• An Erratum to this article was published on 06 September 2018

This article has been updated

Abstract

Pluripotent stem cell–derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transplantation of 750 million cryopreserved human embryonic stem cell–derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions. One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 ± 0.9% vs. 2.5 ± 0.8% in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained 99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.

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Change history

  • 18 July 2018

    In the version of this article initially published, NIH grant P51 OD010425 was omitted. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

These studies were supported in part by NIH Grants R01HL128362, R01 HL084642, P01HL094374, and a grant from the Fondation Leducq Transatlantic Network of Excellence (all to C.E.M.), and grant P51 OD010425 from the NIH Office of Research Infrastructure Programs to the Washington National Primate Research Center. These studies also were supported by the UW Medicine Heart Regeneration Program, the Washington Research Foundation, and a gift from Mike and Lynn Garvey. The manufacture of cells provided by City of Hope was funded in part through the National Heart Lung and Blood Institute's Production Assistance for Cell Therapies (PACT). We also acknowledge the support of the Cell Analysis Facility Flow Cytometry and Imaging Core in the Department of Immunology at the University of Washington. We thank the Garvey Imaging Core for assistance with microscopy. We are indebted to the dedicated staff of the Washington National Primate Research Center for supporting many aspects of this study. We thank M. Laflamme for helpful discussions, W.-Z. Zhu for support with electrophysiological studies, and P. Swanson for consultation on the renal tumor. We thank J. Maki and G. Wilson for help with cardiac MRI protocol.

Author information

Author notes

    • Yen-Wen Liu
    • , Larry Couture
    •  & Stephanie A Tuck

    Present addresses: Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Y.-W.L.); Orbsen Therapeutics, LTD, Orbsen Buildings, National University of Ireland Galway, Galway, Ireland (L.C.); Uptake Medical Technologies, Seattle, Washington, USA. (S.A.T.).

    • Yen-Wen Liu
    • , Billy Chen
    •  & Xiulan Yang

    These authors contributed equally to this work.

Affiliations

  1. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.

    • Yen-Wen Liu
    • , Billy Chen
    • , Xiulan Yang
    • , James A Fugate
    • , Faith A Kalucki
    • , Akiko Futakuchi-Tsuchida
    • , Stephanie A Tuck
    • , Hiroshi Tsuchida
    • , Anna V Naumova
    • , Sarah K Dupras
    • , Dale W Hailey
    • , Hans Reinecke
    • , Lil Pabon
    • , Benjamin H Fryer
    • , W Robb MacLellan
    • , R Scott Thies
    •  & Charles E Murry
  2. Center for Cardiovascular Biology, University of Washington, Seattle, Washington, USA.

    • Yen-Wen Liu
    • , Billy Chen
    • , Xiulan Yang
    • , James A Fugate
    • , Faith A Kalucki
    • , Akiko Futakuchi-Tsuchida
    • , Stephanie A Tuck
    • , Hiroshi Tsuchida
    • , Anna V Naumova
    • , Sarah K Dupras
    • , Hans Reinecke
    • , Lil Pabon
    • , Benjamin H Fryer
    • , W Robb MacLellan
    • , R Scott Thies
    •  & Charles E Murry
  3. Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

    • Yen-Wen Liu
  4. Department of Medicine/Cardiology, University of Washington, Seattle, Washington, USA.

    • Billy Chen
    • , Creighton W Don
    • , Zachary L Steinberg
    • , Stephen P Seslar
    • , James Lee
    • , W Robb MacLellan
    •  & Charles E Murry
  5. Department of Pathology, University of Washington, Seattle, Washington, USA.

    • Xiulan Yang
    • , James A Fugate
    • , Faith A Kalucki
    • , Akiko Futakuchi-Tsuchida
    • , Stephanie A Tuck
    • , Hiroshi Tsuchida
    • , Sarah K Dupras
    • , Hans Reinecke
    • , Lil Pabon
    • , Benjamin H Fryer
    • , R Scott Thies
    •  & Charles E Murry
  6. City of Hope, Beckman Research Institute, Duarte, California, USA.

    • Larry Couture
  7. Washington National Primate Research Center, University of Washington, Seattle, Washington, USA.

    • Keith W Vogel
    • , Clifford A Astley
    • , Audrey Baldessari
    •  & Jason Ogle
  8. Department of Pediatrics, University of Washington, Seattle Children's Hospital, Seattle, Washington, USA.

    • Stephen P Seslar
  9. Department of Radiology, University of Washington, Seattle, Washington, USA.

    • Anna V Naumova
    •  & Milly S Lyu
  10. Research Institute of Biology and Biophysics, National Research Tomsk State University, Tomsk, Russia.

    • Anna V Naumova
  11. Department of Bioengineering, University of Washington, Seattle, Washington, USA.

    • Charles E Murry

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Contributions

Y.-W.L. designed experiments, conducted animal studies, analyzed data and edited the manuscript. B.C. designed experiments, conducted animal studies, performed histology studies, analyzed data and edited the manuscript. X.Y. performed histology, histomorphometry, analyzed data, prepared figures, and edited the manuscript. J.A.F. prepared cells for transplantation and edited the manuscript. F.A.K. prepared cells for transplantation and edited the manuscript. A.F.-T. prepared cells for transplantation and edited the manuscript. L.C. supervised cell manufacturing. K.W.V. designed experiments, conducted animal studies, and provided veterinary care. C.A.A. designed experiments and conducted animal studies. A.B. performed necropsies and provided pathology consultation. J.O. conducted animal studies and edited the manuscript. C.W.D. designed experiments, conducted animal studies and edited the manuscript. Z.L.S. conducted animal studies and edited the manuscript. S.P.S. designed experiments, conducted electrophysiology studies, analyzed data and edited the manuscript. S.A.T. conducted animal studies, analyzed data and edited the manuscript. H.T. conducted animal studies and edited the manuscript. A.V.N. performed MRI studies, analyzed data and edited the manuscript. S.K.D. performed histology. M.S.L. analyzed MRI scans. J.L. analyzed MRI scans and edited the manuscript. D.W.H. advised on and performed microscopy. H.R. designed experiments, performed histology, conducted molecular analyses, analyzed data, and prepared figures. L.P. designed experiments, analyzed data and edited the manuscript. B.H.F. prepared cells for transplantation. WR.M. designed experiments, analyzed data and edited the manuscript. R.S.T. designed experiments, conducted animal studies, oversaw preparation of cells for transplantation, analyzed data, prepared figures and edited the manuscript. C.E.M. supervised all components of this study, designed experiments, performed animal experiments, analyzed data, obtained funding for the study, prepared figures and wrote the manuscript.

Competing interests

C.E.M., R.S.T., and W.R.M. are scientific founders and equity holders in Cytocardia.

Corresponding author

Correspondence to Charles E Murry.

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DOI

https://doi.org/10.1038/nbt.4162

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