Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement
One of the advantages of human stem cell-derived cell-based preclinical screening is the reduction of the false negative/positive misjudgment of lead compounds for predicting their effectiveness and risks during the early stage of development. However, as the community effect of cells was neglected...
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MDPI AG
2023-04-01
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| Series: | Micromachines |
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| Online Access: | https://www.mdpi.com/2072-666X/14/4/854 |
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| author | Kazufumi Sakamoto Suguru Matsumoto Nanami Abe Mitsuru Sentoku Kenji Yasuda |
| author_facet | Kazufumi Sakamoto Suguru Matsumoto Nanami Abe Mitsuru Sentoku Kenji Yasuda |
| author_sort | Kazufumi Sakamoto |
| collection | DOAJ |
| description | One of the advantages of human stem cell-derived cell-based preclinical screening is the reduction of the false negative/positive misjudgment of lead compounds for predicting their effectiveness and risks during the early stage of development. However, as the community effect of cells was neglected in the conventional single cell-based in vitro screening, the potential difference in results caused by the cell number and their spatial arrangement differences has not yet been sufficiently evaluated. Here, we have investigated the effect of the community size and spatial arrangement difference for cardiomyocyte network response against the proarrhythmic compounds from the viewpoint of in vitro cardiotoxicity. Using three different typical types of cell networks of cardiomyocytes, small cluster, large square sheet, and large closed-loop sheet were formed in shaped agarose microchambers fabricated on a multielectrode array chip simultaneously, and their responses were compared against the proarrhythmic compound, E-4031. The interspike intervals (ISIs) in large square sheets and closed-loop sheets were durable and maintained stable against E-4031 even at a high dose of 100 nM. In contrast, those in the small cluster, which fluctuated even without E-4031, acquired stable beating reflecting the antiarrhythmic efficacy of E-4031 from a 10 nM medium dose administration. The repolarization index, field potential duration (FPD), was prolonged in closed-loop sheets with 10 nM E-4031, even though small clusters and large sheets remained normal at this concentration. Moreover, FPDs of large sheets were the most durable against E-4031 among the three geometries of cardiomyocyte networks. The results showed the apparent spatial arrangement dependence on the stability of their interspike intervals, and FPD prolongation, indicating the importance of the geometry control of cell networks for representing the appropriate response of cardiomyocytes against the adequate amount of compounds for in vitro ion channel measurement. |
| first_indexed | 2024-03-11T04:44:13Z |
| format | Article |
| id | doaj.art-fe8c565c93e146aba59a82a22a994eae |
| institution | Directory Open Access Journal |
| issn | 2072-666X |
| language | English |
| last_indexed | 2024-03-11T04:44:13Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Micromachines |
| spelling | doaj.art-fe8c565c93e146aba59a82a22a994eae2023-11-17T20:30:20ZengMDPI AGMicromachines2072-666X2023-04-0114485410.3390/mi14040854Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity MeasurementKazufumi Sakamoto0Suguru Matsumoto1Nanami Abe2Mitsuru Sentoku3Kenji Yasuda4Department of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, JapanDepartment of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, JapanDepartment of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, JapanDepartment of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, JapanDepartment of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, JapanOne of the advantages of human stem cell-derived cell-based preclinical screening is the reduction of the false negative/positive misjudgment of lead compounds for predicting their effectiveness and risks during the early stage of development. However, as the community effect of cells was neglected in the conventional single cell-based in vitro screening, the potential difference in results caused by the cell number and their spatial arrangement differences has not yet been sufficiently evaluated. Here, we have investigated the effect of the community size and spatial arrangement difference for cardiomyocyte network response against the proarrhythmic compounds from the viewpoint of in vitro cardiotoxicity. Using three different typical types of cell networks of cardiomyocytes, small cluster, large square sheet, and large closed-loop sheet were formed in shaped agarose microchambers fabricated on a multielectrode array chip simultaneously, and their responses were compared against the proarrhythmic compound, E-4031. The interspike intervals (ISIs) in large square sheets and closed-loop sheets were durable and maintained stable against E-4031 even at a high dose of 100 nM. In contrast, those in the small cluster, which fluctuated even without E-4031, acquired stable beating reflecting the antiarrhythmic efficacy of E-4031 from a 10 nM medium dose administration. The repolarization index, field potential duration (FPD), was prolonged in closed-loop sheets with 10 nM E-4031, even though small clusters and large sheets remained normal at this concentration. Moreover, FPDs of large sheets were the most durable against E-4031 among the three geometries of cardiomyocyte networks. The results showed the apparent spatial arrangement dependence on the stability of their interspike intervals, and FPD prolongation, indicating the importance of the geometry control of cell networks for representing the appropriate response of cardiomyocytes against the adequate amount of compounds for in vitro ion channel measurement.https://www.mdpi.com/2072-666X/14/4/854cardiomyocytepredictive toxicitysynchronizationgeometry dependencecommunity effect |
| spellingShingle | Kazufumi Sakamoto Suguru Matsumoto Nanami Abe Mitsuru Sentoku Kenji Yasuda Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement Micromachines cardiomyocyte predictive toxicity synchronization geometry dependence community effect |
| title | Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement |
| title_full | Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement |
| title_fullStr | Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement |
| title_full_unstemmed | Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement |
| title_short | Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement |
| title_sort | importance of spatial arrangement of cardiomyocyte network for precise and stable on chip predictive cardiotoxicity measurement |
| topic | cardiomyocyte predictive toxicity synchronization geometry dependence community effect |
| url | https://www.mdpi.com/2072-666X/14/4/854 |
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