Abstract
Three-dimensional liver in vitro systems have recently attracted a lot of attention in drug development. These systems help to gain unprecedented insights into drug-induced liver injury (DILI), as they more closely reproduce liver biology, and as drug effects can be studied in isolated and controllable microenvironments. Many groups established human-based in vitro models but so far neglected the animal equivalent, although the availability of both models would be desirable. Animal in vitro models enable back- and forward translation of in vitro and in vivo findings, bridge the gap between rodent in vivo and human in vitro scenarios, and ultimately support the interpretation of data generated with preclinical species and humans. Since mice are often used in drug development and physiologically relevant in vitro systems are lacking, we established, for the first time, a mouse liver model that encompasses primary parenchymal and non-parenchymal cells with preserved viability and functionality over three weeks. Using our three-dimensional liver spheroids, we were able to predict the toxicity of known DILI compounds, demonstrated the interaction cascades between the different cell types and showed evidence of drug-induced steatosis and cholestasis. In summary, our mouse liver spheroids represent a valuable in vitro model that can be applied to study DILI findings, reported from mouse studies, and offers the potential to detect immune-mediated drug-induced liver toxicity.
Highlights
In drug development, in vivo and in vitro experimental model systems are critical components to support the selection of the most promising drug candidate that show high efficacy and raise little safety concerns in order to be approved for clinical trials
A mouse hepatocyte is larger than a rat or human one, which had to be considered in determining the number of cells to be used for spheroid generation [30,31,32]
Cell viability was measured for both mono- and coculture spheroids by assessing intracellular adenosine-triphosphate (ATP) content, which was sustained over three weeks of culturing (Fig 1C)
Summary
In vivo and in vitro experimental model systems are critical components to support the selection of the most promising drug candidate that show high efficacy and raise little safety concerns in order to be approved for clinical trials. The use of rodent in vivo studies to investigate off-target effects is key to assess the systemic impact of a compound in a living organism [1]. Characterization of a long-term mouse primary liver 3D tissue model and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
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