ERRATUM

Area of Science:

• Hepatology
• Drug Discovery
• Toxicology

Background:

• Rodent models for drug toxicity testing have limitations due to genetic diversity in human populations.
• Current in vitro methods using primary mouse hepatocytes (PMHs) have short functional lifespans, hindering long-term compound exposure studies.
• The liver is a major organ for drug attrition, necessitating better predictive models for hepatotoxicity.

Purpose of the Study:

• To develop a stable in vitro culture system for primary mouse hepatocytes (PMHs) that maintains function for extended periods.
• To compare the performance of the novel culture system against existing methods for assessing liver functions and compound responses.
• To enable strain- and species-specific comparisons of drug effects using mouse and human hepatocytes.

Main Methods:

• Fabrication of mouse micropatterned cocultures (mMPCCs) using PMHs and 3T3-J2 fibroblasts.
• Culturing mMPCCs for up to 4 weeks.
• Assessing liver functions including albumin secretion, urea synthesis, and cytochrome P450 (CYP) activities.
• Exposing mMPCCs to 14 compounds to evaluate CYP induction and hepatotoxicity.
• Comparing mMPCC results with primary human hepatocytes (PHHs).

Main Results:

• mMPCCs maintained high levels of liver functions for 4 weeks, significantly outperforming standard sandwich cultures.
• Albumin secretion, urea synthesis, and CYP activities in mMPCCs were substantially higher than in monocultures.
• Functional longevity allowed for in vivo relevant comparisons of strain-specific responses to compounds.
• mMPCCs facilitated comparisons of drug responses between mouse and human hepatocytes.

Conclusions:

• Mouse micropatterned cocultures (mMPCCs) offer a robust platform for long-term liver cell culture, preserving key liver functions.
• mMPCCs enable the assessment of strain- and species-specific drug effects, aiding in the prediction of human hepatotoxicity.
• This model can leverage mouse genetics to identify susceptible subpopulations and understand genetic determinants of severe drug-induced liver injury.