2022 Fiscal Year Final Research Report

Elucidation of the physiological role of heterogeneous hepatocytes and its application to drug discovery and medicine

Research Project

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Project/Area Number	21K19885
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 90:Biomedical engineering and related fields
Research Institution	The University of Tokyo
Principal Investigator	Sakai Yasuyuki 東京大学, 大学院工学系研究科(工学部), 教授 (00235128)
Co-Investigator(Kenkyū-buntansha)	西川昌輝東京大学, 大学院工学系研究科(工学部), 講師 (40843149) 新宅博文国立研究開発法人理化学研究所, 開拓研究本部, 理研白眉研究チームリーダー (80448050)
Project Period (FY)	2021-07-09 – 2023-03-31
Keywords	肝細胞 / 創薬支援デバイス / 肝機能
Outline of Final Research Achievements	Hepatocytes have diverse karyotypes and approximately 60% are binuclear. However, the physiological role of their heterogeneity is still unknown. The aim of this study was to elucidate the physiological role of heterogeneous hepatocytes and their application in drug discovery and medicine. First, we examined the conditions to separate the binuclei into a single nucleus. We found that by lysing the cytoplasm after treatment with an inhibitor of cytoskeleton formation, the binuclei could be separated into a single nucleus without damaging their shapes. We also confirmed that cytoplasmic RNA could be sufficiently removed under these conditions. Furthermore, the two separated nuclei derived from the same cell could be collected separately using an auto-manipulator, and a library for RNA-seq was created from each single nucleus. Those findings and methodologies paved the way for gene expression analysis of each nucleus in the same cell.
Free Research Field	再生医工学
Academic Significance and Societal Importance of the Research Achievements	肝細胞のヘテロ性の生理学的役割の解明を目指す本研究は、肝臓のZonationのメカニズム理解に直結し、肝臓・肝細胞の培養系や数理モデルの精緻化による創薬や医療への貢献につながる重要な成果となる。メカニズムにもとづくボトムアップ的な肝臓の理解を達成することで、世界に類を見ないバーチャル肝臓の構築に発展しうる。バーチャル肝臓による薬物応答ダイナミズムの高精度な予測やその個別テーラーメード化は、近未来の創薬や医療のスタンダードになると考えられ、本研究はその進展に大きく貢献するものである。