Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes

Abstract Interactions between cardiac myofibroblasts and myocytes may slow conduction and generate spontaneous beating in fibrosis, increasing the chance of life-threatening arrhythmia. While co-culture studies have shown that myofibroblasts can affect cardiomyocyte electrophysiology in vitro, the e...

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Autores principales:	Geran M. Kostecki, Yu Shi, Christopher S. Chen, Daniel H. Reich, Emilia Entcheva, Leslie Tung
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e51090c71a604ba8a2fb67956066842a
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spelling	oai:doaj.org-article:e51090c71a604ba8a2fb67956066842a2021-12-02T11:35:53ZOptogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes10.1038/s41598-021-83398-42045-2322https://doaj.org/article/e51090c71a604ba8a2fb67956066842a2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83398-4https://doaj.org/toc/2045-2322Abstract Interactions between cardiac myofibroblasts and myocytes may slow conduction and generate spontaneous beating in fibrosis, increasing the chance of life-threatening arrhythmia. While co-culture studies have shown that myofibroblasts can affect cardiomyocyte electrophysiology in vitro, the extent of myofibroblast-myocyte electrical conductance in a syncytium is unknown. In this neonatal rat study, cardiac myofibroblasts were transduced with Channelrhodopsin-2, which allowed acute and selective increase of myofibroblast current, and plated on top of cardiomyocytes. Optical mapping revealed significantly decreased conduction velocity (− 27 ± 6%, p < 10–3), upstroke rate (− 13 ± 4%, p = 0.002), and action potential duration (− 14 ± 7%, p = 0.004) in co-cultures when 0.017 mW/mm2 light was applied, as well as focal spontaneous beating in 6/7 samples and a decreased cycle length (− 36 ± 18%, p = 0.002) at 0.057 mW/mm2 light. In silico modeling of the experiments reproduced the experimental findings and suggested the light levels used in experiments produced excess current similar in magnitude to endogenous myofibroblast current. Fitting the model to experimental data predicted a tissue-level electrical conductance across the 3-D interface between myofibroblasts and cardiomyocytes of ~ 5 nS/cardiomyocyte, and showed how increased myofibroblast-myocyte conductance, increased myofibroblast/myocyte capacitance ratio, and increased myofibroblast current, which occur in fibrosis, can work in tandem to produce pro-arrhythmic increases in conduction and spontaneous beating.Geran M. KosteckiYu ShiChristopher S. ChenDaniel H. ReichEmilia EntchevaLeslie TungNature 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 Geran M. Kostecki Yu Shi Christopher S. Chen Daniel H. Reich Emilia Entcheva Leslie Tung Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes
description	Abstract Interactions between cardiac myofibroblasts and myocytes may slow conduction and generate spontaneous beating in fibrosis, increasing the chance of life-threatening arrhythmia. While co-culture studies have shown that myofibroblasts can affect cardiomyocyte electrophysiology in vitro, the extent of myofibroblast-myocyte electrical conductance in a syncytium is unknown. In this neonatal rat study, cardiac myofibroblasts were transduced with Channelrhodopsin-2, which allowed acute and selective increase of myofibroblast current, and plated on top of cardiomyocytes. Optical mapping revealed significantly decreased conduction velocity (− 27 ± 6%, p < 10–3), upstroke rate (− 13 ± 4%, p = 0.002), and action potential duration (− 14 ± 7%, p = 0.004) in co-cultures when 0.017 mW/mm2 light was applied, as well as focal spontaneous beating in 6/7 samples and a decreased cycle length (− 36 ± 18%, p = 0.002) at 0.057 mW/mm2 light. In silico modeling of the experiments reproduced the experimental findings and suggested the light levels used in experiments produced excess current similar in magnitude to endogenous myofibroblast current. Fitting the model to experimental data predicted a tissue-level electrical conductance across the 3-D interface between myofibroblasts and cardiomyocytes of ~ 5 nS/cardiomyocyte, and showed how increased myofibroblast-myocyte conductance, increased myofibroblast/myocyte capacitance ratio, and increased myofibroblast current, which occur in fibrosis, can work in tandem to produce pro-arrhythmic increases in conduction and spontaneous beating.
format	article
author	Geran M. Kostecki Yu Shi Christopher S. Chen Daniel H. Reich Emilia Entcheva Leslie Tung
author_facet	Geran M. Kostecki Yu Shi Christopher S. Chen Daniel H. Reich Emilia Entcheva Leslie Tung
author_sort	Geran M. Kostecki
title	Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes
title_short	Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes
title_full	Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes
title_fullStr	Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes
title_full_unstemmed	Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes
title_sort	optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e51090c71a604ba8a2fb67956066842a
work_keys_str_mv	AT geranmkostecki optogeneticcurrentinmyofibroblastsacutelyalterselectrophysiologyandconductionofcoculturedcardiomyocytes AT yushi optogeneticcurrentinmyofibroblastsacutelyalterselectrophysiologyandconductionofcoculturedcardiomyocytes AT christopherschen optogeneticcurrentinmyofibroblastsacutelyalterselectrophysiologyandconductionofcoculturedcardiomyocytes AT danielhreich optogeneticcurrentinmyofibroblastsacutelyalterselectrophysiologyandconductionofcoculturedcardiomyocytes AT emiliaentcheva optogeneticcurrentinmyofibroblastsacutelyalterselectrophysiologyandconductionofcoculturedcardiomyocytes AT leslietung optogeneticcurrentinmyofibroblastsacutelyalterselectrophysiologyandconductionofcoculturedcardiomyocytes
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Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes

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