使用对齐的人类 iPSC 衍生心肌细胞进行收缩力评估。

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Journal of pharmacological and toxicological methods Pub Date : 2024-07-01 DOI:10.1016/j.vascn.2024.107530
Ayano Satsuka , Alexandre J.S. Ribeiro , Hiroyuki Kawagishi , Shota Yanagida , Naoya Hirata , Takashi Yoshinaga , Junko Kurokawa , Atsushi Sugiyama , David G. Strauss , Yasunari Kanda
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引用次数: 0

摘要

简介:心脏安全性评估,如致命性心律失常和收缩功能障碍,在药物开发过程中至关重要。国际验证研究表明,人类诱导多能干细胞衍生的心肌细胞(hiPSC-CMs)可用于预测药物诱发致心律失常的风险。虽然心脏收缩力是另一项关键功能,但人们对用于评估药物诱导的收缩功能障碍的合适的hiPSC-CMs仍知之甚少。在这项研究中,我们探讨了在纳米图案培养板上对齐 hiPSC-CMs 是否能比非对齐单层培养更有效地评估药物诱导的收缩变化:对齐的hiPSC-CMs是通过在底面带有脊-槽-脊纳米图案的96孔培养板上培养获得的,而未对齐的hiPSC-CMs是在普通的96孔培养板上培养的。对基因表达进行了新一代测序和 qPCR 实验分析。使用基于成像的运动分析系统评估了 hiPSC-CMs 的收缩能力:结果:在纳米花纹板上培养时,hiPSC-CMs表现出排列整齐的形态,并增强了编码调控收缩力的蛋白的基因的表达,包括肌球蛋白重链、钙通道和雷诺丁受体。与普通平板上的培养物相比,排列整齐的 hiPSC-CMs 还显示出更强的收缩和松弛速度。此外,排列整齐的 hiPSC-CMs 对异丙肾上腺素和维拉帕米等正性和负性肌力药物表现出更多的生理反应:总之,与未配对的细胞相比,配对的 hiPSC-CMs 表现出更强的结构和功能特性,从而提高了收缩能力评估的能力。这些发现表明,配准的 hiPSC-CMs 可用于评估药物诱导的心脏收缩力变化。
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Contractility assessment using aligned human iPSC-derived cardiomyocytes

Introduction

Cardiac safety assessment, such as lethal arrhythmias and contractility dysfunction, is critical during drug development. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been shown to be useful in predicting drug-induced proarrhythmic risk through international validation studies. Although cardiac contractility is another key function, fit-for-purpose hiPSC-CMs in evaluating drug-induced contractile dysfunction remain poorly understood. In this study, we investigated whether alignment of hiPSC-CMs on nanopatterned culture plates can assess drug-induced contractile changes more efficiently than non-aligned monolayer culture.

Methods

Aligned hiPSC-CMs were obtained by culturing on 96-well culture plates with a ridge-groove-ridge nanopattern on the bottom surface, while non-aligned hiPSC-CMs were cultured on regular 96-well plates. Next-generation sequencing and qPCR experiments were performed for gene expression analysis. Contractility of the hiPSC-CMs was assessed using an imaging-based motion analysis system.

Results

When cultured on nanopatterned plates, hiPSC-CMs exhibited an aligned morphology and enhanced expression of genes encoding proteins that regulate contractility, including myosin heavy chain, calcium channel, and ryanodine receptor. Compared to cultures on regular plates, the aligned hiPSC-CMs also showed both enhanced contraction and relaxation velocity. In addition, the aligned hiPSC-CMs showed a more physiological response to positive and negative inotropic agents, such as isoproterenol and verapamil.

Discussion

Taken together, the aligned hiPSC-CMs exhibited enhanced structural and functional properties, leading to an improved capacity for contractility assessment compared to the non-aligned cells. These findings suggest that the aligned hiPSC-CMs can be used to evaluate drug-induced cardiac contractile changes.

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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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