Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA.
Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD 21205, USA; Stem Cell and Regenerative Medicine Consortium, LKS Faculty of Medicine, Hong Kong University, Hong Kong, SAR; Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Stem Cell Reports. 2019 May 14;12(5):982-995. doi: 10.1016/j.stemcr.2019.04.002. Epub 2019 May 2.
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for cardiac studies, but their structural and functional immaturity precludes their use as faithful models of adult myocardium. Here we describe engineered heart slices (EHS), preparations of decellularized porcine myocardium repopulated with hiPSC-CMs that exhibit structural and functional improvements over standard culture. EHS exhibited multicellular, aligned bundles of elongated CMs with organized sarcomeres, positive inotropic responses to isoproterenol, anisotropic conduction of action potentials, and electrophysiological functionality for more than 200 days. We developed a new drug assay, GRIDS, that serves as a "fingerprint" of cardiac drug sensitivity for a range of pacing rates and drug concentrations. GRIDS maps characterized differences in drug sensitivity between EHS and monolayers more clearly than changes in action potential durations or conduction velocities. EHS represent a tissue-like model for long-term culture, structural, and functional improvement, and higher fidelity drug response of hiPSC-CMs.
人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）在心脏研究中具有巨大的应用潜力，但由于其结构和功能不成熟，不能作为成人心肌的忠实模型。本文中，我们描述了工程化心脏切片（EHS），这是一种去细胞化的猪心肌再灌注 hiPSC-CMs 的制备方法，与标准培养相比，EHS 表现出结构和功能上的改善。EHS 呈现出具有组织化的肌节的多细胞、排列整齐的长形 CM 束，对异丙肾上腺素表现出正性变力反应，动作电位具有各向异性传导，并且电生理功能可维持 200 天以上。我们开发了一种新的药物检测方法 GRIDS，它可作为一系列起搏率和药物浓度的心脏药物敏感性的“指纹图谱”。GRIDS 图谱比动作电位持续时间或传导速度的变化更清楚地描绘了 EHS 和单层之间药物敏感性的差异。EHS 代表了一种用于长期培养、结构和功能改善以及更高保真度 hiPSC-CMs 药物反应的组织样模型。
