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

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

doi:10.1038/s44161-023-00419-3

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

Nat Cardiovasc Res. 2024 Feb;3(2):145-165. doi: 10.1038/s44161-023-00419-3. Epub 2024 Feb 6.

Authors

Dinesh Selvakumar^#^{1

2}, Zoe E Clayton^#¹, Andrew Prowse³, Steve Dingwall³, Sul Ki Kim^{1

2}, Leila Reyes¹, Jacob George¹, Haisam Shah¹, Siqi Chen¹, Halina H L Leung¹, Robert D Hume¹, Laurentius Tjahjadi¹, Sindhu Igoor¹, Rhys J P Skelton¹, Alfred Hing⁴, Hugh Paterson⁵, Sheryl L Foster^{6

7}, Lachlan Pearson¹, Emma Wilkie¹, Alan D Marcus¹, Prajith Jeyaprakash⁸, Zhixuan Wu⁹, Han Shen Chiu⁹, Cherica Felize J Ongtengco³, Onkar Mulay¹⁰, Jeffrey R McArthur^{11

12}, Tony Barry², Juntang Lu², Vu Tran², Richard Bennett², Yasuhito Kotake², Timothy Campbell², Samual Turnbull², Anunay Gupta², Quan Nguyen¹⁰, Guiyan Ni¹⁰, Stuart M Grieve¹³, Nathan J Palpant⁹, Faraz Pathan^{8

14}, Eddy Kizana^{1

2}, Saurabh Kumar², Peter P Gray³, James J H Chong^{15

16}

Affiliations

¹ Centre for Heart Research, the Westmead Institute for Medical Research, the University of Sydney, Westmead, New South Wales, Australia.
² Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia.
³ Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, St Lucia, Queensland, Australia.
⁴ Department of Cardiothoracic Surgery, Westmead Hospital, Westmead, New South Wales, Australia.
⁵ Sydney Imaging, Core Research Facility, the University of Sydney, Sydney, New South Wales, Australia.
⁶ Department of Radiology, Westmead Hospital, Westmead, New South Wales, Australia.
⁷ Sydney School of Health Sciences, Faculty of Medicine and Health, the University of Sydney, Sydney, New South Wales, Australia.
⁸ Department of Cardiology, Nepean Hospital, Kingswood, New South Wales, Australia.
⁹ Institute for Molecular Bioscience, the University of Queensland, St Lucia, Queensland, Australia.
¹⁰ Genomics and Machine Learning Lab, Division of Genetics and Genomics, Institute for Molecular Bioscience, the University of Queensland, St Lucia, Queensland, Australia.
¹¹ Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
¹² St. Vincent's Clinical School, UNSW, Darlinghurst, New South Wales, Australia.
¹³ Imaging and Phenotyping Laboratory, Faculty of Medicine and Health, Charles Perkins Centre, the University of Sydney, Sydney, New South Wales, Australia.
¹⁴ Sydney Medical School, Charles Perkins Centre Nepean, Faculty of Medicine and Health, the University of Sydney, Sydney, New South Wales, Australia.
¹⁵ Centre for Heart Research, the Westmead Institute for Medical Research, the University of Sydney, Westmead, New South Wales, Australia. james.chong@sydney.edu.au.
¹⁶ Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia. james.chong@sydney.edu.au.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Action Potentials / physiology
Animals
Anti-Arrhythmia Agents / pharmacology
Anti-Arrhythmia Agents / therapeutic use
Arrhythmias, Cardiac* / therapy
Biomarkers / metabolism
Cell Differentiation
Cells, Cultured
Disease Models, Animal
Heart Rate / physiology
Humans
Induced Pluripotent Stem Cells / transplantation
Myocardial Infarction / therapy
Myocytes, Cardiac* / metabolism
Myocytes, Cardiac* / transplantation
Phenotype
Pluripotent Stem Cells / transplantation
Stem Cell Transplantation / methods
Swine

Substances

Biomarkers
Anti-Arrhythmia Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding