OptoDyCE as an automated system for high-throughput all-optical dynamic cardiac electrophysiology

Klimas, Aleksandra; Ambrosi, Christina M.; Jia, Yu; Williams, John C.; Bien, Harold; Entcheva, Emilia

doi:10.1038/ncomms11542

Cited by 141 publications

(159 citation statements)

References 41 publications

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“…Yazawa and colleagues developed a model of LQT8 (Timothy syndrome) and demonstrated that the cyclin-dependent kinase inhibitor roscovitine (Selciclib) could partially rescue the abnormal phenotypes observed in Timothy syndrome hiPSC-CMs 73 . High-throughput platforms to measure AP duration and other electrophysiologic parameters for drug screening have been reported 80 . Whether these methods have the phenotype sensitivity and/or specificity to screen for novel therapeutics is yet to be determined.…”

Section: Use Of Hipsc-derived Cardiomyocytes To Model Inherited Arrhymentioning

confidence: 99%

Modeling Inherited Arrhythmia Disorders Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Bezzerides

Zhang

2017

Circ J

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Inherited arrhythmia disorders are a group of potentially lethal diseases that remain diagnostic and management challenges. While the genetic basis for many of these disorders is well known, the pathogenicity of individual mutations and the resulting clinical outcomes are difficult to predict. Treatment options remain imperfect, and optimizing therapy for individual patients can be difficult. Recent advances in the derivation of induced pluripotent stem cells (iPSCs) from patients and creation of genetically engineered human models using CRISPR/Cas9 has the potential to dramatically advance translational arrhythmia research. In this review, we discuss the current state of modeling inherited arrhythmia disorders using human iPSC-derived cardiomyocytes. We also discuss current limitations and areas for further study.

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Section: Use Of Hipsc-derived Cardiomyocytes To Model Inherited Arrhymentioning

confidence: 99%

Modeling Inherited Arrhythmia Disorders Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Bezzerides

Zhang

2017

Circ J

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“…Recently described systems enabled simultaneous voltage and calcium imaging in free-running or electrically paced hiPSC-CM [21], optogenetic pacing and either voltage or calcium imaging [22], or optogenetic pacing with simultaneous voltage and calcium imaging [23]. …”

Section: Introductionmentioning

confidence: 99%

Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing

et al. 2017

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Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising platform for cardiac studies in vitro, and possibly for tissue repair in humans. However, hiPSC-CM cells tend to retain morphology, metabolism, patterns of gene expression, and electrophysiology similar to that of embryonic cardiomyocytes. We grew hiPSC-CM in patterned islands of different sizes and shapes, and measured the effect of island geometry on action potential waveform and calcium dynamics using optical recordings of voltage and calcium from 970 islands of different sizes. hiPSC-CM in larger islands showed electrical and calcium dynamics indicative of greater functional maturity. We then compared transcriptional signatures of the small and large islands against a developmental time course of cardiac differentiation. Although island size had little effect on expression of most genes whose levels differed between hiPSC-CM and adult primary CM, we identified a subset of genes for which island size drove the majority (58%) of the changes associated with functional maturation. Finally, we patterned hiPSC-CM on islands with a variety of shapes to probe the relative contributions of soluble factors, electrical coupling, and direct cell-cell contacts to the functional maturation. Collectively, our data show that optical electrophysiology is a powerful tool for assaying hiPSC-CM maturation, and that island size powerfully drives activation of a subset of genes involved in cardiac maturation.

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“…In contrast, transmembrane voltage signals obtained using voltage-sensing optical techniques provides an efficient approach to assess the electrophysiological characteristics of hiPSC-CM at both baseline and following the addition of drug. Furthermore, voltage-sensitive fluorescent indicators have previously been used to accurately monitor electrical activity in cardiac cells (Dempsey et al , 2016; Klimas et al , 2016), and this capability offers significant potential when applied to monitoring electrical activity in hiPSC-CM. This combination of instrument plus indicator offers a robust platform on which to advance the use of hiPSC-CM within the proposed guidelines of CiPA.…”

mentioning

confidence: 99%

The Use of Ratiometric Fluorescence Measurements of the Voltage Sensitive Dye Di-4-ANEPPS to Examine Action Potential Characteristics and Drug Effects on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

et al. 2016

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Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and higher throughput platforms have emerged as potential tools to advance cardiac drug safety screening. This study evaluated the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM. Human iPSC-CM from 2 commercial sources (Cor.4U and iCell Cardiomyocytes) were stained with the VSD di-4-ANEPPS and placed in a specialized photometry system that simultaneously monitors 2 wavebands of emitted fluorescence, allowing ratiometric measurement of membrane voltage. Signals were acquired at 10 kHz and analyzed using custom software. Action potential duration (APD) values were normally distributed in cardiomyocytes (CMC) from both sources though the mean and variance differed significantly (APD90: 229 ± 15 ms vs 427 ± 49 ms [mean ± SD, P < 0.01]; average spontaneous cycle length: 0.99 ± 0.02 s vs 1.47 ± 0.35 s [mean ± SD, P < 0.01], Cor.4U vs iCell CMC, respectively). The 10–90% rise time of the AP (Trise) was ∼6 ms and was normally distributed when expressed as 1/normalTrise2 in both cell preparations. Both cell types showed a rate dependence analogous to that of adult human cardiac cells. Furthermore, nifedipine, ranolazine, and E4031 had similar effects on cardiomyocyte electrophysiology in both cell types. However, ranolazine and E4031 induced early after depolarization-like events and high intrinsic firing rates at lower concentrations in iCell CMC. These data show that VSDs provide a minimally invasive, quantitative, and accurate method to assess hiPSC-CM electrophysiology and detect subtle drug-induced effects for drug safety screening while highlighting a need to standardize experimental protocols across preparations.

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OptoDyCE as an automated system for high-throughput all-optical dynamic cardiac electrophysiology

Cited by 141 publications

References 41 publications

Modeling Inherited Arrhythmia Disorders Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Modeling Inherited Arrhythmia Disorders Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing

The Use of Ratiometric Fluorescence Measurements of the Voltage Sensitive Dye Di-4-ANEPPS to Examine Action Potential Characteristics and Drug Effects on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

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