Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes as an in vitro model in toxicology: strengths and weaknesses for hazard identification and risk characterization

Burnett, Sarah D; Blanchette, Alexander D; Chiu, Weihsueh A.; Rusyn, Ivan

doi:10.1080/17425255.2021.1894122

Cited by 33 publications

(32 citation statements)

References 151 publications

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“…However, despite these limitations, due to the increasing prevalence of cardiovascular diseases and the increasing complexity of human exposures to chemicals, it is even more important than ever to consider and adequately test for the potential adverse cardiovascular effects of pharmaceuticals and environmental compounds. However, for drugs and other chemicals, the currently used animal models for cardiovascular endpoints do not provide sufficient information to meet both the high throughput required and human relevance needed, to be able to lower the preventable risks of cardiovascular disease from chemicals ( Burnett et al, 2021 ). The cells used in this assay by Stemina are more metabolically aligned with adult cardiomyocytes, using oxidative phosphorylation instead of glycolysis, which is particularly important as the assay’s cardiotoxicity model is based on changes in the metabolism of key metabolites important for cardiomyocyte function, including lactic acid.…”

Section: Discussionmentioning

confidence: 99%

“…Current in vitro testing strategies for cardiotoxicity predominantly focus on the compound impact on individual ion channels. In addition, pre-clinical animal models used to assess cardiotoxicity are limited due to being low throughput, costly and may lack human relevance ( Burnett et al, 2021 ). The Stemina Cardio quick Predict™ (Cardio qP ) is a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM)-based assay that predicts a test sample’s cardiotoxicity potential using changes in hiPSC-CM metabolism and cell viability.…”

Section: Introductionmentioning

confidence: 99%

“…The reported accuracy, sensitivity, and specificity of the Cardio qP assay are 86%, and 90%, respectively ( Palmer et al, 2020 ). hiPSC-CM expresses most of the human cardiac ion channels and sarcomeric proteins, some of which contribute to action potential generation and are regulated by adrenergic stimulation ( Huo et al, 2017 ; Zhao et al, 2018 ; Burnett et al, 2021 ). This assay adds significantly to other cardiac assays available when used in isolation, or as part of a combined approach, and can be used to screen test articles for potential cardiotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Predict the Cardiotoxicity Potential of Next Generation Nicotine Products

Simms

Palmer

et al. 2022

Front. Toxicol.

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Combustible cigarette smoking is an established risk factor for cardiovascular disease. By contrast, the cardiotoxicity potential of non-combustible next generation nicotine products (NGPs), which includes heated tobacco products (HTPs) and electronic vaping products (EVPs), and how this compares relative to combustible cigarettes is currently an area of scientific exploration. As such, there is a need for a rapid screening assay to assess this endpoint. The Cardio quickPredict is a metabolomics biomarker-based assay that uses human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to screen for potential structural and functional cardiac toxicants based on the changes of four metabolites, lactic acid, arachidonic acid, thymidine, and 2′-deoxycytidine. The study aims were to investigate the cardiotoxicity potential of NGPs compared to cigarettes, in addition to nicotine. To accomplish this, hiPSC-CM were exposed to smoke or aerosol bubbled PBS samples: reference cigarette (1R6F); three variants of HTP; and three EVP variants. The 1R6F bPBS was the most active, having cardiotoxic potential at 0.3–0.6% bPBS (0.4–0.9 μg/mL nicotine), followed by HTP, which displayed cardiotoxic potential at a 10 times higher concentration, 3.3% bPBS (4.1 μg/mL nicotine). Both 1R6F and HTP bPBS (at 10-fold higher concentration than 1R6F) affected all four predictive metabolites, whereas none of the EVP bPBS samples were active in the assay up to the maximal concentration tested (10% bPBS). Nicotine tested on its own was predicted to have cardiotoxic potential at concentrations greater than 80 μg/mL, which is higher than expected physiological levels associated with combustible cigarette smoking. The application of this rapid screening assay to NGP research and the associated findings adds to the weight-of-evidence indicating that NGPs have a tobacco harm reduction potential when compared to combustible cigarettes. Additionally, this technique was shown to be sensitive and robust for the assessment of different NGPs and may be considered as part of a larger overall scientific framework for NGP assessments.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Predict the Cardiotoxicity Potential of Next Generation Nicotine Products

Simms

Palmer

et al. 2022

Front. Toxicol.

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“…Further, the identification of KCs and knowledge of the methods to evaluate them will inform the development of high-throughput assays and in silico screens that could be used to expedite acquisition of information regarding potential CV toxicity ( Blanchette et al. 2019 ; Burnett et al. 2021 ; Sirenko et al.…”

Section: Discussionmentioning

confidence: 99%

Key Characteristics of Cardiovascular Toxicants

Lind¹,

Araujo

Barchowsky

et al. 2021

Environ Health Perspect

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Background: The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches. Objectives: We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them. Methods: An expert working group was convened to discuss mechanisms associated with CV toxicity. Results: The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1–4 below), the vascular system (5–7), or both (8–12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling. Discussion: These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM in aerodynamic diameter ( )] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. https://doi.org/10.1289/EHP9321

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“…We have published methods for using iPSC-derived cells [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ] to assess the toxicity of the individual chemicals [ 20 , 28 , 29 , 30 , 31 , 32 ], whole mixtures [ 11 , 16 ], and complex substances [ 33 , 34 ]. The reasons we chose iPSC-derived cells are because: (i) these cells are more physiological than immortalized cell lines and can be derived for different tissues/organs [ 35 ]; (ii) they can be obtained from the same individual(s) to enable highly reproducible experiments [ 36 ]; (iii) despite some limitations with the degree of maturation, these cells compare well to primary cells in terms of their function and expected organ-specific toxicity [ 35 , 37 , 38 ]; and (iv) a small number of iPSC-derived cell types can be as informative about hazard and safety margins as the larger set of in vitro models [ 33 ], or many ToxCast bioassays [ 20 ]. Specifically, in a study of petroleum substances [ 33 ] we found that bioactivity data from four human iPSC-derived and HUVEC cells are superior to other immortalized cell lines to rank substances in a manner highly concordant with their expected in vivo hazard potential.…”

Section: Methodsmentioning

confidence: 99%

Potential Human Health Hazard of Post-Hurricane Harvey Sediments in Galveston Bay and Houston Ship Channel: A Case Study of Using In Vitro Bioactivity Data to Inform Risk Management Decisions

Chen

Jang

Kaihatu

et al. 2021

IJERPH

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Natural and anthropogenic disasters may be associated with redistribution of chemical contaminants in the environment; however, current methods for assessing hazards and risks of complex mixtures are not suitable for disaster response. This study investigated the suitability of in vitro toxicity testing methods as a rapid means of identifying areas of potential human health concern. We used sediment samples (n = 46) from Galveston Bay and the Houston Ship Channel (GB/HSC) areas after hurricane Harvey, a disaster event that led to broad redistribution of chemically-contaminated sediments, including deposition of the sediment on shore due to flooding. Samples were extracted with cyclohexane and dimethyl sulfoxide and screened in a compendium of human primary or induced pluripotent stem cell (iPSC)-derived cell lines from different tissues (hepatocytes, neuronal, cardiomyocytes, and endothelial) to test for concentration-dependent effects on various functional and cytotoxicity phenotypes (n = 34). Bioactivity data were used to map areas of potential concern and the results compared to the data on concentrations of polycyclic aromatic hydrocarbons (PAHs) in the same samples. We found that setting remediation goals based on reducing bioactivity is protective of both “known” risks associated with PAHs and “unknown” risks associated with bioactivity, but the converse was not true for remediation based on PAH risks alone. Overall, we found that in vitro bioactivity can be used as a comprehensive indicator of potential hazards and is an example of a new approach method (NAM) to inform risk management decisions on site cleanup.

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Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes as an in vitro model in toxicology: strengths and weaknesses for hazard identification and risk characterization

Cited by 33 publications

References 151 publications

Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Predict the Cardiotoxicity Potential of Next Generation Nicotine Products

Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Predict the Cardiotoxicity Potential of Next Generation Nicotine Products

Key Characteristics of Cardiovascular Toxicants

Potential Human Health Hazard of Post-Hurricane Harvey Sediments in Galveston Bay and Houston Ship Channel: A Case Study of Using In Vitro Bioactivity Data to Inform Risk Management Decisions

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