Development and evaluation of next-generation cardiotoxicity assay based on embryonic stem cell-derived cardiomyocytes
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
In accordance with requirements of the ICH S7B safety pharmacology guidelines, numerous next-generation cardiotoxicity studies using human stem cell-derived cardiomyocytes (CMs) are being conducted globally. Although several stem cell-derived CMs are being developed for commercialization, there is insufficient research to verify if these CMs can replace animal experiments. In this study, in vitro high-efficiency CMs derived from human embryonic stem cells (hESC-CMs) were compared with Sprague-Dawley rats as in vivo experimental animals, and primary cultured in vitro rat-CMs for cardiotoxicity tests. In vivo rats were administrated with two consecutive injections of 100 mg/kg isoproterenol, 15 mg/kg doxorubicin, or 100 mg/kg nifedipine, while in vitro rat-CMs and hESC-CMs were treated with 5 μM isoproterenol, 5 μM doxorubicin, and 50 μM nifedipine. We have verified the equivalence of hESC-CMs assessments over various molecular biological markers, morphological analysis. Also, we have identified the advantages of hESC-CMs, which can distinguish between species variability, over electrophysiological analysis of ion channels against cardiac damage. Our findings demonstrate the possibility and advantage of high-efficiency hESC-CMs as next-generation cardiotoxicity assessment.
Abstract
In accordance with requirements of the ICH S7B safety pharmacology guidelines, numerous next-generation cardiotoxicity studies using human stem cell-derived cardiomyocytes (CMs) are being conducted globally. Although several stem cell-derived CMs are being developed for commercialization, there is insufficient research to verify if these CMs can replace animal experiments. In this study, in vitro high-efficiency CMs derived from human embryonic stem cells (hESC-CMs) were compared with Sprague-Dawley rats as in vivo experimental animals, and primary cultured in vitro rat-CMs for cardiotoxicity tests. In vivo rats were administrated with two consecutive injections of 100 mg/kg isoproterenol, 15 mg/kg doxorubicin, or 100 mg/kg nifedipine, while in vitro rat-CMs and hESC-CMs were treated with 5 μM isoproterenol, 5 μM doxorubicin, and 50 μM nifedipine. We have verified the equivalence of hESC-CMs assessments over various molecular biological markers, morphological analysis. Also, we have identified the advantages of hESC-CMs, which can distinguish between species variability, over electrophysiological analysis of ion channels against cardiac damage. Our findings demonstrate the possibility and advantage of high-efficiency hESC-CMs as next-generation cardiotoxicity assessment.
참고문헌 (27)
- Scannell JW, "Diagnosing the decline in pharmaceutical R&D efficiency", Nat Rev Drug Discov, 11, pp.191~200 (2012)
- "The non-clinical evaluation of the potential for delayed ventricular repolarization (Qt Interval Prolongation)by human pharmaceuticals. S7B" (2005)[URL]
- "The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. E14 4" (2006)[URL]
- Hoffmann P, "Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends", J Pharmacol Toxicol Methods, 53, pp.87~105 (2006)
- Guo L, "Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model", Toxicol Sci, 136, pp.581~594 (2013)
- Mercola M, "Induced pluripotent stem cells in cardiovascular drug discovery", Circ Res, 112, pp.534~548 (2013)
- Suter-Dick L, "Stem cell-derived systems in toxicology assessment", Stem Cells Dev, 24, pp.1284~1296 (2015)
- Palpant NJ, "Generating high-purity cardiac and endothelial derivatives from patterned mesoderm using human pluripotent stem cells", Nat Protoc, 12, pp.15~31 (2017)
- Ronaldson-Bouchard K, "Advanced maturation of human cardiac tissue grown from pluripotent stem cells", Nature, 556, pp.239~243 (2018)
- Sirenko O, "Assessment of beating parameters in human induced pluripotent stem cells enables quantiative in vitro screening for cardiotoxicity", Toxicol Appl Pharmacol, 273, pp.500~507 (2013)
- Blinova K, "International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment", Cell Rep, 24, pp.3582~3592 (2018)
- Millard D, "Cross-Site Reliability of Human Induced Pluripotent stem cell-derived Cardiomyocyte Based Safety Assays Using Microelectrode Arrays : Results from a Blinded CiPA Pilot Study", Toxicol Sci, 164, pp.550~562 (2018)
- Takasuna K, "Comprehensive in vitro cardiac safety assessment using human stem cell technology : Overview of CSAHi HEART initiative", J Pharmacol Toxicol Methods, 83, pp.42~54 (2017)
- Magdy T, "Human Induced Pluripotent Stem Cell(hiPSC)-Derived Cells to Assess Drug Cardiotoxicity : Opportunities and Problems", Annu Rev Pharmacol Toxicol, 58, pp.83~103 (2018)
- Burridge PW, "Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicininduced cardiotoxicity", Nat Med, 22, pp.547~556 (2016)
- Burridge PW, "Chemically defined generation of human cardiomyocytes", Nat Methods, 11, pp.855~860 (2014)
- Lian X, "Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling", Proc Natl Acad Sci U S A, 109, pp.E1848~1857 (2012)
- Minami I, "A small molecule that promotes cardiac differentiation of human pluripotent stem cells under defined, cytokine-and xenofree conditions", Cell Rep, 2, pp.1448~1460 (2012)
- Vandenberk B, "Which QT Correction Formulae to Use for QT Monitoring?", J Am Heart Assoc, 5, pp.e003264~ (2016)
- Sagie A, "An improved method for adjusting the QT interval for heart rate(the Framingham Heart Study)", Am J Cardiol, 70, pp.797~801 (1992)
- Park SJ, "Modification of a purification and expansion method for human embryonic stem cell-derived cardiomyocytes", Cardiology, 124, pp.139~150 (2013)
- Lee JY, "Persicarin isolated from Oenanthe javanica protects against diabetes-induced oxidative stress and inflammation in the liver of streptozotocin-induced type 1 diabetic mice", Exp Ther Med, 13, pp.1194~1202 (2017)
- Songbo M, "Oxidative stress injury in doxorubicin-induced cardiotoxicity", Toxicol Lett, 307, pp.41~48 (2019)
- Ayala A, "Lipid peroxidation : production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal", Oxid Med Cell Longev, 2014, pp.360438~ (2014)
- Janssen M, "Malondialdehyde and glutathione production in isolated perfused human and rat hearts", Circ Res, 73, pp.681~688 (1993)
- Singh Y, "Species differences in membrane susceptibility to lipid peroxidation", J Biochem Toxicol, 7, pp.97~105 (1992)
- Ruzsnavszky F, "Asynchronous activation of calcium and potassium currents by isoproterenol in canine ventricular myocytes", Naunyn Schmiedebergs Arch Pharmacol, 387, pp.457~467 (2014)