Development of human pluripotent stem cell-derived hepatic organoids as an alternative model for drug safety assessment

Hyemin Kim, Ilkyun Im, Jang Su Jeon, Eun Hye Kang, Hyang Ae Lee, Seongyea Jo, Ji Woo Kim, Dong Hun Woo, Young Jae Choi, Hyo Jin Kim, Ji Seok Han, Byoung Seok Lee, Jong Hoon Kim, Sang Kyum Kim, Han Jin Park

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Human in vitro hepatic models that faithfully recapitulate liver function are essential for successful basic and translational research. A limitation of current in vitro models, which are extensively used for drug discovery and toxicity testing, is the loss of drug metabolic function due to the low expression and activity of cytochrome P450 (CYP450) enzymes. Here, we aimed to generate human pluripotent stem cell-derived hepatic organoids (hHOs) with a high drug metabolic ability. We established a two-step protocol to produce hHOs from human pluripotent stem cells for long-term expansion and drug testing. Fully differentiated hHOs had multicellular composition and exhibited cellular polarity and hepatobiliary structures. They also displayed remarkable CYP450 activity and recapitulated the metabolic clearance, CYP450-mediated drug toxicity, and metabolism. Furthermore, hHOs successfully modeled Wilson's disease in terms of Cu metabolism, drug responses, and diagnostic marker expression and secretion. In conclusion, hHOs exhibit high capacity for drug testing and disease modeling. Hence, this hepatic model system provides an advanced tool for studying hepatic drug metabolism and diseases.

Original languageEnglish
Article number121575
JournalBiomaterials
Volume286
DOIs
Publication statusPublished - 2022 Jul

Bibliographical note

Funding Information:
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Han-Jin Park reports financial support was provided by Korea Institute of Toxicology . Han-Jin Park reports financial support was provided by Korea Ministry of Science and ICT . Han-Jin Park reports financial support was provided by Korea Ministry of Trade Industry and Energy . Sang Kyum Kim reports financial support was provided by by National Research Foundation of Korea . Han-Jin Park has patent # PCT/KR2021/005001 pending to Korea Research Institute of Chemical Technology .

Funding Information:
This research was supported by the Korea Institute of Toxicology ( 1711133839 ), the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT ( 2018M3A9H1021384 ), the Technology Innovation Program funded by the Ministry of Trade, Industry & Energy ( 20009350 ), and a National Research Foundation of Korea Grant funded by the Korean Government ( 2021R1A2C2004696 ).

Publisher Copyright:
© 2022

Keywords

  • Cytochrome P450
  • Drug metabolism
  • Hepatic organoid
  • Liver
  • Toxicity testing
  • Wilson's disease

ASJC Scopus subject areas

  • Mechanics of Materials
  • Ceramics and Composites
  • Bioengineering
  • Biophysics
  • Biomaterials

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