Study on the regulatory mechanisms of macrophage in the fundamental process of liver fibrosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02801
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Tanaka Minoru 国立研究開発法人国立国際医療研究センター, その他部局等, 細胞療法開発研究室長 (80321909)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 線維化 / マクロファージ / 星細胞 / サイトカイン / 細胞間相互作用

Outline of Final Research Achievements

In this research, based on the discovery that Oncostatin M (OSM) exhibits a powerful fibrotic activity in liver fibrosis, we shed light on a crucial role of cell-cell interaction between hepatic stellate cells and the other non-parenchymal cells during liver fibrogenesis. Especially, we focused on two hepatic macrophages, Kupffer cells (KC), a resident hepatic macrophage and bone marrow-derived macrophages (BMDM). To find OSM-dependent factors relevant to liver fibrosis, we compared the gene expression profiles of KC and BMDM from wild-type and OSM KO mice, which were subjected to chronic hepatitis by RNA-seq analysis. As a result, we could identify several factors of which expression is upregulated in fibrotic liver. Among them, we found that a few factors could induce liver fibrosis in normal liver by their enforced expression via adeno-associated viral vector. Thus, we succeeded to identifying novel secretory factors from macrophages related to liver fibrogenesis.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

慢性肝障害が長い経過を辿ると肝線維化が進行し、やがては肝硬変・肝発がんに至る。そのため、肝線維化の治療法の開発は喫緊の課題となっているが、未だ有効な治療法は確立されていない。肝線維化は多くの細胞が関わる複雑なプロセスにより進行することが想定されているが、その全容については不明な点が多く残る。本研究では肝星細胞と肝マクロファージ間の細胞間相互作用が肝線維化において重要であることを明らかにするとともに、マクロファージが産生する新規線維化促進因子の同定にも成功しており、今後、新たな治療法の開発につながることが期待される。