Analysis of reproducibility and robustness of a human microfluidic four-cell liver acinus microphysiology system (LAMPS).
Drug toxicity
Hepatotoxicity
In vitro
Journal
Toxicology
ISSN: 1879-3185
Titre abrégé: Toxicology
Pays: Ireland
ID NLM: 0361055
Informations de publication
Date de publication:
30 01 2021
30 01 2021
Historique:
received:
29
07
2020
revised:
06
10
2020
accepted:
27
11
2020
pubmed:
12
12
2020
medline:
13
5
2021
entrez:
11
12
2020
Statut:
ppublish
Résumé
A human microfluidic four-cell liver acinus microphysiology system (LAMPS), was evaluated for reproducibility and robustness as a model for drug pharmacokinetics and toxicology. The model was constructed using primary human hepatocytes or human induced pluripotent stem cell (iPSC)-derived hepatocytes and 3 human cell lines for the endothelial, Kupffer and stellate cells. The model was tested in two laboratories and demonstrated to be reproducible in terms of basal function of hepatocytes, Terfenadine metabolism, and effects of Tolcapone (88 μM), Troglitazone (150 μM), and caffeine (600 μM) over 9 days in culture. Additional experiments compared basal outputs of albumin, urea, lactate dehydrogenase (LDH) and tumor necrosis factor (TNF)α, as well as drug metabolism and toxicity in the LAMPS model, and in 2D cultures seeded with either primary hepatocytes or iPSC-hepatocytes. Further experiments to study the effects of Terfenadine (10 μM), Tolcapone (88 μM), Trovafloxacin (150 μM with or without 1 μg/mL lipopolysaccharide), Troglitazone (28 μM), Rosiglitazone (0.8 μM), Pioglitazone (3 μM), and caffeine (600 μM) were carried out over 10 days. We found that both primary human hepatocytes and iPSC-derived hepatocytes in 3D culture maintained excellent basal liver function and Terfenadine metabolism over 10 days compared the same cells in 2D cultures. In 2D, non-overlay monolayer cultures, both cell types lost hepatocyte phenotypes after 48 h. With respect to drug effects, both cell types demonstrated comparable and more human-relevant effects in LAMPS, as compared to 2D cultures. Overall, these studies show that LAMPS is a robust and reproducible in vitro liver model, comparable in performance when seeded with either primary human hepatocytes or iPSC-derived hepatocytes, and more physiologically and clinically relevant than 2D monolayer cultures.
Identifiants
pubmed: 33307106
pii: S0300-483X(20)30290-0
doi: 10.1016/j.tox.2020.152651
pmc: PMC7785655
mid: NIHMS1653468
pii:
doi:
Substances chimiques
Histamine H1 Antagonists, Non-Sedating
0
Terfenadine
7BA5G9Y06Q
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
152651Subventions
Organisme : NCATS NIH HHS
ID : UH2 TR000503
Pays : United States
Organisme : NCATS NIH HHS
ID : U24 TR002633
Pays : United States
Organisme : NIDDK NIH HHS
ID : UH3 DK119973
Pays : United States
Organisme : NIH HHS
ID : S10 OD012269
Pays : United States
Organisme : NIEHS NIH HHS
ID : T32 ES026568
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES029067
Pays : United States
Organisme : NIDDK NIH HHS
ID : UG3 DK119973
Pays : United States
Organisme : NCATS NIH HHS
ID : U24 TR001950
Pays : United States
Organisme : NIEHS NIH HHS
ID : P42 ES027704
Pays : United States
Organisme : NCATS NIH HHS
ID : UH3 TR000503
Pays : United States
Organisme : NCATS NIH HHS
ID : U24 TR001935
Pays : United States
Organisme : NCATS NIH HHS
ID : U24 TR002632
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
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