Publication Date:
2014-04-30
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154594/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154594/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chong, James J H -- Yang, Xiulan -- Don, Creighton W -- Minami, Elina -- Liu, Yen-Wen -- Weyers, Jill J -- Mahoney, William M -- Van Biber, Benjamin -- Cook, Savannah M -- Palpant, Nathan J -- Gantz, Jay A -- Fugate, James A -- Muskheli, Veronica -- Gough, G Michael -- Vogel, Keith W -- Astley, Cliff A -- Hotchkiss, Charlotte E -- Baldessari, Audrey -- Pabon, Lil -- Reinecke, Hans -- Gill, Edward A -- Nelson, Veronica -- Kiem, Hans-Peter -- Laflamme, Michael A -- Murry, Charles E -- P01 GM081619/GM/NIGMS NIH HHS/ -- P01 HL094374/HL/NHLBI NIH HHS/ -- P01GM081619/GM/NIGMS NIH HHS/ -- P01HL094374/HL/NHLBI NIH HHS/ -- P51 OD010425/OD/NIH HHS/ -- R01 HL084642/HL/NHLBI NIH HHS/ -- R01 HL117991/HL/NHLBI NIH HHS/ -- R01HL084642/HL/NHLBI NIH HHS/ -- T32 GM007266/GM/NIGMS NIH HHS/ -- U01 HL100405/HL/NHLBI NIH HHS/ -- U01HL100405/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Jun 12;510(7504):273-7. doi: 10.1038/nature13233. Epub 2014 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; 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. ; Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA. ; 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. ; Department of Comparative Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA. ; 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. ; Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; 1] Department of Pathology, University of Washington, Seattle, Washington 98195, USA [2] Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24776797" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Arrhythmias, Cardiac/physiopathology
;
Calcium/metabolism
;
Cell Survival
;
Coronary Vessels/physiology
;
Cryopreservation
;
Disease Models, Animal
;
Electrocardiography
;
Embryonic Stem Cells/*cytology
;
*Heart
;
Humans
;
Macaca nemestrina
;
Male
;
Mice
;
Myocardial Infarction/*pathology/*therapy
;
Myocytes, Cardiac/*cytology
;
*Regeneration
;
Regenerative Medicine/methods
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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