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Required G(K1) to Suppress Automaticity of iPSC-CMs Depends Strongly on I(K1) Model Structure

Human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) are a virtually endless source of human cardiomyocytes that may become a great tool for safety pharmacology; however, their electrical phenotype is immature: they show spontaneous action potentials (APs) and an unstable and depo...

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Autores principales: Fabbri, Alan, Goversen, Birgit, Vos, Marc A., van Veen, Toon A.B., de Boer, Teun P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Biophysical Society 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990378/
https://www.ncbi.nlm.nih.gov/pubmed/31623886
http://dx.doi.org/10.1016/j.bpj.2019.08.040
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author Fabbri, Alan
Goversen, Birgit
Vos, Marc A.
van Veen, Toon A.B.
de Boer, Teun P.
author_facet Fabbri, Alan
Goversen, Birgit
Vos, Marc A.
van Veen, Toon A.B.
de Boer, Teun P.
author_sort Fabbri, Alan
collection PubMed
description Human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) are a virtually endless source of human cardiomyocytes that may become a great tool for safety pharmacology; however, their electrical phenotype is immature: they show spontaneous action potentials (APs) and an unstable and depolarized resting membrane potential (RMP) because of lack of I(K1). Such immaturity hampers their application in assessing drug safety. The electronic overexpression of I(K1) (e.g., through the dynamic clamp (DC) technique) is an option to overcome this deficit. In this computational study, we aim to estimate how much I(K1) is needed to bring hiPSC-CMs to a stable and hyperpolarized RMP and which mathematical description of I(K1) is most suitable for DC experiments. We compared five mature I(K1) formulations (Bett, Dhamoon, Ishihara, O’Hara-Rudy, and ten Tusscher) with the native one (Paci), evaluating the main properties (outward peak, degree of rectification), and we quantified their effects on AP features (RMP, [Formula: see text] , APD(50), APD(90) (AP duration at 50 and 90% of repolarization), and APD(50)/APD(90)) after including them in the hiPSC-CM mathematical model by Paci. Then, we automatically identified the critical conductance for I(K1) ( G(K1, critical)), the minimally required amount of I(K1) suppressing spontaneous activity. Preconditioning the cell model with depolarizing/hyperpolarizing prepulses allowed us to highlight time dependency of the I(K1) formulations. Simulations showed that inclusion of mature I(K1) formulations resulted in hyperpolarized RMP and higher [Formula: see text] , and observed G(K1, critical) and the effect on AP duration strongly depended on I(K1) formulation. Finally, the Ishihara I(K1) led to shorter (−16.3%) and prolonged (+6.5%) APD(90) in response to hyperpolarizing and depolarizing prepulses, respectively, whereas other models showed negligible effects. Fine-tuning of G(K1) is an important step in DC experiments. Our computational work proposes a procedure to automatically identify how much I(K1) current is required to inject to stop the spontaneous activity and suggests the use of the Ishihara I(K1) model to perform DC experiments in hiPSC-CMs.
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spelling pubmed-69903782020-10-10 Required G(K1) to Suppress Automaticity of iPSC-CMs Depends Strongly on I(K1) Model Structure Fabbri, Alan Goversen, Birgit Vos, Marc A. van Veen, Toon A.B. de Boer, Teun P. Biophys J Articles Human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) are a virtually endless source of human cardiomyocytes that may become a great tool for safety pharmacology; however, their electrical phenotype is immature: they show spontaneous action potentials (APs) and an unstable and depolarized resting membrane potential (RMP) because of lack of I(K1). Such immaturity hampers their application in assessing drug safety. The electronic overexpression of I(K1) (e.g., through the dynamic clamp (DC) technique) is an option to overcome this deficit. In this computational study, we aim to estimate how much I(K1) is needed to bring hiPSC-CMs to a stable and hyperpolarized RMP and which mathematical description of I(K1) is most suitable for DC experiments. We compared five mature I(K1) formulations (Bett, Dhamoon, Ishihara, O’Hara-Rudy, and ten Tusscher) with the native one (Paci), evaluating the main properties (outward peak, degree of rectification), and we quantified their effects on AP features (RMP, [Formula: see text] , APD(50), APD(90) (AP duration at 50 and 90% of repolarization), and APD(50)/APD(90)) after including them in the hiPSC-CM mathematical model by Paci. Then, we automatically identified the critical conductance for I(K1) ( G(K1, critical)), the minimally required amount of I(K1) suppressing spontaneous activity. Preconditioning the cell model with depolarizing/hyperpolarizing prepulses allowed us to highlight time dependency of the I(K1) formulations. Simulations showed that inclusion of mature I(K1) formulations resulted in hyperpolarized RMP and higher [Formula: see text] , and observed G(K1, critical) and the effect on AP duration strongly depended on I(K1) formulation. Finally, the Ishihara I(K1) led to shorter (−16.3%) and prolonged (+6.5%) APD(90) in response to hyperpolarizing and depolarizing prepulses, respectively, whereas other models showed negligible effects. Fine-tuning of G(K1) is an important step in DC experiments. Our computational work proposes a procedure to automatically identify how much I(K1) current is required to inject to stop the spontaneous activity and suggests the use of the Ishihara I(K1) model to perform DC experiments in hiPSC-CMs. The Biophysical Society 2019-12-17 2019-09-13 /pmc/articles/PMC6990378/ /pubmed/31623886 http://dx.doi.org/10.1016/j.bpj.2019.08.040 Text en © 2019 Biophysical Society. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Articles
Fabbri, Alan
Goversen, Birgit
Vos, Marc A.
van Veen, Toon A.B.
de Boer, Teun P.
Required G(K1) to Suppress Automaticity of iPSC-CMs Depends Strongly on I(K1) Model Structure
title Required G(K1) to Suppress Automaticity of iPSC-CMs Depends Strongly on I(K1) Model Structure
title_full Required G(K1) to Suppress Automaticity of iPSC-CMs Depends Strongly on I(K1) Model Structure
title_fullStr Required G(K1) to Suppress Automaticity of iPSC-CMs Depends Strongly on I(K1) Model Structure
title_full_unstemmed Required G(K1) to Suppress Automaticity of iPSC-CMs Depends Strongly on I(K1) Model Structure
title_short Required G(K1) to Suppress Automaticity of iPSC-CMs Depends Strongly on I(K1) Model Structure
title_sort required g(k1) to suppress automaticity of ipsc-cms depends strongly on i(k1) model structure
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990378/
https://www.ncbi.nlm.nih.gov/pubmed/31623886
http://dx.doi.org/10.1016/j.bpj.2019.08.040
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