Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.
Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Cardiology Westmead Hospital, Westmead, New South Wales 2145, Australia [4] School of Medicine, University of Sydney, Sydney, New South Wales 2006, Australia [5] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [6] University of Sydney School of Medicine, Sydney, New South Wales 2006, Australia and Westmead Millennium Institute and Westmead Hospital, Westmead, New South Wales 2145, Australia.
James J H
JJ
Chong
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Xiulan
X
Yang
Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA.
Creighton W
CW
Don
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [4] Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA.
Elina
E
Minami
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Yen-Wen
YW
Liu
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Jill J
JJ
Weyers
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
William M
WM
Mahoney
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Benjamin
B
Van Biber
Department of Comparative Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
Savannah M
SM
Cook
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Nathan J
NJ
Palpant
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [4] Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA.
Jay A
JA
Gantz
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
James A
JA
Fugate
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Veronica
V
Muskheli
Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA.
G Michael
GM
Gough
Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA.
Keith W
KW
Vogel
Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA.
Cliff A
CA
Astley
Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA.
Charlotte E
CE
Hotchkiss
Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA.
Audrey
A
Baldessari
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Lil
L
Pabon
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Hans
H
Reinecke
Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA.
Edward A
EA
Gill
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Veronica
V
Nelson
1] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [2] Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Hans-Peter
HP
Kiem
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Michael A
MA
Laflamme
1] Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA [2] Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA [3] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [4] Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA [5] Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA.
Charles E
CE
Murry
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D003331:Coronary Vessels / Q000502:physiology; D015925:Cryopreservation; D004195:Disease Models, Animal; D004562:Electrocardiography; D053595:Embryonic Stem Cells / Q000166:cytology*; D006321:Heart; D006801:Humans; D008254:Macaca nemestrina; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology* / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology*; D012038:Regeneration; D044968:Regenerative Medicine / Q000379:methods
D002118:Calcium