Generation of zone-specific hepatocyte for study of liver injury and diseases

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K19657
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: General internal medicine and related fields
• Research Institution: Osaka University
• Principal Investigator: Takayama Kazuo 大阪大学, 薬学研究科, 助教 (10759509)
• Research Collaborator: Mizuguchi Hiroyuki ; Imagawa Kazuo ; Mitani Seiji
• Project Period (FY): 2017-06-30 – 2019-03-31
• Keywords: 肝細胞 / 毒性 / 薬物代謝 / zonation / ヒトiPS細胞 / ヒトES細胞

Outline of Final Research Achievements

The function of hepatocytes largely depends on their position in the liver lobule. Although the method of differentiating hepatocytes from human pluripotent stem cells has been largely improved over the past decade, there remains no technique for generating hepatocyte-like cells (HLCs) with zone-specific hepatic properties. In this study, we searched for the factors that promote acquisition of zone-specific properties of HLCs. Here, we identified that WNT7B and WNT8B play important roles in achieving perivenous zone-specific characteristics, such as the enhancement of glutamine secretion, citric acid cycle, cytochrome P450 (CYP) 1A2 metabolism, and CYP1A2 induction capacities. We also found that WNT inhibitory factor (WIF-1) was necessary for achieving periportal zone-specific characteristics, such as the enhancement of urea secretion and gluconeogenesis capacities. Therefore, WNT signal modulators conferred zone-specific hepatic properties onto HLCs.

Free Research Field

幹細胞学

Academic Significance and Societal Importance of the Research Achievements

医薬品の毒性判明による市場撤退・開発中止のうち、多くの事例で肝障害が認められることから、肝障害の高精度な予測技術は不可欠である。しかし、多くの肝障害にzone特異性が見られるものの、既存の創薬ではzone特異的なヒト肝細胞モデルが存在しないため、zonation情報を考慮した毒性予測試験が実施できなかった。本研究成果を応用することにより、肝臓を構成する肝細胞の不均一性を加味した医薬品の安全性試験を初めて実施できる可能性があり、従来の創薬プロセスを大きく進歩させる潜在性を有する。