Electrophysiological and contractile function of cardiomyocytes derived from human embryonic stem cells

Blazeski, Adriana; Zhu, Renjun; Hunter, David W.; Weinberg, Seth H.; Boheler, Kenneth R.; Zambidis, Elias T.; Tung, Leslie

doi:10.1016/j.pbiomolbio.2012.07.012

Cited by 69 publications

(53 citation statements)

References 213 publications

(465 reference statements)

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“…Finally, introducing voltage transients derived from human cardiac myocyte APs in VSFP2.3 mouse cardiac myocytes provided conceptual evidence for the suitability of cardiac myocyte-targeted VSFP2.3 in monitoring cardiac myocyte APs in species with intrinsically slower repolarization (APD 90 , ≈300 ms in human versus <100 ms in mouse). [35][36][37][38] Targeting of VSFP2.3 to the sarcolemma is essential for its voltage-dependent activity and may even allow for the analysis of sarcolemma-associated subcompartments such as t-tubules by super-resolution microscopy 39 using biophysically optimized fluorochromes (ie, with enhanced stability under high-power laser excitation and reduction in physical size). A particularly exciting application could be the parallel optical assessment of membrane voltage changes and calcium release events at the sarcolemma/SR dyads.…”

Section: Discussionmentioning

confidence: 99%

Sensing Cardiac Electrical Activity With a Cardiac Myocyte–Targeted Optogenetic Voltage Indicator

Liao

Boer

Mutoh

et al. 2015

Circulation Research

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Rationale: Monitoring and controlling cardiac myocyte activity with optogenetic tools offer exciting possibilities for fundamental and translational cardiovascular research. Genetically encoded voltage indicators may be particularly attractive for minimal invasive and repeated assessments of cardiac excitation from the cellular to the whole heart level. Objective: To test the hypothesis that cardiac myocyte–targeted voltage-sensitive fluorescence protein 2.3 (VSFP2.3) can be exploited as optogenetic tool for the monitoring of electric activity in isolated cardiac myocytes and the whole heart as well as function and maturity in induced pluripotent stem cell–derived cardiac myocytes. Methods and Results: We first generated mice with cardiac myocyte–restricted expression of VSFP2.3 and demonstrated distinct localization of VSFP2.3 at the t-tubulus/junctional sarcoplasmic reticulum microdomain without any signs for associated pathologies (assessed by echocardiography, RNA-sequencing, and patch clamping). Optically recorded VSFP2.3 signals correlated well with membrane voltage measured simultaneously by patch clamping. The use of VSFP2.3 for human action potential recordings was confirmed by simulation of immature and mature action potentials in murine VSFP2.3 cardiac myocytes. Optical cardiograms could be monitored in whole hearts ex vivo and minimally invasively in vivo via fiber optics at physiological heart rate (10 Hz) and under pacing-induced arrhythmia. Finally, we reprogrammed tail-tip fibroblasts from transgenic mice and used the VSFP2.3 sensor for benchmarking functional and structural maturation in induced pluripotent stem cell–derived cardiac myocytes. Conclusions: We introduce a novel transgenic voltage-sensor model as a new method in cardiovascular research and provide proof of concept for its use in optogenetic sensing of physiological and pathological excitation in mature and immature cardiac myocytes in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Sensing Cardiac Electrical Activity With a Cardiac Myocyte–Targeted Optogenetic Voltage Indicator

Liao

Boer

Mutoh

et al. 2015

Circulation Research

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“…For each film, a minimum of three recordings were taken with an average length of 10 sec at a rate of approximately 500 frames per second. Data was analyzed using a modified version of a previously established MATLAB (MathWorks, Natick, MA) script[37][38][39]. Using this script, calcium transient velocity, calcium transient duration (time to 50% recovery), and calcium wave frequency were quantified for each condition (n = 3 to 4).…”

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confidence: 99%

Conductive interpenetrating networks of polypyrrole and polycaprolactone encourage electrophysiological development of cardiac cells

et al. 2015

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Current conductive materials for use in cardiac regeneration are limited by cytotoxicity or cost in implementation. In this manuscript, we demonstrate for the first time the application of a biocompatible, conductive polypyrrole-polycaprolactone film as a platform for culturing cardiomyocytes for cardiac regeneration. This study shows that the novel conductive film is capable of enhancing cell-cell communication through the formation of connexin-43, leading to higher velocities for calcium wave propagation and reduced calcium transient durations among cultured cardiomyocyte monolayers. Furthermore, it was demonstrated that chemical modification of polycaprolactone through alkaline-mediated hydrolysis increased overall cardiomyocyte adhesion. The results of this study provide insight into how cardiomyocytes interact with conductive substrates and will inform future research efforts to enhance the functional properties of cardiomyocytes, which is critical for their use in pharmaceutical testing and cell therapy.

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“…Generally, hESC-CMs have been found to be immature in both cellular structure and electrophysiology [5], [15], [16]. The cells usually have a small and rounded morphology, less organized sarcomere [5] and possess immature calcium handling mechanisms [17].…”

Section: Introductionmentioning

confidence: 99%

Automated Grouping of Action Potentials of Human Embryonic Stem Cell-Derived Cardiomyocytes

Gorospe

Zhu

Millrod

et al. 2014

IEEE Trans. Biomed. Eng.

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Methods for obtaining cardiomyocytes from human embryonic stem cells (hESCs) are improving at a significant rate. However, the characterization of these cardiomyocytes is evolving at a relatively slower rate. In particular, there is still uncertainty in classifying the phenotype (ventricular-like, atrial-like, nodal-like, etc.) of an hESC-derived cardiomyocyte (hESC-CM). While previous studies identified the phenotype of a cardiomyocyte based on electrophysiological features of its action potential, the criteria for classification were typically subjective and differed across studies. In this paper, we use techniques from signal processing and machine learning to develop an automated approach to discriminate the electrophysiological differences between hESC-CMs. Specifically, we propose a spectral grouping-based algorithm to separate a population of cardiomyocytes into distinct groups based on the similarity of their action potential shapes. We applied this method to a dataset of optical maps of cardiac cell clusters dissected from human embryoid bodies (hEBs). While some of the 9 cell clusters in the dataset presented with just one phenotype, the majority of the cell clusters presented with multiple phenotypes. The proposed algorithm is generally applicable to other action potential datasets and could prove useful in investigating the purification of specific types of cardiomyocytes from an electrophysiological perspective.

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Electrophysiological and contractile function of cardiomyocytes derived from human embryonic stem cells

Cited by 69 publications

References 213 publications

Sensing Cardiac Electrical Activity With a Cardiac Myocyte–Targeted Optogenetic Voltage Indicator

Sensing Cardiac Electrical Activity With a Cardiac Myocyte–Targeted Optogenetic Voltage Indicator

Conductive interpenetrating networks of polypyrrole and polycaprolactone encourage electrophysiological development of cardiac cells

Automated Grouping of Action Potentials of Human Embryonic Stem Cell-Derived Cardiomyocytes

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