Human embryonic stem cell-derived cardiomyocytes: demonstration of a portion of cardiac cells with fairly mature electrical phenotype

被引:50
作者
Pekkanen-Mattila, Mari [1 ,2 ]
Chapman, Hugh [3 ]
Kerkela, Erja [1 ,2 ]
Suuronen, Riitta [1 ,2 ,4 ,5 ]
Skottman, Heli [1 ,2 ]
Koivisto, Ari-Pekka [3 ]
Aalto-Setala, Katriina [1 ,2 ,6 ]
机构
[1] Univ Tampere, Inst Regenerat Med, REGEA, Tampere 33520, Finland
[2] Tampere Univ Hosp, Tampere, Finland
[3] Orion Corp Farmos, Orion Pharma, Dept In Vitro Pharmacol, FIN-20101 Turku, Finland
[4] Tampere Univ Technol, Dept Biomed Engn, FIN-33101 Tampere, Finland
[5] Tampere Univ Hosp, Dept Eye Ear & Oral Dis, Tampere, Finland
[6] Tampere Univ Hosp, Ctr Heart, Tampere, Finland
基金
芬兰科学院;
关键词
human embryonic stem cells; cardiomyocytes; differentiation; action potential; cell model; pharmacological testing; QT INTERVAL PROLONGATION; TORSADE-DE-POINTES; VENTRICULAR MYOCYTES; K+ CURRENT; DIFFERENTIATION; PROARRHYTHMIA; TRIANGULATION; DRUGS;
D O I
10.1258/ebm.2010.009345
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Cardiomyocytes (CMs) derived from human embryonic stem cells (hESC) provide a promising tool for the pharmaceutical industry. In this study the electrical properties and maturation of hESC-CM derived using two differentiation methods were compared and the suitability of hESC-CMs as a cell model for the assessment of drug-induced repolarization delay was evaluated. CMs were differentiated either in END-2 co-culture or by spontaneous differentiation. Action potentials (APs) were recorded from cells in spontaneously beating areas using the whole-cell patch-clamp technique. The hESC-CMs exhibited predominantly a ventricular-like phenotype with heterogeneous properties. Heterogeneity was indicative of the spectrum of hESC-CM maturation from embryonic-like with AP upstroke velocities <30 V/s and maximum diastolic potential (MDP) of close to -60 mV to more mature with values >150 V/s and -80 mV, respectively. The mean MDP was -70 mV and a significant difference was observed between the two differentiation methods (-66 versus -75 mV, P < 0.001). The age of the CMs did not correlate with phenotype maturation. The addition of the hERG blocker E-4031 and the sodium channel modulator veratridine significantly prolonged the AP duration. Furthermore, proarrhythmic indices were induced. In conclusion, the main observation was the heterogeneity in electrical properties of the hESC-CMs and this was observed with both differentiation methods. One-third of the hESC-CMs exhibited fairly mature electrophysiological properties, suggesting that mature CMs could be obtained from hESCs. However, improved differentiation methods are needed to produce homogeneous mature human CMs for pharmaceutical and toxicological applications.
引用
收藏
页码:522 / 530
页数:9
相关论文
共 29 条
[1]   Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes:: insights into molecular composition of ventricular Ito [J].
Akar, FG ;
Wu, RC ;
Deschenes, I ;
Armoundas, AA ;
Piacentino, V ;
Houser, SR ;
Tomaselli, GF .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2004, 286 (02) :H602-H609
[2]  
[Anonymous], 2005, S7B ICH
[3]   Assessing predictors of drug-induced torsade de pointes [J].
Belardinelli, L ;
Antzelevitch, C ;
Vos, MA .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2003, 24 (12) :619-625
[4]   Transcriptional and Functional Profiling of Human Embryonic Stem Cell-Derived Cardiomyocytes [J].
Cao, Feng ;
Wagner, Roger A. ;
Wilson, Kitchener D. ;
Xie, Xiaoyan ;
Fu, Ji-Dong ;
Drukker, Micha ;
Lee, Andrew ;
Li, Ronald A. ;
Gambhir, Sanjiv S. ;
Weissman, Irving L. ;
Robbins, Robert C. ;
Wu, Joseph C. .
PLOS ONE, 2008, 3 (10)
[5]   In Vitro Electrophysiological Drug Testing Using Human Embryonic Stem Cell Derived Cardiomyocytes [J].
Caspi, Oren ;
Itzhaki, Ilanit ;
Kehat, Izhak ;
Gepstein, Amira ;
Arbel, Gil ;
Huber, Irit ;
Satin, Jonathan ;
Gepstein, Lior .
STEM CELLS AND DEVELOPMENT, 2009, 18 (01) :161-172
[6]   Comparison of K+ currents in cardiac Purkinje cells isolated from rabbit and dog [J].
Dumaine, Robert ;
Cordeiro, Jonathan M. .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2007, 42 (02) :378-389
[7]   L-type calcium current reactivation contributes to arrhythmogenesis associated with action potential triangulation [J].
Guo, Donglin ;
Zhao, Xiaojing ;
Wu, Ying ;
Liu, Tengxian ;
Kowey, Peter R. ;
Yan, Gan-Xin .
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, 2007, 18 (02) :196-203
[8]   The hERG potassium channel and hERG screening for drug-induced torsades de pointes [J].
Hancox, Jules C. ;
McPate, Mark J. ;
El Harchi, Aziza ;
Zhang, Yi Hong .
PHARMACOLOGY & THERAPEUTICS, 2008, 119 (02) :118-132
[9]   Human embryonic stem cells develop into multiple types of cardiac myocytes - Action potential characterization [J].
He, JQ ;
Ma, Y ;
Lee, Y ;
Thomson, JA ;
Kamp, TJ .
CIRCULATION RESEARCH, 2003, 93 (01) :32-39
[10]  
Hondeghem LM, 2001, CIRCULATION, V103, P2004