Establishment of three dimensional HBV infection model which reflects the pathological progression

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K15773
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Himeno Misao 東京大学, 定量生命科学研究所, 特別研究員 (80706416)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: B型肝炎ウイルス / 星細胞 / 類洞内皮細胞 / iPS細胞 / 三次元培養

Outline of Final Research Achievements

I constructed an HBV infection model using liver parenchymal or non-parenchymal cells derived from iPS cells in this project.
I found that the liver progenitor cells derived from iPS cells expressed NTCP, an HBV infection receptor, which is not expressed in liver cancer cell lines. We clarified that liver sinusoidal endothelial cells induce cell surface expression of EGFR on the hepatocytes, which is a coupling factor of HBV infection, and increase the efficiency of HBV infection. And we also clarified that the hepatic stellate cells derived from iPS cells which we had been developed before are partially activated, therefore, we established a new differentiation method for quiescent stellate cells. Three-dimensional co-culture of these quiescent stellate cells and hepatocytes showed a development of HBV replication efficiency.
By all results stated above, we could establish a new HBV infection model which could be used for drug discovery or elucidation of pathology.

Free Research Field

基礎医学

Academic Significance and Societal Importance of the Research Achievements

HBVに感染し持続感染の状態になると、その排除が困難である上、肝硬変や肝細胞がんへと移行するリスクがあり治療法の開発が急務である。
現在、研究に用いられているHBV感染モデルは、材料の入手が困難である、または、臨床での多様な患者や生体内での感染に伴う反応を反映していないなど課題があった。本研究で開発したHBV感染モデルはiPS細胞を用いるため多様な患者背景を反映することが可能である。また、肝細胞単独培養では得られない細胞間の影響を調べることが可能となった。このモデルを用いることで新規創薬開発や病態の解明に役立つと期待される。