Human Engineered Heart Tissue: Analysis of Contractile Force.
Human Engineered Heart Tissue: Analysis of Contractile Force.
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人类工程心脏组织：收缩力的分析。
DOI：
10.1016/j.stemcr.2016.04.011
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发表时间：
2016-07-12
影响因子：
5.9
通讯作者：
Hansen A
中科院分区：
文献类型：
--
作者：
Mannhardt I;Breckwoldt K;Letuffe-Brenière D;Schaaf S;Schulz H;Neuber C;Benzin A;Werner T;Eder A;Schulze T;Klampe B;Christ T;Hirt MN;Huebner N;Moretti A;Eschenhagen T;Hansen A
分析收缩力，体内心肌细胞最重要和最好理解的功能在人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）中没有建立。本研究描述了从hiPSC-CM生成3D、条形、力生成工程化心脏组织（EHT）及其生理和药理学特性。通过基于生长因子的三阶段方案将CM与hiPSC区分开。生成EHT并进行组织学和功能分析。EHT中的HiPSC-CM显示出发达的肌节组织和排列，以及频繁的线粒体。系统的收缩力分析（26浓度-反应曲线）表明，EHT复制经典的反应，以前所未有的精度生理和药理学调节剂的收缩力，膜和钙时钟介导的起搏，离子通道电流的调制器，和promammic化合物。该分析证明了EHT形式的hiPSC-CM与天然人心脏组织之间的高度相似性，表明人EHT可用于临床前药物测试和疾病建模。来自hiPSC-CM的工程化心脏组织（EHT）以高再现性产生，EHT显示具有组织化肌节和未成熟t小管的对齐的心肌细胞。自发搏动由膜-和钙-时钟机制调节，EHT响应于生理和药理学干预，如人心脏组织汉森和埃森哈根及其同事描述了来自hiPSC的人工程化心脏组织中的收缩力的分析。EHT的生理和药理学特征显示与人类心脏组织高度相似，表明人类EHT可能用于临床前药物测试和疾病建模。
Analyzing contractile force, the most important and best understood function of cardiomyocytes in vivo is not established in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). This study describes the generation of 3D, strip-format, force-generating engineered heart tissues (EHT) from hiPSC-CM and their physiological and pharmacological properties. CM were differentiated from hiPSC by a growth factor-based three-stage protocol. EHTs were generated and analyzed histologically and functionally. HiPSC-CM in EHTs showed well-developed sarcomeric organization and alignment, and frequent mitochondria. Systematic contractility analysis (26 concentration-response curves) reveals that EHTs replicated canonical response to physiological and pharmacological regulators of inotropy, membrane- and calcium-clock mediators of pacemaking, modulators of ion-channel currents, and proarrhythmic compounds with unprecedented precision. The analysis demonstrates a high degree of similarity between hiPSC-CM in EHT format and native human heart tissue, indicating that human EHTs are useful for preclinical drug testing and disease modeling. Engineered heart tissues (EHTs) from hiPSC-CM are generated with high reproducibility EHTs show aligned cardiomyocytes with organized sarcomeres and immature t tubules Spontaneous beating is regulated by both, membrane- and calcium-clock mechanisms EHTs respond to physiological and pharmacological interventions like human heart tissue Hansen and Eschenhagen and colleagues describe the analysis of contractile force in human engineered heart tissue from hiPSC. The physiological and pharmacological characterization of EHTs revealed a high degree of similarity to human heart tissue, indicating that human EHTs might be useful for preclinical drug testing and disease modeling.