Mathematical modelling of the action potential of human embryonic stem cell derived cardiomyocytes

Paci, Michelangelo; Sartiani, Laura; Lungo, Martina Del; Jaconi, Marisa; Mugelli, Alessandro; Cerbai, Elisabetta; Severi, Stefano

doi:10.1186/1475-925x-11-61

Cited by 25 publications

(18 citation statements)

References 54 publications

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“…In this line, the hypothesis of a progressive clustering of HCN4 channels into caveolae and the interaction with the Cav3 protein during maturation of hESC-CM fully agrees with our previous data demonstrating that the frequency of spontaneous action potentials and the rate of the diastolic depolarization phase slows down during hESC-CM maturation [4,21].…”

Section: Discussionsupporting

confidence: 91%

Molecular and Functional Evidence of HCN4 and Caveolin-3 Interaction During Cardiomyocyte Differentiation from Human Embryonic Stem Cells

Bosman

Sartiani

Spinelli

et al. 2013

Stem Cells and Development

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Maturation of human embryonic stem cell-derived cardiomyocytes (hESC-CM) is accompanied by changes in ion channel expression, with relevant electrophysiological consequences. In rodent CM, the properties of hyperpolarization-activated cyclic nucleotide-gated channel (HCN)4, a major f-channel isoform, depends on the association with caveolin-3 (Cav3). To date, no information exists on changes in Cav3 expression and its associative relationship with HCN4 upon hESC-CM maturation. We hypothesize that Cav3 expression and its compartmentalization with HCN4 channels during hESC-CM maturation accounts for the progression of f-current properties toward adult phenotypes. To address this, hESC were differentiated into spontaneously beating CM and examined at *30, *60, and *110 days of differentiation. Human adult and fetal CM served as references. HCN4 and Cav3 expression and localization were analyzed by real time PCR and immunocyto/histochemistry. F-current was measured in patch-clamped single cells. HCN4 and Cav3 colocalize in adult human atrial and ventricular CM, but not in fetal CM. Proteins and mRNA for Cav3 were not detected in undifferentiated hESC, but expression increased during hESC-CM maturation. At 110 days, HCN4 appeared to be colocalized with Cav3. Voltage-dependent activation of the f-current was significantly more positive in fetal CM and 60-day hESC-CM (midpoint activation, V 1/2 , * -82 mV) than in 110-day hESC-CM or adult CM (V 1/2 *-100 mV). In the latter cells, caveolae disruption reversed voltage dependence toward a more positive or an immature phenotype, with V 1/2 at -75 mV, while in fetal CM voltage dependence was not affected. Our data show, for the first time, a developmental change in HCN4-Cav3 association in hESC-CM. Cav3 expression and its association with ionic channels likely represent a crucial step of cardiac maturation.

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Section: Discussionsupporting

confidence: 91%

Molecular and Functional Evidence of HCN4 and Caveolin-3 Interaction During Cardiomyocyte Differentiation from Human Embryonic Stem Cells

Bosman

Sartiani

Spinelli

et al. 2013

Stem Cells and Development

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“…The result is that current mathematical AP models of hPSC‐CMs (Paci et al , 2013, 2015, 2012) still represent a fraction of the heterogeneity that has been experimentally observed in literature, although their usefulness and predictivity are beyond doubt (Figure 3). In this context, the coordination and promotion of standard methodologies for phenotypic characterization of differentiated cells may come from cell banks.…”

Section: Assays and Readoutsmentioning

confidence: 95%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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“…11. According to the action potential in contractile cells (48)(49)(50)(51), and for the purpose of easy calculation, the parameter of peak value A in the model of the assumptive A p is set to be 110 mV, and the conversion factor a in Eq. 11 is 0.01.…”

Section: Theoretical Modelmentioning

confidence: 99%

Dynamic Model for Characterizing Contractile Behaviors and Mechanical Properties of a Cardiomyocyte

Zhang

Wang

et al. 2018

Biophysical Journal

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Studies on the contractile dynamics of heart cells have attracted broad attention for the development of both heart disease therapies and cardiomyocyte-actuated micro-robotics. In this study, a linear dynamic model of a single cardiomyocyte cell was proposed at the subcellular scale to characterize the contractile behaviors of heart cells, with system parameters representing the mechanical properties of the subcellular components of living cardiomyocytes. The system parameters of the dynamic model were identified with the cellular beating pattern measured by a scanning ion conductance microscope. The experiments were implemented with cardiomyocytes in one control group and two experimental groups with the drugs cytochalasin-D or nocodazole, to identify the system parameters of the model based on scanning ion conductance microscope measurements, measurement of the cellular Young's modulus with atomic force microscopy indentation, measurement of cellular contraction forces using the micro-pillar technique, and immunofluorescence staining and imaging of the cytoskeleton. The proposed mathematical model was both indirectly and qualitatively verified by the variation in cytoskeleton, beating amplitude, and contractility of cardiomyocytes among the control and the experimental groups, as well as directly and quantitatively validated by the simulation and the significant consistency of 90.5% in the comparison between the ratios of the Young's modulus and the equivalent comprehensive cellular elasticities of cells in the experimental groups to those in the control group. Apart from mechanical properties (mass, elasticity, and viscosity) of subcellular structures, other properties of cardiomyocytes have also been studied, such as the properties of the relative action potential pattern and cellular beating frequency. This work has potential implications for research on cytobiology, drug screening, mechanisms of the heart, and cardiomyocyte-based bio-syncretic robotics.

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Mathematical modelling of the action potential of human embryonic stem cell derived cardiomyocytes

Cited by 25 publications

References 54 publications

Molecular and Functional Evidence of HCN4 and Caveolin-3 Interaction During Cardiomyocyte Differentiation from Human Embryonic Stem Cells

Molecular and Functional Evidence of HCN4 and Caveolin-3 Interaction During Cardiomyocyte Differentiation from Human Embryonic Stem Cells

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Dynamic Model for Characterizing Contractile Behaviors and Mechanical Properties of a Cardiomyocyte

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