Functionality of primary hepatic non-parenchymal cells in a 3D spheroid model and contribution to acetaminophen hepatotoxicity

In addition to hepatocytes, the liver comprises a host of specialised non-parenchymal cells which are important to consider in the development of in vitro models which are both physiologically and toxicologically relevant. We have characterized a 3D co-culture system comprising primary human hepatoc...

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Bibliographic Details
Published in:Archives of toxicology Vol. 94; no. 4; pp. 1251 - 1263
Main Authors: Bell, Catherine C., Chouhan, Bhavik, Andersson, Linda C., Andersson, Håkan, Dear, James W., Williams, Dominic P., Söderberg, Magnus
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2020
Springer Nature B.V
Subjects:
Acetaminophen
Acetaminophen - adverse effects
Acetaminophen - toxicity
Analgesics
Analgesics, Non-Narcotic - adverse effects
Analgesics, Non-Narcotic - toxicity
Animals
Biocompatibility
Biomedical and Life Sciences
Biomedicine
Cell culture
Chemical and Drug Induced Liver Injury
Coculture Techniques
Cytochrome P-450 Enzyme System
Depletion
Environmental Health
Glutathione
Hepatocytes
Hepatotoxicity
Humans
Immunohistochemistry
In Vitro Systems
Inflammation
Lipopolysaccharides
Liver
Liver - drug effects
Male
Metabolism
MicroRNAs
miRNA
Molecular Conformation
Occupational Medicine/Industrial Medicine
Pharmacology/Toxicology
Regeneration
Spheroids
Three dimensional models
Toxicity
miRNA
In vitro toxicology
Hepatotoxicity
3D models
ISSN:0340-5761, 1432-0738, 1432-0738
Online Access:Get full text
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Summary:In addition to hepatocytes, the liver comprises a host of specialised non-parenchymal cells which are important to consider in the development of in vitro models which are both physiologically and toxicologically relevant. We have characterized a 3D co-culture system comprising primary human hepatocytes (PHH) and non-parenchymal cells (NPC) and applied it to the investigation of acetaminophen-induced toxicity. Firstly, we titrated ratios of PHH:NPC and confirmed the presence of functional NPCs via both immunohistochemistry and activation with both LPS and TGF-β. Based on these data we selected a ratio of 2:1 PHH:NPC for further studies. We observed that spheroids supplemented with NPCs were protected against acetaminophen (APAP) toxicity as determined by ATP (up to threefold difference in EC 50 at day 14 compared to hepatocytes alone) and glutathione depletion, as well as miR-122 release. APAP metabolism was also altered in the presence of NPCs, with significantly lower levels of APAP-GSH detected. Expression of several CYP450 enzymes involved in the bioactivation of APAP was also lower in NPC-containing spheroids. Spheroids containing NPCs also expressed higher levels of miRNAs which have been implicated in APAP-induced hepatotoxicity, including miR-382 and miR-155 which have potential roles in liver regeneration and inflammation, respectively. These data indicate that the interaction between hepatocytes and NPCs can have significant metabolic and toxicological consequences important for the correct elucidation of hepatic safety mechanisms.
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ISSN:0340-5761
1432-0738
1432-0738
DOI:10.1007/s00204-020-02682-w