Development of a hepatitis model

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22614
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Kido Taketomo 東京大学, 定量生命科学研究所, 特任講師 (00401034)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: 肝臓 / 肝細胞 / 星細胞 / 類洞内皮細胞 / 肝疾患

Outline of Final Research Achievements

The liver is a central organ for metabolism and homeostasis, and consists of parenchymal hepatocytes and non-parenchymal cells, such as hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs). Regardless of etiology, chronic liver injury induces fibrosis that often proceeds to cirrhosis and cancer. We have already established a protocol to generate HSCs and LSECs from iPSCs, which can be used to develop human liver model. In this study, we generated macrophages from iPSCs using the 2D culture method previously reported, with minor modifications. iPSC-derived CD45+CD14+ cells were found after 16 days of differentiation. CD14+ cells were induced into macrophages (M0) by M-CSF stimulation. These cells were polarized to the M1 or M2 state by LPS and IFNg, or IL4. We evaluated the ability of iPSC-derived macrophages to promote fibrosis in a co-culture system. HSC activation was observed by co-culture with iPSC-derived macrophages.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

現在開発中の肝疾患治療薬の多くは主に肝細胞を対象としており、線維化の主体である星細胞を対象としていない。各種の肝構成細胞を用いたin vitro肝炎モデルが開発されれば、肝細胞への障害を起点として誘導される星細胞の活性化を定量的に評価するスクリーニング系を開発することが可能である。よって、本研究は肝細胞のみを標的とした従来の薬剤探索法のブレークスルーとなることが期待でき、肝細胞と星細胞の両方を標的とした新たな肝疾患治療薬の開発に貢献することができる。