Exploring Chronic Drug Effects on Microengineered Human Liver Cultures Using Global Gene Expression Profiling

Ware, Brenton R.; McVay, Michael; Sunada, Wendy Y.; Khetani, Salman R.

doi:10.1093/toxsci/kfx059

Cited by 24 publications

(16 citation statements)

References 33 publications

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“…Similar toxicogenomic approaches in MPCC revealed transcriptomic perturbations upon treatment with troglitazone, nefazodone, ibufenac, and tolcapone. Interestingly, the authors found that the number of differentially expressed genes was higher in MPCCs treated with these hepatotoxins compared to those cultures dosed with the corresponding nontoxic analogues (rosiglitazone, buspirone, ibuprofen, and entacapone) …”

Section: Applications Of Advanced Primary Human Hepatocyte Culture Momentioning

confidence: 99%

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

Lauschke

Shafagh

Hendriks

et al. 2019

Biotechnology Journal

105

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Recent research has shown that the maintenance of relevant liver functions ex vivo requires models in which the cells exhibit an in vivo‐like phenotype, often achieved by reconstitution of appropriate cellular interactions. Multiple different models have been presented that differ in the cells utilized, media, and culture conditions. Furthermore, several technologically different approaches have been presented including bioreactors, chips, and plate‐based systems in fluidic or static media constituting of chemically diverse materials. Using such models, the ability to predict drug metabolism, drug toxicity, and liver functionality have increased tremendously as compared to conventional in vitro models in which cells are cultured as 2D monolayers. Here, the authors highlight important considerations for microphysiological systems for primary hepatocyte culture, review current culture paradigms, and discuss their opportunities for studies of drug metabolism, hepatotoxicity, liver biology, and disease.

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Section: Applications Of Advanced Primary Human Hepatocyte Culture Momentioning

confidence: 99%

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

Lauschke

Shafagh

Hendriks

et al. 2019

Biotechnology Journal

105

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“…Nowadays, studies have demonstrated the utility of human liver cell-derived micropatterned co-cultures in drug development, including DILI assessment (Khetani et al 2013;Trask et al 2014), yet only few studies have attempted to apply omics technologies to these in vitro culture platforms (Ware et al 2017). Using a micropatterned co-culture model containing PHH and mouse 3T3-J2 fibroblasts, Ware et al explored the hepatotoxic effects of chronic (up to 14 days) and low-dose exposure to several DILI-inducing drugs (Ware et al 2017). The authors found that these hepatotoxins led to a greater number of DEGs in the co-culture modes compared to their non-liver-toxic analogs.…”

Section: Micropatterned (Co-)culture Systemsmentioning

confidence: 99%

“…The authors found that these hepatotoxins led to a greater number of DEGs in the co-culture modes compared to their non-liver-toxic analogs. They also pointed out the transcriptome changes in fatty acid-and drug metabolism-related pathways after troglitazone exposure were responsible for its hepatotoxicity (Ware et al 2017).…”

Section: Micropatterned (Co-)culture Systemsmentioning

confidence: 99%

The application of omics-based human liver platforms for investigating the mechanism of drug-induced hepatotoxicity in vitro

et al. 2019

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Drug-induced liver injury (DILI) complicates safety assessment for new drugs and poses major threats to both patient health and drug development in the pharmaceutical industry. A number of human liver cell-based in vitro models combined with toxicogenomics methods have been developed as an alternative to animal testing for studying human DILI mechanisms. In this review, we discuss the in vitro human liver systems and their applications in omics-based drug-induced hepatotoxicity studies. We furthermore present bioinformatic approaches that are useful for analyzing toxicogenomic data generated from these models and discuss their current and potential contributions to the understanding of mechanisms of DILI. Human pluripotent stem cells, carrying donor-specific genetic information, hold great potential for advancing the study of individualspecific toxicological responses. When co-cultured with other liver-derived non-parenchymal cells in a microfluidic device, the resulting dynamic platform enables us to study immune-mediated drug hypersensitivity and accelerates personalized drug toxicology studies. A flexible microfluidic platform would also support the assembly of a more advanced organs-ona-chip device, further bridging gap between in vitro and in vivo conditions. The standard transcriptomic analysis of these cell systems can be complemented with causality-inferring approaches to improve the understanding of DILI mechanisms. These approaches involve statistical techniques capable of elucidating regulatory interactions in parts of these mechanisms. The use of more elaborated human liver models, in harmony with causality-inferring bioinformatic approaches will pave the way for establishing a powerful methodology to systematically assess DILI mechanisms across a wide range of conditions. Keywords Drug-induced hepatotoxicity • In vitro human liver model • Omics approaches • Bioinformatics • Graphical Gaussian networks • Bayesian networks

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“…PHH and HepaRG cells in 2D sandwich and 3D spheroid cultures were repeatedly treated with ibuprofen, ibufenac, acetaminophen, and aflatoxin B1 (Sigma-Aldrich, St. Louis, MO). A wide range of concentrations for each chemical was selected based on previous reports 10, 20 that cover relevant concentrations reported in human serum associated with hepatotoxicity.…”

Section: Repeated Compound Exposure and Cytotoxicity Assessmentmentioning

confidence: 99%

Functional Comparison of HepaRG Cells and Primary Human Hepatocytes in Sandwich and Spheroid Culture as Repeated-Exposure Models for Hepatotoxicity

Settivari

LeBaron

et al. 2019

Applied In Vitro Toxicology

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Introduction: Reliable and effective predictions of hepatotoxicity resulting from repeated exposure to chemicals are of critical importance for the safety assessment of chemicals; however, in vitro long-term repeated-exposure studies are difficult to conduct using conventional hepatocyte monolayer cultures due to de-differentiation and subsequent loss of hepatocyte function. Alternative in vitro culture techniques have emerged to address this challenge and have improved the longevity of hepatocyte cultures. Materials and Methods: Two promising cell models, HepaRG and primary human hepatocytes (PHHs), were compared in both spheroid and sandwich cultures to evaluate their potential as predictive models for repeatedexposure hepatotoxicity. Results: When compared to sandwich cultures, untreated cells in spheroid culture maintained higher levels of viability for a longer duration. Likewise, functional characterization revealed higher levels of xenobiotic metabolic activity (CYP1A2, CYP2B6, and CYP3A4) and urea production in spheroid than in sandwich cultures. In repeated-exposure studies (7 days), both PHH and HepaRG spheroid cultures showed increased sensitivity to a set of hepatotoxic compounds compared to their respective sandwich cultures, and the sensitivity was further elevated in an extended exposure duration (14 days). Discussion and Conclusion: Spheroid cultures can maintain robust hepatic functions during prolonged culture periods and predicted hepatotoxicity at toxicologically relevant levels after repeated exposure. In addition, Hepa-RG spheroids exhibited similar sensitivity as PHH spheroids, especially in extended exposure, suggesting that HepaRG spheroids could be a reliable surrogate for PHH spheroids and serve as a repeated-exposure model to predict hepatotoxicity.

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Exploring Chronic Drug Effects on Microengineered Human Liver Cultures Using Global Gene Expression Profiling

Cited by 24 publications

References 33 publications

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

The application of omics-based human liver platforms for investigating the mechanism of drug-induced hepatotoxicity in vitro

Functional Comparison of HepaRG Cells and Primary Human Hepatocytes in Sandwich and Spheroid Culture as Repeated-Exposure Models for Hepatotoxicity

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