Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

Lee-Montiel, Felipe T.; Laemmle, Alexander; Charwat, Verena; Dumont, Laure; Lee, Caleb S.; Huebsch, Nathaniel; Okochi, Hideaki; Hancock, Matthew; Siemons, Brian; Boggess, Steven; Goswami, Ishan; Miller, Evan W.; Willenbring, Holger; Healy, Kevin E.

doi:10.3389/fphar.2021.667010

Cited by 33 publications

(31 citation statements)

References 119 publications

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“…Our results also showed that the potential inhibitors of CYP3A4 had the similar effect of miR-4277 on sorafenib in HCC cells. The effect of ketoconazole is significantly stronger than amprenavir or diltiazem (49)(50)(51)(52)(53)(54)(55). Since ketoconazole is also considered to be an inhibitor of PXR, this needs to be discussed in depth.…”

Section: Discussionmentioning

confidence: 99%

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

Sun

Jiang

et al. 2021

Front. Oncol.

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Increasing evidence has shown that the metabolism and clearance of molecular targeted agents, such as sorafenib, plays an important role in mediating the resistance of HCC cells to these agents. Metabolism of sorafenib is performed by oxidative metabolism, which is initially mediated by CYP3A4. Thus, targeting CYP3A4 is a promising approach to enhance the sensitivity of HCC cells to chemotherapeutic agents. In the present work, we examined the association between CYP3A4 and the prognosis of HCC patients receiving sorafenib. Using the online tool miRDB, we predicted that has-microRNA-4277 (miR-4277), an online miRNA targets the 3’UTR of the transcript of cyp3a4. Furthermore, overexpression of miR-4277 in HCC cells repressed the expression of CYP3A4 and reduced the elimination of sorafenib in HCC cells. Moreover, miR-4277 enhanced the sensitivity of HCC cells to sorafenib in vitro and in vivo. Therefore, our results not only expand our understanding of CYP3A4 regulation in HCC, but also provide evidence for the use of miR-4277 as a potential therapeutic in advanced HCC.

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Section: Discussionmentioning

confidence: 99%

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

Sun

Jiang

et al. 2021

Front. Oncol.

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“…In a further increased complex culture model, Lee-Montiel et al incorporated PSC hepatic progeny and PSC-cardiac progeny derived from the same iPSC in a functionally coupled OoC system. This enabled the characterization of drug-drug interactions between cisapride and ketoconazole, as the authors could demonstrate that Ketoconazole inhibited the CYP3A4 induced conversion of cisapride to norcisapride, leading to cardiac arrhythmia [168].…”

Section: Microphysiological Systemsmentioning

confidence: 99%

Current Status and Challenges of Human Induced Pluripotent Stem Cell-Derived Liver Models in Drug Discovery

Tricot

Verfaillie

Kumar

2022

Cells

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The pharmaceutical industry is in high need of efficient and relevant in vitro liver models, which can be incorporated in their drug discovery pipelines to identify potential drugs and their toxicity profiles. Current liver models often rely on cancer cell lines or primary cells, which both have major limitations. However, the development of human induced pluripotent stem cells (hiPSCs) has created a new opportunity for liver disease modeling, drug discovery and liver toxicity research. hiPSCs can be differentiated to any cell of interest, which makes them good candidates for disease modeling and drug discovery. Moreover, hiPSCs, unlike primary cells, can be easily genome-edited, allowing the creation of reporter lines or isogenic controls for patient-derived hiPSCs. Unfortunately, even though liver progeny from hiPSCs has characteristics similar to their in vivo counterparts, the differentiation of iPSCs to fully mature progeny remains highly challenging and is a major obstacle for the full exploitation of these models by pharmaceutical industries. In this review, we discuss current liver-cell differentiation protocols and in vitro iPSC-based liver models that could be used for disease modeling and drug discovery. Furthermore, we will discuss the challenges that still need to be overcome to allow for the successful implementation of these models into pharmaceutical drug discovery platforms.

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“…For a proof-of-concept drug study in this coupled liver–cardiac device, inhibition of cisapride (drug to treat heartburn) metabolism by the liver device via a CYP3A4 inhibitor, ketoconazole, led to a significantly prolonged action potential duration in the coupled cardiac microfluidic system. 124 In another platform, a PHH chamber was connected fluidically to an iPSC-derived cardiomyocyte chamber with integrated microelectrode array and cantilever chips to evaluate the electrical and mechanical properties of the cardiomyocytes [ Fig. 4(d) ]; 125 when cardiotoxic compounds (e.g., cyclophosphamide, a chemotherapy drug that is metabolized by the liver into a cardiotoxic by-product) were tested in this device, iPSC-derived cardiomyocyte beating rate and viability decreased without affecting PHH functions.…”

Section: Multi-organ-on-a-chip Approachesmentioning

confidence: 99%

Latest impact of engineered human liver platforms on drug development

2021

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Drug-induced liver injury (DILI) is a leading cause of drug attrition, which is partly due to differences between preclinical animals and humans in metabolic pathways. Therefore, in vitro human liver models are utilized in biopharmaceutical practice to mitigate DILI risk and assess related mechanisms of drug transport and metabolism. However, liver cells lose phenotypic functions within 1–3 days in two-dimensional monocultures on collagen-coated polystyrene/glass, which precludes their use to model the chronic effects of drugs and disease stimuli. To mitigate such a limitation, bioengineers have adapted tools from the semiconductor industry and additive manufacturing to precisely control the microenvironment of liver cells. Such tools have led to the fabrication of advanced two-dimensional and three-dimensional human liver platforms for different throughput needs and assay endpoints (e.g., micropatterned cocultures, spheroids, organoids, bioprinted tissues, and microfluidic devices); such platforms have significantly enhanced liver functions closer to physiologic levels and improved functional lifetime to >4 weeks, which has translated to higher sensitivity for predicting drug outcomes and enabling modeling of diseased phenotypes for novel drug discovery. Here, we focus on commercialized engineered liver platforms and case studies from the biopharmaceutical industry showcasing their impact on drug development. We also discuss emerging multi-organ microfluidic devices containing a liver compartment that allow modeling of inter-tissue crosstalk following drug exposure. Finally, we end with key requirements for engineered liver platforms to become routine fixtures in the biopharmaceutical industry toward reducing animal usage and providing patients with safe and efficacious drugs with unprecedented speed and reduced cost.

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Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

Cited by 33 publications

References 119 publications

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

Current Status and Challenges of Human Induced Pluripotent Stem Cell-Derived Liver Models in Drug Discovery

Latest impact of engineered human liver platforms on drug development

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