The lineage plasticity fo mature hepatocytes during liver injury and regeneration

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08716
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: Tanimizu Naoki 札幌医科大学, 医学部, 准教授 (00333386)
• Research Collaborator: Mitaka Toshihiro 札幌医科大学, フロンティア医学研究所組織再生学部門, 教授 (50231618)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 肝臓 / 再生 / 肝細胞 / 分化可塑性 / 脱分化

Outline of Final Research Achievements

We focus on the lineage plasticity of hepatocytes and cholangiocytes during development and regeneration. After acetaminophen administration, SOX9(+) dedifferentiated hepatocytes appeared around the necrotic area, which was suppressed in aged livers. Given that the survival of mice was remarkably decreased, hepatocyte de-differentiation could be correlated with the protection of liver tissue. When hepatocytes were introduced with the intracellular domain of Notch 2 and Grhl2, they transdifferentiated into CK19(+) cholangiocyte-like cells after chronic injury. ON the other hand, Grhl2 null cholangiocytes isolated from chronically injured liver differentiated into hepatocytes in vitro. Furthermore, we found that part of hepatocyte express SOX9 during formation of hepatocellular carcinoma induced by diethylnitrosamine. Since SOX9 expression was observed before foci formation, de-differentiation could be involved in the early stage of tumorigenesis.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

肝疾患形成過程において肝細胞の脱分化が組織保護に寄与している可能性を見出した。また、NotchシグナルとGrhl2が協調して、肝上皮細胞の分化可塑性を制御することが明らかになった。NotchシグナルやGrhl2の活性を制御することで、障害時に出現する内在性の肝前駆細胞から肝細胞への分化をコントロールし、肝組織再生の促進に活用できる可能性がある。また、腫瘍形成初期に現れるSOX9(+)肝細胞を解析することで、肝細胞が癌化する際の初期に現れる変化を明らかにできる可能性を示すことができた。