Leila Reyes,
Jacob George,
Haisam Shah,
Siqi Chen,
Halina H. L. Leung,
Robert D. Hume,
Laurentius Tjahjadi,
Sindhu Igoor,
Rhys J. P. Skelton,
Alfred Hing,
Hugh Paterson,
Sheryl L. Foster,
Lachlan Pearson,
Emma Wilkie,
Alan D. Marcus,
Prajith Jeyaprakash,
Zhixuan Wu,
Han Shen Chiu,
Cherica Felize J. Ongtengco,
Onkar Mulay,
Jeffrey R. McArthur,
Tony Barry,
Juntang Lu,
Vu Tran,
Richard Bennett,
Yasuhito Kotake,
Timothy Campbell,
Samual Turnbull,
Anunay Gupta,
Quan Nguyen,
Guiyan Ni,
Stuart M. Grieve,
Nathan J. Palpant,
Faraz Pathan,
Eddy Kizana,
Saurabh Kumar,
Peter P. Gray,
James J. H. Chong

摘要

Preclinical data have confirmed that human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) can remuscularize the injured or diseased heart, with several clinical trials now in planning or recruitment stages. However, because ventricular arrhythmias represent a complication following engraftment of intramyocardially injected PSC-CMs, it is necessary to provide treatment strategies to control or prevent engraftment arrhythmias (EAs). Here, we show in a porcine model of myocardial infarction and PSC-CM transplantation that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. Two unique surface marker signatures, signal regulatory protein α (SIRPA)⁺CD90⁻CD200⁺ and SIRPA⁺CD90⁻CD200⁻, identify arrhythmogenic and non-arrhythmogenic cardiomyocytes, respectively. Our data suggest that modifications to current PSC-CM-production and/or PSC-CM-selection protocols could potentially prevent EAs. We further show that pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias.