Cellular heterogeneity of pluripotent stem cell-derived cardiomyocyte grafts is mechanistically linked to treatable arrhythmias
Dinesh Selvakumar, Zoë E. Clayton, Andrew B.J. Prowse, Steve Dingwall, Sul Ki Kim, Leila Reyes, Jacob George, Haisam Shah, Chen Si-qi, Halina Leung, Robert D. Hume, Laurentius Tjahjadi, Sindhu Igoor, Rhys J.P. Skelton, Alfred Hing, Hugh S. Paterson, Sheryl Foster, Lachlan Pearson, Emma Wilkie, Alan Marcus, Prajith Jeyaprakash, Zhixuan Wu, Han Shen Chiu, Cherica Felize J. Ongtengco, Onkar Mulay, Jeffrey R. McArthur, Tony Barry, Juntang Lu, Vu Tran, Richard G. 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
Abstract
Abstract 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.