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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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Autores principales: Sakamoto, Kazufumi, Matsumoto, Suguru, Abe, Nanami, Sentoku, Mitsuru, Yasuda, Kenji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10143097/
https://www.ncbi.nlm.nih.gov/pubmed/37421087
http://dx.doi.org/10.3390/mi14040854
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author Sakamoto, Kazufumi
Matsumoto, Suguru
Abe, Nanami
Sentoku, Mitsuru
Yasuda, Kenji
author_facet Sakamoto, Kazufumi
Matsumoto, Suguru
Abe, Nanami
Sentoku, Mitsuru
Yasuda, Kenji
author_sort Sakamoto, Kazufumi
collection PubMed
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.
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spelling pubmed-101430972023-04-29 Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement Sakamoto, Kazufumi Matsumoto, Suguru Abe, Nanami Sentoku, Mitsuru Yasuda, Kenji Micromachines (Basel) Article 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. MDPI 2023-04-14 /pmc/articles/PMC10143097/ /pubmed/37421087 http://dx.doi.org/10.3390/mi14040854 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sakamoto, Kazufumi
Matsumoto, Suguru
Abe, Nanami
Sentoku, Mitsuru
Yasuda, Kenji
Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10143097/
https://www.ncbi.nlm.nih.gov/pubmed/37421087
http://dx.doi.org/10.3390/mi14040854
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