Mathematical modelling of the mechano-electric coupling in the human cardiomyocyte electrically connected with fibroblasts

Bazhutina, Anastasia; Balakina-Vikulova, Nathalie; Kursanov, Alexander; Solovyova, Olga; Panfilov, Alexander; Katsnelson, Leonid B.

doi:10.1016/j.pbiomolbio.2020.08.003

Cited by 15 publications

(23 citation statements)

References 53 publications

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“…Based on previous evidence, organoids enriched with hiPSC-CFs present a complex electromechanical behavior. On the one hand, CFs provide mechanical and chemical cues that are important for cellular survival and maturation. , Also, it has been reported that CFs present conductance and membrane potential different from those of the CMs, influencing in the overall electrical conduction of cardiac tissues . In consequence, it was expected that our coculture experimental group showed a slower conduction velocity.…”

Section: Methodsmentioning

confidence: 87%

“…55,57 Also, it has been reported that CFs present conductance and membrane potential different from those of the CMs, influencing in the overall electrical conduction of cardiac tissues. 64 In consequence, it was expected that our coculture experimental group showed a slower conduction velocity. These findings highlight the importance of an optimized coculture cellular ratio that can support the mechanical and chemical environment of the scaffold-free tissues but also do not hinder the desired electrophysiological properties of the organoids.…”

Section: Transcriptional Profile Of the Cardiacmentioning

confidence: 89%

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Development and Characterization of Isogenic Cardiac Organoids from Human-Induced Pluripotent Stem Cells Under Supplement Starvation Regimen

Patino-Guerrero

Wong

Kodibagkar

et al. 2022

ACS Biomater. Sci. Eng.

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The prevalence of cardiovascular risk factors is expected to increase the occurrence of cardiovascular diseases (CVDs) worldwide. Cardiac organoids are promising candidates for bridging the gap between in vitro experimentation and translational applications in drug development and cardiac repair due to their attractive features. Here we present the fabrication and characterization of isogenic scaffold-free cardiac organoids derived from human induced pluripotent stem cells (hiPSCs) formed under a supplement-deprivation regimen that allows for metabolic synchronization and maturation of hiPSC-derived cardiac cells. We propose the formation of coculture cardiac organoids that include hiPSC-derived cardiomyocytes and hiPSC-derived cardiac fibroblasts (hiPSC-CMs and hiPSC-CFs, respectively). The cardiac organoids were characterized through extensive morphological assessment, evaluation of cellular ultrastructures, and analysis of transcriptomic and electrophysiological profiles. The morphology and transcriptomic profile of the organoids were improved by coculture of hiPSC-CMs with hiPSC-CFs. Specifically, upregulation of Ca2+ handling-related genes, such as RYR2 and SERCA, and structure-related genes, such as TNNT2 and MYH6, was observed. Additionally, the electrophysiological characterization of the organoids under supplement deprivation shows a trend for reduced conduction velocity for coculture organoids. These studies help us gain a better understanding of the role of other isogenic cells such as hiPSC-CFs in the formation of mature cardiac organoids, along with the introduction of exogenous chemical cues, such as supplement starvation.

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Section: Methodsmentioning

confidence: 87%

Section: Transcriptional Profile Of the Cardiacmentioning

confidence: 89%

Development and Characterization of Isogenic Cardiac Organoids from Human-Induced Pluripotent Stem Cells Under Supplement Starvation Regimen

Patino-Guerrero

Wong

Kodibagkar

et al. 2022

ACS Biomater. Sci. Eng.

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show abstract

“…It includes the MEF in each of these two cell types: the lengthdependent dissociation of CaTnC complexes leading to the length dependence of AP in the myocyte, and the mechanosensitive ion channels in fibroblasts (MSC-FB). This model is a further development of our earlier published model describing only the electrical interaction between electromechanically active human cardiomyocyte and cardiac fibroblasts (Bazhutina et al, 2021). The earlier simulation shows that the electrical interaction significantly affects not only the electrical but also the mechanical function of the cardiomyocyte.…”

Section: Introductionmentioning

confidence: 78%

“…The earlier simulation shows that the electrical interaction significantly affects not only the electrical but also the mechanical function of the cardiomyocyte. However, the electrical interaction itself had no effect on the lengthdependence of the RP in both myocytes and fibroblasts (Bazhutina et al, 2021). Now we have added to this model a description of the mechanical interaction between myocyte and fibroblasts and a description of MSC-FB.…”

Section: Introductionmentioning

confidence: 99%

In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia

Kursanov

Balakina-Vikulova²,

Solovyova³

et al. 2023

Front. Physiol.

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Although fibroblasts are about 5–10 times smaller than cardiomyocytes, their number in the ventricle is about twice that of cardiomyocytes. The high density of fibroblasts in myocardial tissue leads to a noticeable effect of their electromechanical interaction with cardiomyocytes on the electrical and mechanical functions of the latter. Our work focuses on the analysis of the mechanisms of spontaneous electrical and mechanical activity of the fibroblast-coupled cardiomyocyte during its calcium overload, which occurs in a variety of pathologies, including acute ischemia. For this study, we developed a mathematical model of the electromechanical interaction between cardiomyocyte and fibroblasts and used it to simulate the impact of overloading cardiomyocytes. In contrast to modeling only the electrical interaction between cardiomyocyte and fibroblasts, the following new features emerge in simulations with the model that accounts for both electrical and mechanical coupling and mechano-electrical feedback loops in the interacting cells. First, the activity of mechanosensitive ion channels in the coupled fibroblasts depolarizes their resting potential. Second, this additional depolarization increases the resting potential of the coupled myocyte, thus augmenting its susceptibility to triggered activity. The triggered activity associated with the cardiomyocyte calcium overload manifests itself in the model either as early afterdepolarizations or as extrasystoles, i.e., extra action potentials and extra contractions. Analysis of the model simulations showed that mechanics contribute significantly to the proarrhythmic effects in the cardiomyocyte overloaded with calcium and coupled with fibroblasts, and that mechano-electrical feedback loops in both the cardiomyocyte and fibroblasts play a key role in this phenomenon.

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“…However, few studies have attempted to investigate the functional impacts of myocyte-fibroblast coupling on the mechanical activities of cardiac tissue and most previous studies have focused on the investigation of the electrical consequence of the coupling. In their study, Bazhutina et al (2021a) , Bazutina et al (2021b) investigated at the single cell level how the electrotonic interaction with fibroblasts affects the mechanical activity of cardiomyocyte, resulting in reduction of contractility manifested by reduced cell length shortening and the product of active force. These compromising effects of FMEC on cardiac electromechanics were enhanced by increasing number of coupled fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Effects of fibroblast on electromechanical dynamics of human atrial tissue—insights from a 2D discrete element model

Brocklehurst

Zhang²,

Ye³

2022

Front. Physiol.

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Roughly 75% of normal myocardial tissue volume is comprised of myocytes, however, fibroblasts by number are the most predominant cells in cardiac tissue. Previous studies have shown distinctive differences in cellular electrophysiology and excitability between myocytes and fibroblasts. However, it is still unclear how the electrical coupling between the two and the increased population of fibroblasts affects the electromechanical dynamics of cardiac tissue. This paper focuses on investigating effects of fibroblast-myocyte electrical coupling (FMEC) and fibroblast population on atrial electrical conduction and mechanical contractility by using a two-dimensional Discrete Element Method (DEM) model of cardiac tissue that is different to finite element method (FEM). In the model, the electro-mechanics of atrial cells are modelled by a biophysically detailed model for atrial electrical action potentials and myofilament kinetics, and the atrial fibroblasts are modelled by an active model that considers four active membrane ionic channel currents. Our simulation results show that the FMEC impairs myocytes’ electrical action potential and mechanical contractibility, manifested by reduced upstroke velocity, amplitude and duration of action potentials, as well as cell length shortening. At the tissue level, the FMEC slows down the conduction of excitation waves, and reduces strain of the tissue produced during a contraction course. These findings provide new insights into understandings of how FMEC impairs cardiac electrical and mechanical dynamics of the heart.

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Mathematical modelling of the mechano-electric coupling in the human cardiomyocyte electrically connected with fibroblasts

Cited by 15 publications

References 53 publications

Development and Characterization of Isogenic Cardiac Organoids from Human-Induced Pluripotent Stem Cells Under Supplement Starvation Regimen

Development and Characterization of Isogenic Cardiac Organoids from Human-Induced Pluripotent Stem Cells Under Supplement Starvation Regimen

In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia

Effects of fibroblast on electromechanical dynamics of human atrial tissue—insights from a 2D discrete element model

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