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Advanced maturation of human cardiac tissue grown from pluripotent stem cells

机译:由多能干细胞生长的人类心脏组织的高级成熟

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摘要

Cardiac tissues generated from human induced pluripotent stem cells (iPSCs) can serve as platforms for patient-specific studies of physiology and disease(1-6). However, the predictive power of these models is presently limited by the immature state of the cells(1,2,5,6). Here we show that this fundamental limitation can be overcome if cardiac tissues are formed from early-stage iPSC-derived cardiomyocytes soon after the initiation of spontaneous contractions and are subjected to physical conditioning with increasing intensity over time. After only four weeks of culture, for all iPSC lines studied, such tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiological sarcomere length (2.2 mu m) and density of mitochondria (30%), the presence of transverse tubules, oxidative metabolism, a positive force-frequency relationship and functional calcium handling. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiological responses to isoproterenol and recapitulating pathological hypertrophy, supporting the utility of this tissue model for studies of cardiac development and disease.
机译:由人诱导的多能干细胞(iPSC)产生的心脏组织可作为针对患者的生理学和疾病研究的平台(1-6)。然而,这些模型的预测能力目前受到细胞未成熟状态的限制(1,2,5,6)。在这里,我们表明,如果自发性收缩开始后不久就由早期iPSC衍生的心肌细胞形成心脏组织,并且随着时间的推移强度不断增强,则可以克服这一基本局限性。在仅培养四个星期后,对于所有研究的iPSC品系,此类组织均显示出成年状基因表达谱,超微结构,生理性肌小节长度(2.2微米)和线粒体密度(30%),横管,氧化代谢,正向频率关系和功能性钙处理。机电性能发展较慢,并且未达到在成人心肌中看到的成熟阶段。组织成熟对于实现对异丙肾上腺素的生理反应和概括病理性肥大是必要的,从而支持该组织模型在心脏发育和疾病研究中的实用性。

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  • 来源
    《Nature》 |2018年第7700期|239-243|共5页
  • 作者单位

    Columbia Univ, Dept Biomed Engn, Lab Stem Cells & Tissue Engn, New York, NY 10027 USA;

    Columbia Univ, Dept Biomed Engn, Lab Stem Cells & Tissue Engn, New York, NY 10027 USA;

    Columbia Univ, Dept Biomed Engn, Lab Stem Cells & Tissue Engn, New York, NY 10027 USA;

    Columbia Univ, Dept Biomed Engn, Lab Stem Cells & Tissue Engn, New York, NY 10027 USA;

    Columbia Univ, Coll Phys & Surg, Dept Pharmacol, Dept Rehabil & Regenerat Med, New York, NY USA;

    Columbia Univ, Dept Biomed Engn, Lab Stem Cells & Tissue Engn, New York, NY 10027 USA;

    Columbia Univ, Coll Phys & Surg, Dept Pharmacol, Dept Rehabil & Regenerat Med, New York, NY USA;

    Columbia Univ, Dept Biomed Engn, Lab Stem Cells & Tissue Engn, New York, NY 10027 USA;

    Columbia Univ, Coll Phys & Surg, Dept Pharmacol, Dept Rehabil & Regenerat Med, New York, NY USA;

    Columbia Univ, Dept Biomed Engn, Lab Stem Cells & Tissue Engn, New York, NY 10027 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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