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In vivo cardiac reprogramming contributes to zebrafish heart regeneration

机译：体内心脏重编程有助于斑马鱼心脏再生

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摘要

对心脏衰竭患者使用干细胞疗法所存存的障碍包括：难以确保心脏祖细胞分化成功能性心室心肌细胞，以及堆以确保能将分化的细胞输送和集成到患者的“心室肌”中。Neil Chi及其同事研究了特定心肌细胞类型有斑马鱼胚胎心脏中分化成密切相关的、但却截然不同的细胞类型的能力。他们发现，分化的心房心肌细胞在心脏受伤时能转变成心室心肌细胞，而且Notch信号作用通道诱导这种再生。这项研究将内源性心脏细胞类群确定为心室再生的一个潜在来源。%Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the developed world due to the limited capacity of adult mammalian ventricular cardio-myocytes to divide and replace ventricular myocardium lost from ischaemia-induced infarct. Hence there is great interest to identify potential cellular sources and strategies to generate new ventricular myocardium. Past studies have shown that fish and amphibians and early postnatal mammalian ventricular cardiomyocytes can proliferate to help regenerate injured ventricles; however, recent studies have suggested that additional endogenous cellular sources may contribute to this overall ventricular regeneration. Here we have developed, in the zebrafish (Danio rerio), a combination of fluorescent reporter transgenes, genetic fate-mapping strategies and a ventricle-specific genetic ablation system to discover that differentiated atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Using in vivo time-lapse and confocal imaging, we monitored the dynamic cellular events during atrial-to-vent-ricular cardiomyocyte transdifferentiation to define intermediate cardiac reprogramming stages. We observed that Notch signalling becomes activated in the atrial endocardium following ventricular ablation, and discovered that inhibiting Notch signalling blocked the atrial-to-ventricular transdifferentiation and cardiac regeneration. Overall, these studies not only provide evidence for the plasticity of cardiac lineages during myocardial injury, but more importantly reveal an abundant new potential cardiac resident cellular source for cardiac ventricular regeneration.
机译：对心脏衰竭患者使用干细胞疗法所存存的障碍包括：难以确保心脏祖细胞分化成功能性心室心肌细胞，以及堆以确保能将分化的细胞输送和集成到患者的“心室肌”中。Neil Chi及其同事研究了特定心肌细胞类型有斑马鱼胚胎心脏中分化成密切相关的、但却截然不同的细胞类型的能力。他们发现，分化的心房心肌细胞在心脏受伤时能转变成心室心肌细胞，而且Notch信号作用通道诱导这种再生。这项研究将内源性心脏细胞类群确定为心室再生的一个潜在来源。%Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the developed world due to the limited capacity of adult mammalian ventricular cardio-myocytes to divide and replace ventricular myocardium lost from ischaemia-induced infarct. Hence there is great interest to identify potential cellular sources and strategies to generate new ventricular myocardium. Past studies have shown that fish and amphibians and early postnatal mammalian ventricular cardiomyocytes can proliferate to help regenerate injured ventricles; however, recent studies have suggested that additional endogenous cellular sources may contribute to this overall ventricular regeneration. Here we have developed, in the zebrafish (Danio rerio), a combination of fluorescent reporter transgenes, genetic fate-mapping strategies and a ventricle-specific genetic ablation system to discover that differentiated atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Using in vivo time-lapse and confocal imaging, we monitored the dynamic cellular events during atrial-to-vent-ricular cardiomyocyte transdifferentiation to define intermediate cardiac reprogramming stages. We observed that Notch signalling becomes activated in the atrial endocardium following ventricular ablation, and discovered that inhibiting Notch signalling blocked the atrial-to-ventricular transdifferentiation and cardiac regeneration. Overall, these studies not only provide evidence for the plasticity of cardiac lineages during myocardial injury, but more importantly reveal an abundant new potential cardiac resident cellular source for cardiac ventricular regeneration.

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  • 来源
    《Nature》 |2013年第7455期|497-501395|共6页
  • 作者

    Ruilin Zhang; Peidong Han; Hongbo Yang; Kunfu Ouyang; Derek Lee; Yi-Fan Lin; Karen Ocorr; Guson Kang; Ju Chen; Didier Y. R. Stainier; Deborah Yelon; Neil C. Chi;

  • 作者单位

    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA.;

    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA.;

    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA.;

    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA.;

    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA.;

    Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA.;

    Development and Aging Program, Sanford-Burnham Institute for Medical Research, La Jolla, California 92037, USA.;

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158, USA.;

    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA.;

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158, USA, Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany;

    Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA.;

    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA, Institute of Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA.;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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