2021 Fiscal Year Final Research Report

Development and progression mechanism of NASH from the viewpoint of cell-cell interaction and medical application

Research Project

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Project/Area Number	19H01054
Research Category	Grant-in-Aid for Scientific Research (A)
Allocation Type	Single-year Grants
Section	一般
Review Section	Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
Research Institution	Kyushu University
Principal Investigator	Ogawa Yoshihiro 九州大学, 医学研究院, 教授 (70291424)
Co-Investigator(Kenkyū-buntansha)	国府島庸之九州大学, 医学研究院, 准教授 (00650748) 宮澤崇九州大学, 大学病院, 講師 (30443500)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	NASH / ミトコンドリア / 細胞間相互作用 / マクロファージ / シングルセルトランスクリプトーム解析
Outline of Final Research Achievements	This study focused upon hepatic crown-like structures (hCLS) as an origin of hepatic inflammation and fibrosis in the NASH liver, so that we may understand the pathogenesis of NASH, from the viewpoint of the crosstalk between parenchymal cells and non-parenchymal cells. We demonstrated that mitochondrial fission factor (Mff) plays an important role in the development of NASH. Using the single cell RNA sequencing (scRNA-seq) analysis, we identified a SPP1-positive macrophage cell population which increases during the progression from simple steatosis to NASH. The SPP-1 positive macrophages were located around hCLS and in close proximity to activated Ito cells. Recently, using a microdissection-based technique, we established a highly efficient method to obtain non-parenchymal cells from hCLS, which are to be subjected to scRNA-seq analysis.
Free Research Field	内科学、内分泌代謝学、糖尿病学
Academic Significance and Societal Importance of the Research Achievements	近年、糖尿病・肥満患者の増加や超高齢社会を背景として、NASHあるいはNASH肝癌の罹患率が急増している。NASHは肝不全や虚血性心疾患の発症に関連するため、脂肪肝からNASHを経て胞癌を発症する一連の病態変化の解明と予防・治療戦略の開発は喫緊の課題である。本研究により、我々が独自に開発したヒトNASH病態に酷似した新しいNASHマウスを用いて、肝実質細胞とマクロファージあるいは線維芽細胞などの間質細胞の相互作用に着目して、脂肪肝からNASHを経て肝癌を発症する一連の経時変化と分子機構を明らかにすることができ、現在有効な治療法がないNASHに対する医学応用の手掛かりが得られた。