Cellular heterogeneity of pluripotent stem cell-derived cardiomyocyte grafts is mechanistically linked to treatable arrhythmias
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Published:2024-02-06
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ISSN:2731-0590
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Container-title:Nature Cardiovascular Research
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language:en
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Short-container-title:Nat Cardiovasc Res
Author:
Selvakumar Dinesh, Clayton Zoe E., Prowse Andrew, Dingwall Steve, Kim Sul Ki, Reyes Leila, George Jacob, Shah Haisam, Chen SiqiORCID, Leung Halina H. L., Hume Robert D., Tjahjadi Laurentius, Igoor Sindhu, Skelton Rhys J. P., Hing Alfred, Paterson Hugh, Foster Sheryl L.ORCID, Pearson Lachlan, Wilkie Emma, Marcus Alan D.ORCID, Jeyaprakash Prajith, Wu Zhixuan, Chiu Han Shen, Ongtengco Cherica Felize J., Mulay Onkar, McArthur Jeffrey R., Barry Tony, Lu Juntang, Tran Vu, Bennett Richard, Kotake Yasuhito, Campbell TimothyORCID, Turnbull SamualORCID, Gupta Anunay, Nguyen QuanORCID, Ni Guiyan, Grieve Stuart M., Palpant Nathan J.ORCID, Pathan Faraz, Kizana EddyORCID, Kumar Saurabh, Gray Peter P., Chong James J. H.ORCID
Abstract
AbstractPreclinical 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.
Funder
Department of Health | National Health and Medical Research Council National Stem Cell Foundation New South Wales Government Office of Health and Medical Research Merchant Charitable Foundation JEM Research Foundation Royal Australasian College of Physicians Institute of Clinical Pathology and Medical Research Australian Government Research Training Program National Heart Foundation of Australia
Publisher
Springer Science and Business Media LLC
Reference80 articles.
1. Laflamme, M. A. & Murry, C. E. Heart regeneration. Nature 473, 326–335 (2011). 2. Nguyen, P. K., Rhee, J.-W. & Wu, J. C. Adult stem cell therapy and heart failure, 2000 to 2016: a systematic review. JAMA Cardiol. 1, 831–841 (2016). 3. Fisher, S. A., Doree, C., Mathur, A., Taggart, D. P. & Martin-Rendon, E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst. Rev. 12, CD007888 (2016). 4. Menasché, P. Cell therapy trials for heart regeneration — lessons learned and future directions. Nat. Rev. Cardiol. 15, 659–671 (2018). 5. Eschenhagen, T. et al. Cardiomyocyte regeneration: a consensus statement. Circulation 136, 680–686 (2017).
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