{"title":"Enhancing the functional maturity of hiPSC-derived cardiomyocytes to assess inotropic compounds","authors":"Xiaoyu Zhang , Praful Aggarwal , Ulrich Broeckel , Yama A. Abassi","doi":"10.1016/j.vascn.2023.107282","DOIUrl":null,"url":null,"abstract":"<div><p>Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) present an attractive in vitro platform to model safety and toxicity assessments—notably screening pro-arrhythmic compounds. The utility of the platform is stymied by a hiPSC-CM contractile apparatus and calcium handling mechanism akin to fetal phenotypes, evidenced by a negative force-frequency relationship. As such, hiPSC-CMs are limited in their ability to assess compounds that modulate contraction mediated by ionotropic compounds (Robertson, Tran, & George, 2013). To address this limitation, we utilize Agilent's xCELLigence Real-Time Cell Analyzer ePacer (RTCA ePacer) to enhance hiPSC-CM functional maturity. A continuous, progressive increase of electrical pacing is applied to hiPSC-CMs for up to 15 days. Contraction and viability are recorded by measurement of impedance using the RTCA ePacer. Our data confirms hiPSC-CMs inherently demonstrate a negative impedance amplitude frequency that is reversed after long-term electrical pacing. The data also indicate positive inotropic compounds increase the contractility of paced cardiomyocytes and calcium handling machinery is improved. Increased expression of genes critical to cardiomyocyte maturation further underscores the maturity of paced cells. In summary, our data suggest the application of continuous electrical pacing can functionally mature hiPSC-CMs, enhancing cellular response to positive inotropic compounds and improving calcium handling.</p></div><div><h3>Summary</h3><p>Long-term electrical stimulation of hiPSC-CM leads to functional maturation enabling predictive assessment of inotropic compounds.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3000,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of pharmacological and toxicological methods","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1056871923000333","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 1
Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) present an attractive in vitro platform to model safety and toxicity assessments—notably screening pro-arrhythmic compounds. The utility of the platform is stymied by a hiPSC-CM contractile apparatus and calcium handling mechanism akin to fetal phenotypes, evidenced by a negative force-frequency relationship. As such, hiPSC-CMs are limited in their ability to assess compounds that modulate contraction mediated by ionotropic compounds (Robertson, Tran, & George, 2013). To address this limitation, we utilize Agilent's xCELLigence Real-Time Cell Analyzer ePacer (RTCA ePacer) to enhance hiPSC-CM functional maturity. A continuous, progressive increase of electrical pacing is applied to hiPSC-CMs for up to 15 days. Contraction and viability are recorded by measurement of impedance using the RTCA ePacer. Our data confirms hiPSC-CMs inherently demonstrate a negative impedance amplitude frequency that is reversed after long-term electrical pacing. The data also indicate positive inotropic compounds increase the contractility of paced cardiomyocytes and calcium handling machinery is improved. Increased expression of genes critical to cardiomyocyte maturation further underscores the maturity of paced cells. In summary, our data suggest the application of continuous electrical pacing can functionally mature hiPSC-CMs, enhancing cellular response to positive inotropic compounds and improving calcium handling.
Summary
Long-term electrical stimulation of hiPSC-CM leads to functional maturation enabling predictive assessment of inotropic compounds.
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.