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

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

Keywords

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

ASJC Scopus subject areas

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

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