Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types

Abstract We hypothesized that an appropriate ratio of cardiomyocytes, fibroblasts, endothelial cells, and extracellular matrix (ECM) factors would be required for the development of three-dimensional cardiac tissues (3D-CTs) as drug screening systems. To verify this hypothesis, ECM-coated human-indu...

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Autores principales:	Maki Takeda, Shigeru Miyagawa, Emiko Ito, Akima Harada, Noriko Mochizuki-Oda, Michiya Matsusaki, Mitsuru Akashi, Yoshiki Sawa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e8d088719a1542128974b40335af742f
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spelling	oai:doaj.org-article:e8d088719a1542128974b40335af742f2021-12-02T13:20:21ZDevelopment of a drug screening system using three-dimensional cardiac tissues containing multiple cell types10.1038/s41598-021-85261-y2045-2322https://doaj.org/article/e8d088719a1542128974b40335af742f2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85261-yhttps://doaj.org/toc/2045-2322Abstract We hypothesized that an appropriate ratio of cardiomyocytes, fibroblasts, endothelial cells, and extracellular matrix (ECM) factors would be required for the development of three-dimensional cardiac tissues (3D-CTs) as drug screening systems. To verify this hypothesis, ECM-coated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), ECM-coated cardiac fibroblasts (CFs), and uncoated cardiac endothelial cells (CEs) were mixed in the following ratios: 10:0:0 (10CT), 7:2:1 (7CT), 5:4:1 (5CT), and 2:7:1 (2CT). The expression of cardiac-, fibroblasts-, and endothelial-specific markers was assessed by FACS, qPCR, and immunostaining while that of ECM-, cell adhesion-, and ion channel-related genes was examined by qPCR. Finally, the contractile properties of the tissues were evaluated in the absence or presence of E-4031 and isoproterenol. The expression of ECM- and adhesion-related genes significantly increased, while that of ion channel-related genes significantly decreased with the CF proportion. Notably, 7CT showed the greatest contractility of all 3D-CTs. When exposed to E-4031 (hERG K channel blocker), 7CT and 5CT showed significantly decreased contractility and increased QT prolongation. Moreover, 10CT and 7CT exhibited a stronger response to isoproterenol than did the other 3D-CTs. Finally, 7CT showed the highest drug sensitivity among all 3D-CTs. In conclusion, 3D-CTs with an appropriate amount of fibroblasts/endothelial cells (7CT in this study) are suitable drug screening systems, e.g. for the detection of drug-induced arrhythmia.Maki TakedaShigeru MiyagawaEmiko ItoAkima HaradaNoriko Mochizuki-OdaMichiya MatsusakiMitsuru AkashiYoshiki SawaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maki Takeda Shigeru Miyagawa Emiko Ito Akima Harada Noriko Mochizuki-Oda Michiya Matsusaki Mitsuru Akashi Yoshiki Sawa Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types
description	Abstract We hypothesized that an appropriate ratio of cardiomyocytes, fibroblasts, endothelial cells, and extracellular matrix (ECM) factors would be required for the development of three-dimensional cardiac tissues (3D-CTs) as drug screening systems. To verify this hypothesis, ECM-coated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), ECM-coated cardiac fibroblasts (CFs), and uncoated cardiac endothelial cells (CEs) were mixed in the following ratios: 10:0:0 (10CT), 7:2:1 (7CT), 5:4:1 (5CT), and 2:7:1 (2CT). The expression of cardiac-, fibroblasts-, and endothelial-specific markers was assessed by FACS, qPCR, and immunostaining while that of ECM-, cell adhesion-, and ion channel-related genes was examined by qPCR. Finally, the contractile properties of the tissues were evaluated in the absence or presence of E-4031 and isoproterenol. The expression of ECM- and adhesion-related genes significantly increased, while that of ion channel-related genes significantly decreased with the CF proportion. Notably, 7CT showed the greatest contractility of all 3D-CTs. When exposed to E-4031 (hERG K channel blocker), 7CT and 5CT showed significantly decreased contractility and increased QT prolongation. Moreover, 10CT and 7CT exhibited a stronger response to isoproterenol than did the other 3D-CTs. Finally, 7CT showed the highest drug sensitivity among all 3D-CTs. In conclusion, 3D-CTs with an appropriate amount of fibroblasts/endothelial cells (7CT in this study) are suitable drug screening systems, e.g. for the detection of drug-induced arrhythmia.
format	article
author	Maki Takeda Shigeru Miyagawa Emiko Ito Akima Harada Noriko Mochizuki-Oda Michiya Matsusaki Mitsuru Akashi Yoshiki Sawa
author_facet	Maki Takeda Shigeru Miyagawa Emiko Ito Akima Harada Noriko Mochizuki-Oda Michiya Matsusaki Mitsuru Akashi Yoshiki Sawa
author_sort	Maki Takeda
title	Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types
title_short	Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types
title_full	Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types
title_fullStr	Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types
title_full_unstemmed	Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types
title_sort	development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e8d088719a1542128974b40335af742f
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Development of a drug screening system using three-dimensional cardiac tissues containing multiple cell types

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