High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell–Derived Organoids

Shinozawa, Tadahiro; Kimura, Masaki; Cai, Yuqi; Saiki, Norikazu; Yoneyama, Yoshimasa; Ouchi, Rie; Koike, Hiroyuki; Maezawa, Mari; Zhang, Ranran; Dunn, Andrew; Ferguson, Autumn; Togo, Shodai; Lewis, Kyle; Thompson, Wendy L.; Asai, Akihiro; Takebe, Takanori

doi:10.1053/j.gastro.2020.10.002

Cited by 175 publications

(163 citation statements)

References 52 publications

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“…The recently developed models of both mouse [ 80 ] and human [ 81 ] derived liver organoid cultures from tissue resident stem cells, as well as pluripotent stem cell-derived liver cultures [ 82 , 83 , 84 , 85 ], may represent an ideal model for studying radiation-induced liver disease in the future. These models display cellular, functional activity and have structural organisation, while they have been successfully utilised to study genetic liver disorders mimicking the clinical pathology [ 81 ] and drug-induced liver injury [ 86 ]. Understanding the mechanisms of radiation-induced liver disease may eventually allow for increased treatment options for liver cancers.…”

Section: Organoids and Regeneration Of Radiation-induced Damaged Tmentioning

confidence: 99%

Current and Future Perspectives of the Use of Organoids in Radiobiology

Nagle

Coppes

2020

Cells

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The majority of cancer patients will be treated with radiotherapy, either alone or together with chemotherapy and/or surgery. Optimising the balance between tumour control and the probability of normal tissue side effects is the primary goal of radiation treatment. Therefore, it is imperative to understand the effects that irradiation will have on both normal and cancer tissue. The more classical lab models of immortal cell lines and in vivo animal models have been fundamental to radiobiological studies to date. However, each of these comes with their own limitations and new complementary models are required to fill the gaps left by these traditional models. In this review, we discuss how organoids, three-dimensional tissue-resembling structures derived from tissue-resident, embryonic or induced pluripotent stem cells, overcome the limitations of these models and thus have a growing importance in the field of radiation biology research. The roles of organoids in understanding radiation-induced tissue responses and in moving towards precision medicine are examined. Finally, the limitations of organoids in radiobiology and the steps being made to overcome these limitations are considered.

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Section: Organoids and Regeneration Of Radiation-induced Damaged Tmentioning

confidence: 99%

Current and Future Perspectives of the Use of Organoids in Radiobiology

Nagle

Coppes

2020

Cells

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“…Self-assembled organoids (larger than spheroids and with compartments of different cell types) using iPSCs have become popular choices for developing expandable 3D cultures with diverse compositions of liver cells for applications in disease modeling and drug screening capabilities. 40,41 However, methods to differentiate iPSC-HHs still lead to relatively immature hepatocytes as compared with adult PHHs; therefore, genetic engineering techniques have been used to improve cellular maturity. Specifically, overexpression of developmental genes combined with CRISPR-based transcriptional activation, 42 gene knock-in and knock-out approaches, 43 and transduction of cells with key regulators of cellular differentiation 44 have shown promise in accelerating liver tissue development and function in iPSC liver organoids.…”

Section: Self-assembled 3d Spheroids and Organoidsmentioning

confidence: 99%

Bioengineered Liver Models for Investigating Disease Pathogenesis and Regenerative Medicine

Kukla

Khetani

2021

Semin Liver Dis

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Owing to species-specific differences in liver pathways, in vitro human liver models are utilized for elucidating mechanisms underlying disease pathogenesis, drug development, and regenerative medicine. To mitigate limitations with de-differentiated cultures, bioengineers have developed advanced techniques/platforms, including micropatterned cocultures, spheroids/organoids, bioprinting, and microfluidic devices, for perfusing cell cultures and liver slices. Such techniques improve mature functions and culture lifetime of primary and stem-cell human liver cells. Furthermore, bioengineered liver models display several features of liver diseases including infections with pathogens (e.g., malaria, hepatitis C/B viruses, Zika, dengue, yellow fever), alcoholic/nonalcoholic fatty liver disease, and cancer. Here, we discuss features of bioengineered human liver models, their uses for modeling aforementioned diseases, and how such models are being augmented/adapted for fabricating implantable human liver tissues for clinical therapy. Ultimately, continued advances in bioengineered human liver models have the potential to aid the development of novel, safe, and efficacious therapies for liver disease.

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“…Drug disposition-related transporters and metabolic enzymes were successfully expressed in this intestinal organoid, providing a human-relevant tool for PK studies. To screen for hepatotoxic compounds, human liver organoids with bile canaliculi-like architectures were developed using hiPSC [ 52 ]. The generated liver organoids were considered a potential assay platform for liver toxicity screening due to their high sensitivity and specificity in predicting the hepatotoxicity of marketed drugs.…”

Section: Cell Culture Modelsmentioning

confidence: 99%

The Combination of Cell Cultured Technology and In Silico Model to Inform the Drug Development

et al. 2021

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Human-derived in vitro models can provide high-throughput efficacy and toxicity data without a species gap in drug development. Challenges are still encountered regarding the full utilisation of massive data in clinical settings. The lack of translated methods hinders the reliable prediction of clinical outcomes. Therefore, in this study, in silico models were proposed to tackle these obstacles from in vitro to in vivo translation, and the current major cell culture methods were introduced, such as human-induced pluripotent stem cells (hiPSCs), 3D cells, organoids, and microphysiological systems (MPS). Furthermore, the role and applications of several in silico models were summarised, including the physiologically based pharmacokinetic model (PBPK), pharmacokinetic/pharmacodynamic model (PK/PD), quantitative systems pharmacology model (QSP), and virtual clinical trials. These credible translation cases will provide templates for subsequent in vitro to in vivo translation. We believe that synergising high-quality in vitro data with existing models can better guide drug development and clinical use.

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High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell–Derived Organoids

Cited by 175 publications

References 52 publications

Current and Future Perspectives of the Use of Organoids in Radiobiology

Current and Future Perspectives of the Use of Organoids in Radiobiology

Bioengineered Liver Models for Investigating Disease Pathogenesis and Regenerative Medicine

The Combination of Cell Cultured Technology and In Silico Model to Inform the Drug Development

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