کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8553111 | 1562578 | 2018 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Probing flecainide block of INa using human pluripotent stem cell-derived ventricular cardiomyocytes adapted to automated patch-clamping and 2D monolayers
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کلمات کلیدی
VCMFlecainideTnnT2FLEHpSCESCsEADIPSCsAPDLQTShESC - hescElectrophysiology - الکتروفیزیولوژیConduction properties - خواص هدایتHuman embryonic stem cell - سلول بنیادی جنینی انسانHuman pluripotent stem cell - سلول بنیادی پلورپوفنت انسانیInduced pluripotent stem cells - سلول های بنیادی پرتوان القاییEmbryonic stem cells - سلولهای بنیادی جنینیLong QT syndrome - سندرم QT طولانیAction potential duration - مدت زمان بالقوه عملaction potential - پتانسیل عمل Ventricular cardiomyocyte - کاردیومیوسیت بطنیSodium Channel - کانال سدیم
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are emerging tools for applications such as drug discovery and screening for pro-arrhythmogenicity and cardiotoxicity as leading causes for drug attrition. Understanding the electrophysiology (EP) of hPSC-CMs is essential but conventional manual patch-clamping is highly laborious and low-throughput. Here we adapted hPSC-CMs derived from two human embryonic stem cell (hESC) lines, HES2 and H7, for a 16-channel automated planar-recording approach for single-cell EP characterization. Automated current- and voltage-clamping, with an overall success rate of 55.0â¯Â±â¯11.3%, indicated that 90% of hPSC-CMs displayed ventricular-like action potential (AP) and the ventricular cardiomyocytes (VCMs) derived from the two hESC lines expressed similar levels of INa, ICaL, Ikr and If and similarly lacked Ito and IK1. These well-characterized hPSC-VCMs could also be readily adapted for automated assays of pro-arrhythmic drug screening. As an example, we showed that flecainide (FLE) induced INa blockade, leftward steady-state inactivation shift, slowed recovery from inactivation in our hPSC-VCMs. Since single-cell EP assay is insufficient to predict drug-induced reentrant arrhythmias, hPSC-VCMs were further reassembled into 2D human ventricular cardiac monolayers (hvCMLs) for multi-cellular electrophysiological assessments. Indeed, FLE significantly slowed the conduction velocity while causing AP prolongation. Our RNA-seq data suggested that cell-cell interaction enhanced the maturity of hPSC-VCMs. Taken collectively, a combinatorial approach using single-cell EP and hvCMLs is needed to comprehensively assess drug-induced arrhythmogenicity.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology Letters - Volume 294, 15 September 2018, Pages 61-72
Journal: Toxicology Letters - Volume 294, 15 September 2018, Pages 61-72
نویسندگان
Lin Geng, Chi-Wing Kong, Andy O.T. Wong, Angie Man-Yee Shum, Maggie Z.Y. Chow, Hui Che, Chenzi Zhang, Ka-Long Yau, Camie W. Chan, Wendy Keung, Ronald A. Li,