Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG
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 standar...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2012
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| _version_ | 1826274591770673152 |
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| author | Jonsson, M Vos, M Mirams, G Duker, G Sartipy, P De Boer, T Van Veen, T |
| author_facet | Jonsson, M Vos, M Mirams, G Duker, G Sartipy, P De Boer, T Van Veen, T |
| author_sort | Jonsson, M |
| collection | OXFORD |
| description | 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: I Kr (-12.5±6.9), I Ks (0.65±0.12), I Na,peak (-72±21), I Na,late (-1.10±0.36), and I Ca,L (-4.3±0.6). I f density was larger (-10±1.1) and I K1 not existent or very small (-2.67±0.3). The low I K1 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 (100μmol/l) and Bay K8644 (1μmol/l) both significantly prolonged APD 90. ATX-II (<1μmol/l ) and BaCl 2 (10μmol/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 I Na-channels, and result in lower peak/maximal currents of several other channels, compared to the adult situation. Lack of functional I K1 channels and shifted I Na 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. © 2012 Elsevier Ltd. |
| first_indexed | 2024-03-06T22:45:45Z |
| format | Journal article |
| id | oxford-uuid:5d1bf64a-4b2f-4ad5-95f5-6dc713939857 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:45:45Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:5d1bf64a-4b2f-4ad5-95f5-6dc7139398572022-03-26T17:32:28ZApplication of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERGJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5d1bf64a-4b2f-4ad5-95f5-6dc713939857EnglishSymplectic Elements at Oxford2012Jonsson, MVos, MMirams, GDuker, GSartipy, PDe Boer, TVan Veen, THuman 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: I Kr (-12.5±6.9), I Ks (0.65±0.12), I Na,peak (-72±21), I Na,late (-1.10±0.36), and I Ca,L (-4.3±0.6). I f density was larger (-10±1.1) and I K1 not existent or very small (-2.67±0.3). The low I K1 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 (100μmol/l) and Bay K8644 (1μmol/l) both significantly prolonged APD 90. ATX-II (<1μmol/l ) and BaCl 2 (10μmol/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 I Na-channels, and result in lower peak/maximal currents of several other channels, compared to the adult situation. Lack of functional I K1 channels and shifted I Na 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. © 2012 Elsevier Ltd. |
| spellingShingle | Jonsson, M Vos, M Mirams, G Duker, G Sartipy, P De Boer, T Van Veen, T Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG |
| title | Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG |
| title_full | Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG |
| title_fullStr | Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG |
| title_full_unstemmed | Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG |
| title_short | Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG |
| title_sort | application of human stem cell derived cardiomyocytes in safety pharmacology requires caution beyond herg |
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