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, L L Wang, Tadanori Yamada, Yasuyuki Sakai, Ryuichiro Nakato, Atsushi Miyajima, Taketomo Kido
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.