4.8 Article

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

期刊

BIOMATERIALS
卷 286, 期 -, 页码 -

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2022.121575

关键词

Hepatic organoid; Drug metabolism; Toxicity testing; Liver; Cytochrome P450

资金

  1. Korea Institute of Toxicology [1711133839]
  2. Bio AMP
  3. Medical Technology Development Program of the National Research Foundation (NRF) [2018M3A9H1021384]
  4. Technology Innovation Program - Ministry of Trade, Industry Energy [20009350]
  5. National Research Foundation of Korea - Korean Government [2021R1A2C2004696]
  6. National Research Foundation of Korea [2018M3A9H1021384, 2021R1A2C2004696] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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This study aims to generate liver organoids with high drug metabolic ability using human pluripotent stem cells. The fully differentiated organoids exhibit cellular polarity, hepatobiliary structures, and remarkable drug metabolic function. They can also successfully model Wilson's disease and provide an advanced tool for studying hepatic drug metabolism and diseases.
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.

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