Calcium Transient Assays for Compound Screening with Human iPSC-derived Cardiomyocytes: Evaluating New Tools

Daily, Neil; Santos, Radleigh; Vecchi, Joseph T.; Kemanli, Pinar; Wakatsuki, Toshiyuki

doi:10.14302/issn.2574-4372.jesr-16-1395

Cited by 14 publications

(10 citation statements)

References 20 publications

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“…Human-induced pluripotent stem cells (iPSCs) have emerged as a powerful system to model human cardiac disease and study Ca 2+ handling [41][42][43][44]. To confirm that our findings are not restricted to the mouse model, we assessed Ca 2+ transients in spontaneously contracting clusters of cardiomyocytes generated from patientderived (SMA) and unaffected control iPSCs.…”

Section: Smn Deficiency Slows [Ca 2+ ] I Reuptake Kinetics and Reducementioning

confidence: 63%

SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs

Khayrullina

Moritz

Schooley³

et al. 2020

Skeletal Muscle

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Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of alpha motor neurons and skeletal muscle atrophy. The disease is caused by mutations of the SMN1 gene that result in reduced functional expression of survival motor neuron (SMN) protein. SMN is ubiquitously expressed, and there have been reports of cardiovascular dysfunction in the most severe SMA patients and animal models of the disease. In this study, we directly assessed the function of cardiomyocytes isolated from a severe SMA model mouse and cardiomyocytes generated from patient-derived IPSCs. Consistent with impaired cardiovascular function at the very early disease stages in mice, heart failure markers such as brain natriuretic peptide were significantly elevated. Functionally, cardiomyocyte relaxation kinetics were markedly slowed and the T 50 for Ca 2+ sequestration increased to 146 ± 4 ms in SMN-deficient cardiomyocytes from 126 ± 4 ms in wild type cells. Reducing SMN levels in cardiomyocytes from control patient IPSCs slowed calcium reuptake similar to SMA patent-derived cardiac cells. Importantly, restoring SMN increased calcium reuptake rate. Taken together, these results indicate that SMN deficiency impairs cardiomyocyte function at least partially through intracellular Ca 2+ cycling dysregulation.

show abstract

Section: Smn Deficiency Slows [Ca 2+ ] I Reuptake Kinetics and Reducementioning

confidence: 63%

SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs

Khayrullina

Moritz

Schooley³

et al. 2020

Skeletal Muscle

View full text Add to dashboard Cite

show abstract

“…Human induced pluripotent stem cells (iPSCs) have emerged as a powerful system to model human cardiac disease and study Ca 2+ handling [41][42][43][44]. To confirm that our findings are not restricted to the mouse model, we assessed Ca 2+ transients in spontaneously contracting clusters of cardiomyocytes generated from patient derived (SMA) and unaffected control iPSCs.…”

Section: Smn Deficiency Slows [Ca 2+ ] I Reuptake Kinetics and Reducementioning

confidence: 63%

SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs

Khayrullina

Moritz

Schooley

et al. 2020

Preprint

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Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of alpha motor neurons and skeletal muscle atrophy. The disease is caused by mutations of the SMN1 gene that result in reduced functional expression of survival motor neuron (SMN) protein. SMN is ubiquitously expressed and there have been reports of cardiovascular dysfunction in the most severe SMA patients and animal models of the disease. In this study, we directly assessed the function of cardiomyocytes isolated from a severe SMA model mouse and cardiomyocytes generated from patient-derived IPSCs. Consistent with impaired cardiovascular function at the very early disease stages in mice, heart failure markers such as brain natriuretic peptide were significantly elevated. Functionally, cardiomyocyte relaxation kinetics were markedly slowed and the T50 for Ca2+ sequestration increased to 146 ± 4 msec in SMN-deficient cardiomyocytes from 126 ± 4 msec in wild type cells. Reducing SMN levels in cardiomyocytes from control patient IPSCs slowed calcium reuptake similar to SMA patent derived cardiac cells. Importantly, restoring SMN increased calcium reuptake rate. Taken together, these results indicate that SMN deficiency impairs cardiomyocyte function at least partially through intracellular Ca2+ cycling dysregulation.

show abstract

“…Intracellular calcium transients link electrical excitation to contraction, and various methods have been developed to measure the kinetics of both calcium handling and contraction. For calcium handling, small molecule dyes can be used to measure calcium transient kinetics in high throughput [7,32].…”

Section: High-throughput Physiological Screening Of Cardiomyocytesmentioning

confidence: 99%

“…An exciting new paradigm in cardiovascular drug discovery is the use of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) and vascular cells to create in vitro models of human physiology. In addition, improvements in high throughput physiological assay technology make it now feasible to optically quantify action potentials [3,4], calcium transients [5–7], and cell motion [8] at scale. Despite the potential impact of these advances, there remains considerable debate as to whether the combination of these two technologies will revolutionize cardiovascular drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Will iPSC-cardiomyocytes revolutionize the discovery of drugs for heart disease?

Bruyneel

McKeithan

Feyen

et al. 2018

Current Opinion in Pharmacology

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Cardiovascular disease remains the largest single cause of mortality in the Western world, despite significant advances in clinical management over the years. Unfortunately, the development of new cardiovascular medicines is stagnating and can in part be attributed to the difficulty of screening for novel therapeutic strategies due to a lack of suitable models. The advent of human induced pluripotent stem cells and the ability to make limitless numbers of cardiomyocytes could revolutionize heart disease modeling and drug discovery. This review summarizes the state of the art in the field, describes the strengths and weaknesses of the technology, and applications where the model system would be most appropriate.

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Calcium Transient Assays for Compound Screening with Human iPSC-derived Cardiomyocytes: Evaluating New Tools

Cited by 14 publications

References 20 publications

SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs

SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs

SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs

Will iPSC-cardiomyocytes revolutionize the discovery of drugs for heart disease?

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