SHIMIZU Tatsuya    Department   Research Institutes and Facilities, Research Institutes and Facilities    Position   Professor
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	Functional Analysis of Induced Human Ballooned Hepatocytes in a Cell Sheet-Based Three Dimensional Model.
Journal	Formal name：Tissue engineering and regenerative medicine Abbreviation：Tissue Eng Regen Med ISSN code：22125469/17382696
Domestic / Foregin	Foregin
Publisher	Springer
Volume, Issue, Page	18,pp.217-224
Author and coauthor	GAO Botao†, SAKAGUCHI Katsuhisa, OGAWA Tetsuya, KAGAWA Yuki, KUBO Hirotsugu, SHIMIZU Tatsuya*
Authorship	Last author,Corresponding author
Publication date	2021/01/30
Summary	BACKGROUND:Ballooned hepatocytes (BH) are a key histological hallmark of nonalcoholic steatohepatitis (NASH), yet their consequences for liver-specific functions are unknown.METHODS:In our previous study, an experimental model of human induced-BHs (iBH) has been successfully developed based on cell sheet technology. This study aimed to determine the functions of iBHs in the primary human hepatocyte/normal human dermal fibroblast (PHH/NHDF) co-culture cell sheets. Normal hepatocytes in the PHH/3T3-J2 co-culture cell sheets were set as a control, since 3T3-J2 murine embryonic fibroblasts have exhibited previously long term maintenance of PHH functions.RESULTS:It was found that, albumin secretion was not affected in iBHs, but urea synthesis as well as cytochrome P450 enzyme (CYP) activities including CYP1A2 and CYP3A4, were significantly reduced in iBHs. Besides, loss of bile canaliculi was observed in iBHs. These findings are consistent with clinical studies of human NASH. In addition, PHH/NHDF cell sheets demonstrated two fold higher TGF-β1 secretion compared with PHH/3T3-J2 cell sheets. Furthermore, treatment with a TGF-β inhibitor and a semi-synthetic bile acid analogue (obeticholic acid, phase 3 trial of NASH therapy) ameliorated the histological appearance of established iBHs.CONCLUSION:In summary, this study demonstrates the priority of iBHs in recapitulating not only histology but also clinically relevant hepatic dysfunctions in human NASH and suggests TGF-β and bile acid related signal pathway may play important roles in the formation of iBHs.
DOI	10.1007/s13770-020-00297-x
PMID	33517537