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首页> 外文期刊>Nature >Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts
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Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts

机译：人类胚胎干细胞衍生的心肌细胞再生非人类灵长类动物的心脏

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摘要

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 en-graftment. 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.
机译：多能干细胞通过提供人类心肌细胞来支持心脏再生，为当前的心力衰竭流行率提供了潜在的解决方案。在小动物模型中对人类胚胎干细胞衍生的心肌细胞（hESC-CMs）的研究显示了这种治疗的良好效果。但是，临床规模的hESC-CM移植是否可行，安全或能否提供足够的心肌再生仍然未知。在这里，我们表明，hESC-CMs可以临床规模生产（每批超过十亿个细胞），并具有良好的生存能力。使用非人类灵长类动物心肌缺血再灌注后的模型，我们显示了十亿hESC-CM的冷冻保存和心肌内递送可对梗塞的心脏产生广泛的肌肉再生。 hESC-CMs在三个月的时间内显示出进行性但不完全的成熟。移植物通过宿主脉管系统进行灌注，并且在移植后2周内出现了移植物与宿主肌细胞之间的机电连接。重要的是，移植物显示出规律的钙瞬变，其与宿主心电图同步，表明机电耦合。与小动物模型相比，在hESC-CM植入的灵长类动物中观察到非致死性室性心律失常。因此，hESC-CMs可以使大量的梗死的猴子心脏肌肉再生。人的心脏应具有类似的肌肉再生能力，但需要克服潜在的心律失常并发症。

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  • 来源
    《Nature》 |2014年第7504期|273-277|共5页
  • 作者

    James J. H. Chong; Xiulan Yang; Creighton W. Don; Elina Minami; Yen-Wen Liu; Jill J. Weyers; William M. Mahoney Jr; Benjamin Van Biber; Savannah M. Cook; Nathan J. Palpant; Jay A. Gantz; James A. Fugate; Veronica Muskheli; G. Michael Gough; Keith W. Vogel; Cliff A. Astley; Charlotte E. Hotchkiss; Audrey Baldessari; Lil Pabon; Hans Reinecke; Edward A. Gill; Veronica Nelson; Hans-Peter Kiem; Michael A. Laflamme; Charles E. Murry;

  • 作者单位

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Cardiology Westmead Hospital, Westmead, New South Wales 2145, Australia,School of Medicine, University of Sydney, Sydney, New South Wales 2006, Australia,Department of Pathology, University of Washington, Seattle, Washington 98195, USA,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;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA,Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, 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;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA,Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA;

    Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA;

    Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA;

    Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA;

    Washington National Primate Research Center, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA;

    Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;

    Department of Pathology, University of Washington, Seattle, Washington 98195, USA,Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA;

    Center for Cardiovascular Biology, University of Washington, Seattle, Washington 98109, USA,Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA,Department of Pathology, University of Washington, Seattle, Washington 98195, USA,Department of Medicine/Cardiology, University of Washington, Seattle, Washington 98195, USA,Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA;

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