Population-based toxicity screening in human induced pluripotent stem cell-derived cardiomyocytes

Burnett, Sarah D; Blanchette, Alexander D; Grimm, Fabian A.; House, John S.; Reif, David M.; Wright, Fred A.; Chiu, Weihsueh A.; Rusyn, Ivan

doi:10.1016/j.taap.2019.114711

Cited by 48 publications

(49 citation statements)

References 36 publications

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“…

flux data were processed in R studio (version 1.0.136, with R version 3.3.2; R Development Core Team) as described elsewhere ( Blanchette et al. 2019 ; Burnett et al. 2019 ).…”

Section: Methodsmentioning

confidence: 99%

“…Ca 2+ flux data were processed in R studio (version 1.0.136, with R version 3.3.2; R Development Core Team) as described elsewhere (Blanchette et al 2019;Burnett et al 2019). Calculated quantitative metrics included the means and coefficients of variation (CV) of the peak height, which can be indicative of cytotoxicity, inhibition, or stimulation of beating.…”

Section: Evaluation Of the Effects On The Function Of Cmsmentioning

confidence: 99%

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Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites

Grimm

Klaren

et al. 2020

Environ Health Perspect

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BACKGROUND: Xenobiotic metabolism is complex, and accounting for bioactivation and detoxification processes of chemicals remains among the most challenging aspects for decision making with in vitro new approach methods data. OBJECTIVES: Considering the physiological relevance of human organotypic culture models and their utility for high-throughput screening, we hypothesized that multidimensional chemical-biological profiling of chemicals and their major metabolites is a sensible alternative for the toxicological characterization of parent molecules vs. metabolites in vitro. METHODS: In this study, we tested 25 polychlorinated biphenyls (PCBs) [PCB 3, 11, 52, 126, 136, and 153 and their relevant metabolites (hydroxylated, methoxylated, sulfated, and quinone)] in concentration-response (10 nM-100 lM) for effects in human induced pluripotent stem cell (iPSC)derived cardiomyocytes (CMs) and endothelial cells (ECs) (iPSC-derived and HUVECs). Functional phenotypic end points included effects on beating parameters and intracellular Ca 2+ flux in CMs and inhibition of tubulogenesis in ECs. High-content imaging was used to evaluate cytotoxicity, mitochondrial integrity, and oxidative stress. RESULTS: Data integration of a total of 19 physicochemical descriptors and 36 in vitro phenotypes revealed that chlorination status and metabolite class are strong predictors of the in vitro cardiovascular effects of PCBs. Oxidation of PCBs, especially to di-hydroxylated and quinone metabolites, was associated with the most pronounced effects, whereas sulfation and methoxylation of PCBs resulted in diminished bioactivity. DISCUSSION: Risk characterization analysis showed that although in vitro derived effective concentrations exceeded the levels measured in the general population, risks cannot be ruled out due to the potential for population variability in susceptibility and the need to fill data gaps using read-across approaches. This study demonstrated a strategy for how in vitro data can be used to characterize human health risks from PCBs and their metabolites.

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“…

flux data were processed in R studio (version 1.0.136, with R version 3.3.2; R Development Core Team) as described elsewhere ( Blanchette et al. 2019 ; Burnett et al. 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Evaluation Of the Effects On The Function Of Cmsmentioning

confidence: 99%

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites

Grimm

Klaren

et al. 2020

Environ Health Perspect

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“…One of the key advantages of using iPSC-CMs is their ability to capture patient-specific drug responses, which may arise from a variety for underlying genetic or metabolic alterations. On a broader scale, iPSC-CMs have shown to exhibit inter-individual variability that enables us to extend our understanding to a larger group of individuals or population for better categorization into responders and non-responders toward a treatment ( Burnett et al, 2019 ).…”

Section: Induced Pluripotent Stem Cells Cardiomyocytes In Cancer Drugmentioning

confidence: 99%

Building Multi-Dimensional Induced Pluripotent Stem Cells-Based Model Platforms to Assess Cardiotoxicity in Cancer Therapies

2021

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Cardiovascular disease (CVD) complications have contributed significantly toward poor survival of cancer patients worldwide. These complications that result in myocardial and vascular damage lead to long-term multisystemic disorders. In some patient cohorts, the progression from acute to symptomatic CVD state may be accelerated due to exacerbation of underlying comorbidities such as obesity, diabetes and hypertension. In such situations, cardio-oncologists are often left with a clinical predicament in finding the optimal therapeutic balance to minimize cardiovascular risks and maximize the benefits in treating cancer. Hence, prognostically there is an urgent need for cost-effective, rapid, sensitive and patient-specific screening platform to allow risk-adapted decision making to prevent cancer therapy related cardiotoxicity. In recent years, momentous progress has been made toward the successful derivation of human cardiovascular cells from induced pluripotent stem cells (iPSCs). This technology has not only provided deeper mechanistic insights into basic cardiovascular biology but has also seamlessly integrated within the drug screening and discovery programs for early efficacy and safety evaluation. In this review, we discuss how iPSC-derived cardiovascular cells have been utilized for testing oncotherapeutics to pre-determine patient predisposition to cardiovascular toxicity. Lastly, we highlight the convergence of tissue engineering technologies and precision medicine that can enable patient-specific cardiotoxicity prognosis and treatment on a multi-organ level.

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“…Furthermore, patient-specific hiPSC-derived CMs were employed to assess the cardiotoxicity of chemotherapeutics, such as doxorubicin and trastuzumab, showing how prolonged exposure to such drugs, induced decreased cell viability, perturbation in Ca 2+ management, mitochondrial malfunction, and contraction impairment ( Burridge et al, 2016 ; Chaudhari et al, 2016 ; Kitani et al, 2019 ). The available high-throughput assays and high-scale production of hiPSC-derived CMs enabled the simultaneous screening of multiple drugs on different lines of hiPSC-derived CMs, thus generating a faster assessment of drug-induced cardiotoxicity ( del Álamo et al, 2016 ; Denning et al, 2016 ; Blinova et al, 2018 ; Grimm et al, 2018 ; Millard et al, 2018 ; Sharma et al, 2018 ; Burnett et al, 2019 ). Drug cardiotoxicity represents one of the main concerns in cancer treatment; thus, the development of hiPSC-based therapies provided an unprecedented advantage to evaluate and discover the cardiovascular toxicity of specific drugs, prior to clinical trials ( Sharma et al, 2018 ).…”

Section: Drug Development and Screeningmentioning

confidence: 99%

Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering

Gähwiler

Motta

Martin

et al. 2021

Front. Cell Dev. Biol.

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Induced pluripotent stem cells (iPSCs) originate from the reprogramming of adult somatic cells using four Yamanaka transcription factors. Since their discovery, the stem cell (SC) field achieved significant milestones and opened several gateways in the area of disease modeling, drug discovery, and regenerative medicine. In parallel, the emergence of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) revolutionized the field of genome engineering, allowing the generation of genetically modified cell lines and achieving a precise genome recombination or random insertions/deletions, usefully translated for wider applications. Cardiovascular diseases represent a constantly increasing societal concern, with limited understanding of the underlying cellular and molecular mechanisms. The ability of iPSCs to differentiate into multiple cell types combined with CRISPR-Cas9 technology could enable the systematic investigation of pathophysiological mechanisms or drug screening for potential therapeutics. Furthermore, these technologies can provide a cellular platform for cardiovascular tissue engineering (TE) approaches by modulating the expression or inhibition of targeted proteins, thereby creating the possibility to engineer new cell lines and/or fine-tune biomimetic scaffolds. This review will focus on the application of iPSCs, CRISPR-Cas9, and a combination thereof to the field of cardiovascular TE. In particular, the clinical translatability of such technologies will be discussed ranging from disease modeling to drug screening and TE applications.

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Population-based toxicity screening in human induced pluripotent stem cell-derived cardiomyocytes

Cited by 48 publications

References 36 publications

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites

Building Multi-Dimensional Induced Pluripotent Stem Cells-Based Model Platforms to Assess Cardiotoxicity in Cancer Therapies

Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering

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