Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG

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• 作者：Malin K.B. Jonsson^a ; ^{m.k.b.jonsson@umcutrecht.nl} ; Marc A. Vos^a ; Gary R. Mirams^b ; G&ouml ; ran Duker^c ; Peter Sartipy^d ; Teun P. de Boer^a ; ¹ ; Toon A.B. van Veen^a ; ¹
• 关键词：APD ; action potential duration ; APD50/90 ; action potential duration at 50/90%of repolarization ; BVR ; beat-to-beat variability of repolarization ; EAD ; early afterdepolarization ; hESC-CM ; human embryonic stem cell-derived cardiomyocyte ; hiPSC-CM ; human ind
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2012
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：May, 2012
• 卷：52
• 期：5
• 页码：998-1008
• 文件大小：4599 K

摘要

Human embryonic stem cell-derived cardiomyocytes (hESC-CM) have been proposed as a new model for safety pharmacology. So far, a thorough description of their basic electrophysiology and extensive testing, and mechanistic explanations, of their overall pro-arrhythmic ability is lacking. Under standardized conditions, we have evaluated the sensitivity of hESC-CM to proarrhythmic provocations by blockade of hERG and other channels. Using voltage patch clamp, some ion current densities (pA/pF) in hESC-CM were comparable to adult CM: Ib>Krb> (鈭?#xA0;12.5 卤 6.9), Ib>Ksb> (0.65 卤 0.12), Ib>Na,peakb> (鈭?#xA0;72 卤 21), Ib>Na,lateb> (鈭?#xA0;1.10 卤 0.36), and Ib>Ca,Lb> (鈭?#xA0;4.3 卤 0.6). Ib>fb> density was larger (鈭?#xA0;10 卤 1.1) and Ib>K1b> not existent or very small (鈭?#xA0;2.67 卤 0.3). The low Ib>K1b> density was corroborated by low KCNJ2 mRNA levels. Effects of pro-arrhythmic compounds on action potential (AP) parameters and provocation of early afterdepolarizations (EADs) revealed that Chromanol293B (100 渭mol/l) and Bay K8644 (1 渭mol/l) both significantly prolonged APDb>90b>. ATX-II (< 1 渭mol/l ) and BaClb>2b> (10 渭mol/l ) had no effect on APD. The only compound that triggered EADs was hERG blocker Cisapride. Computer simulations and AP clamp showed that the immature AP of hESC-CM prevents proper functioning of Ib>Nab>-channels, and result in lower peak/maximal currents of several other channels, compared to the adult situation. Lack of functional Ib>K1b> channels and shifted Ib>Nab> channel activation cause a rather immature electrophysiological phenotype in hESC-CM, and thereby limits the potential of this model to respond accurately to pro-arrhythmic triggers other than hERG block. Maturation of the electrical phenotype is a prerequiste for future implementation of the model in arrhythmogenic safety testing.