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HepaRG cells undergo increased levels of post-differentiation patterning in physiologic conditions when maintained as 3D cultures in paper-based scaffolds

Thomas J. Diprospero, Lauren G. Brown, Trevor D. Fachko, View ORCID ProfileMatthew R. Lockett
doi: https://doi.org/10.1101/2023.01.16.524330
Thomas J. Diprospero
aDepartment of Chemistry, University of North Carolina at Chapel Hill, Kenan and Caudill Laboratories, Chapel Hill, NC 27599-3290, United States
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Lauren G. Brown
aDepartment of Chemistry, University of North Carolina at Chapel Hill, Kenan and Caudill Laboratories, Chapel Hill, NC 27599-3290, United States
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Trevor D. Fachko
aDepartment of Chemistry, University of North Carolina at Chapel Hill, Kenan and Caudill Laboratories, Chapel Hill, NC 27599-3290, United States
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Matthew R. Lockett
aDepartment of Chemistry, University of North Carolina at Chapel Hill, Kenan and Caudill Laboratories, Chapel Hill, NC 27599-3290, United States
bLineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 37599-7295, United States
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  • ORCID record for Matthew R. Lockett
  • For correspondence: mlockett@unc.edu
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Abstract

Monolayer cultures of hepatocytes lack many aspects of the liver sinusoid, including a tissue-level organization that results from extracellular matrix interactions and gradients of soluble molecules that span from the portal triad to the central vein. We measured the activity and transcript levels of drug-metabolizing enzymes in HepaRG cells maintained in three different culture configurations: as monolayers, seeded onto paper scaffolds that were pre-loaded with a collagen matrix, and when seeded directly into the paper scaffolds as a cell-laden gel. Drug metabolism was significantly decreased in the presence of the paper scaffolds compared to monolayer configurations when cells were exposed to standard culture conditions. Despite this decreased function, transcript levels suggest the cells undergo increased polarization and adopt a biliary-like character in the paper scaffolds, including the increased expression of transporter proteins (e.g., ABCB11 and SLOC1B1) and the KRT19 cholangiocyte marker. When exposed to representative periportal or perivenous culture conditions, we observed in vivo zonal-like patterns, including increased cytochrome P450 (CYP) activity and transcript levels in the perivenous condition. This increased CYP activity is more pronounced in the laden configuration, supporting the need to include multiple aspects of the liver microenvironment to observe the post-differentiation processing of hepatocytes.

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Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 19, 2023.
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HepaRG cells undergo increased levels of post-differentiation patterning in physiologic conditions when maintained as 3D cultures in paper-based scaffolds
Thomas J. Diprospero, Lauren G. Brown, Trevor D. Fachko, Matthew R. Lockett
bioRxiv 2023.01.16.524330; doi: https://doi.org/10.1101/2023.01.16.524330
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HepaRG cells undergo increased levels of post-differentiation patterning in physiologic conditions when maintained as 3D cultures in paper-based scaffolds
Thomas J. Diprospero, Lauren G. Brown, Trevor D. Fachko, Matthew R. Lockett
bioRxiv 2023.01.16.524330; doi: https://doi.org/10.1101/2023.01.16.524330

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