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Citation
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HERO ID
8635453
Reference Type
Journal Article
Title
Culture density contributes to hepatic functions of fresh human hepatocytes isolated from chimeric mice with humanized livers: Novel, long-term, functional two-dimensional in vitro tool for developing new drugs
Author(s)
Yamasaki, C; Ishida, Y; Yanagi, A; Yoshizane, Y; Kojima, Y; Ogawa, Y; Kageyama, Y; Iwasaki, Y; Ishida, S; Chayama, K; Tateno, C
Year
2020
Is Peer Reviewed?
1
Journal
PLoS ONE
EISSN:
1932-6203
Volume
15
Issue
9
Page Numbers
e0237809
Language
English
PMID
32915792
DOI
10.1371/journal.pone.0237809
Web of Science Id
WOS:000571887500061
URL
http://
://WOS:000571887500061
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Abstract
Chimeric mice with humanized livers are considered a useful animal model for predicting human (h-) drug metabolism and toxicity. In this study, the characteristics of fresh h-hepatocytes (cFHHs, PXB-cells®) isolated from chimeric mice (PXB-mice®) were evaluated in vitro to confirm their utility for drug development. cFHHs cultured at high density (2.13 × 105 cells/cm2) displayed stable production of h-albumin and cytochrome P450 (CYP) 3A activities for at least 21 days. The mRNA expression levels of 10 of 13 CYP, UDP-glucuronosyltransferase (UGT), and transporters were maintained at >10% of the levels of freshly isolated cFHHs after 21 days. From 1 week, many bile canaliculi were observed between cFHHs, and the accumulation of the multidrug resistance-associated protein and bile salt export pump substrates in these bile canaliculi was clearly inhibited by cyclosporin A. Microarray analysis of cFHHs cultured at high density and at low density (0.53 × 105 cells/cm2) revealed that high density culture maintained high expressions of some transcription factors (HNF4α, PXR, and FXR) perhaps involved in the high CYP, UGT and transporter gene expressions of cFHHs. These results strongly suggest that cFHHs could be a novel in vitro tool for drug development studies.
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