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Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

Three-dimensional (3D) microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional monolayer cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of hum...

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Autores principales: Lee-Montiel, Felipe T., Laemmle, Alexander, Charwat, Verena, Dumont, Laure, Lee, Caleb S., Huebsch, Nathaniel, Okochi, Hideaki, Hancock, Matthew J., Siemons, Brian, Boggess, Steven C., Goswami, Ishan, Miller, Evan W., Willenbring, Holger, Healy, Kevin E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138446/
https://www.ncbi.nlm.nih.gov/pubmed/34025426
http://dx.doi.org/10.3389/fphar.2021.667010
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author Lee-Montiel, Felipe T.
Laemmle, Alexander
Charwat, Verena
Dumont, Laure
Lee, Caleb S.
Huebsch, Nathaniel
Okochi, Hideaki
Hancock, Matthew J.
Siemons, Brian
Boggess, Steven C.
Goswami, Ishan
Miller, Evan W.
Willenbring, Holger
Healy, Kevin E.
author_facet Lee-Montiel, Felipe T.
Laemmle, Alexander
Charwat, Verena
Dumont, Laure
Lee, Caleb S.
Huebsch, Nathaniel
Okochi, Hideaki
Hancock, Matthew J.
Siemons, Brian
Boggess, Steven C.
Goswami, Ishan
Miller, Evan W.
Willenbring, Holger
Healy, Kevin E.
author_sort Lee-Montiel, Felipe T.
collection PubMed
description Three-dimensional (3D) microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional monolayer cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS—both created with the same hiPSC line—to study drug–drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish integration of hiPSC-based liver and cardiac MPSs to facilitate screening for DDI, and thus drug efficacy and toxicity, isogenic in the same genetic background.
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spelling pubmed-81384462021-05-22 Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction Lee-Montiel, Felipe T. Laemmle, Alexander Charwat, Verena Dumont, Laure Lee, Caleb S. Huebsch, Nathaniel Okochi, Hideaki Hancock, Matthew J. Siemons, Brian Boggess, Steven C. Goswami, Ishan Miller, Evan W. Willenbring, Holger Healy, Kevin E. Front Pharmacol Pharmacology Three-dimensional (3D) microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional monolayer cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS—both created with the same hiPSC line—to study drug–drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish integration of hiPSC-based liver and cardiac MPSs to facilitate screening for DDI, and thus drug efficacy and toxicity, isogenic in the same genetic background. Frontiers Media S.A. 2021-05-07 /pmc/articles/PMC8138446/ /pubmed/34025426 http://dx.doi.org/10.3389/fphar.2021.667010 Text en Copyright © 2021 Lee-Montiel, Laemmle, Charwat, Dumont, Lee, Huebsch, Okochi, Hancock, Siemons, Boggess, Goswami, Miller, Willenbring and Healy. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Lee-Montiel, Felipe T.
Laemmle, Alexander
Charwat, Verena
Dumont, Laure
Lee, Caleb S.
Huebsch, Nathaniel
Okochi, Hideaki
Hancock, Matthew J.
Siemons, Brian
Boggess, Steven C.
Goswami, Ishan
Miller, Evan W.
Willenbring, Holger
Healy, Kevin E.
Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction
title Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction
title_full Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction
title_fullStr Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction
title_full_unstemmed Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction
title_short Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction
title_sort integrated isogenic human induced pluripotent stem cell–based liver and heart microphysiological systems predict unsafe drug–drug interaction
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138446/
https://www.ncbi.nlm.nih.gov/pubmed/34025426
http://dx.doi.org/10.3389/fphar.2021.667010
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