Development of human iPSC-derived quiescent hepatic stellate cell-like cells for drug discovery and in vitro disease modeling

Yuta Koui; Misao Himeno; Yusuke Mori; Yasuhiro Nakano; Eiko Saijou; Naoki Tanimizu; Yoshiko Kamiya; Hiroko Anzai; Natsuki Maeda; Luyao Wang; Tadanori Yamada; Yasuyuki Sakai; Ryuichiro Nakato; Atsushi Miyajima; Taketomo Kido

doi:10.1016/j.stemcr.2021.11.002

Development of human iPSC-derived quiescent hepatic stellate cell-like cells for drug discovery and in vitro disease modeling

Stem Cell Reports. 2021 Dec 14;16(12):3050-3063. doi: 10.1016/j.stemcr.2021.11.002. Epub 2021 Dec 2.

Authors

Affiliations

¹ Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
² Bio Science & Engineering Laboratory, Research & Development Management Headquarters, FUJIFILM Corporation, 577 Ushijima, Kaisei-machi, Ashigarakami-gun, Kanagawa 258-8577, Japan.
³ Laboratory of Computational Genomics, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
⁴ Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo 060-8556, Japan.
⁵ Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
⁶ Department of Chemical System Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
⁷ Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: kido@iqb.u-tokyo.ac.jp.

Abstract

Hepatic stellate cells (HSCs) play a central role in the progression of liver fibrosis by producing extracellular matrices. The development of drugs to suppress liver fibrosis has been hampered by the lack of human quiescent HSCs (qHSCs) and an appropriate in vitro model that faithfully recapitulates HSC activation. In the present study, we developed a culture system to generate qHSC-like cells from human-induced pluripotent stem cells (hiPSCs) that can be converted into activated HSCs in culture. To monitor the activation process, a red fluorescent protein (RFP) gene was inserted in hiPSCs downstream of the activation marker gene actin alpha 2 smooth muscle (ACTA2). Using qHSC-like cells derived from RFP reporter iPSCs, we screened a repurposing chemical library and identified therapeutic candidates that prevent liver fibrosis. Hence, hiPSC-derived qHSC-like cells will be a useful tool to study the mechanism of HSC activation and to identify therapeutic agents.

Keywords: drug screening; hepatic stellate cells; induced pluripotent stem cells; liver fibrosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Culture Techniques*
Cell Cycle*
Drug Discovery*
Drug Evaluation, Preclinical
Gene Expression Profiling
Hepatic Stellate Cells / cytology*
Hepatic Stellate Cells / metabolism
Humans
Induced Pluripotent Stem Cells / cytology*
Induced Pluripotent Stem Cells / metabolism
Liver Cirrhosis / genetics
Liver Cirrhosis / pathology
Male
Mice
Mice, Inbred C57BL
Models, Biological*