Effect of extracellular matrix on hepatocyte function in liver cirrhosis

• Project/Area Number: 17H06749
• Research Category: Grant-in-Aid for Research Activity start-up
• Allocation Type: Single-year Grants
• Research Field: Digestive surgery
• Research Institution: Kyoto University
• Principal Investigator: Ogiso Satoshi 京都大学, 医学研究科, 助教 (10804734)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 脱細胞化 / 線維化 / 肝硬変 / 肝細胞 / 細胞外基質 / 上皮間葉転換 / インテグリン / FAK

Outline of Final Research Achievements

Hepatocyte decreased hepatocytic protein synthesis and gene expression, when cultivated within the extracellular matrix derived from fibrotic liver. Hepatocyte also increased EMT-associated gene expressions of Snail1 and Vimentin, gene expression of integrinβ1, and phosphorylated FAK protein. After treated with the FAK inhibitor, hepatocyte decreased gene expression of Snail1 and increased gene expression of HNF4a. The outcomes demonstrate that liver fibrosis activates integrin-FAK signal between extracellular matrix and hepatocytes to impair hepatocytic funtion, possibly through inducing EMT. Furthermore, FAK inhibitor is a candidate of drugs to recover liver function impaired by liver fibrosis.

Academic Significance and Societal Importance of the Research Achievements

慢性肝疾患の進行に伴って肝に線維化が起こり肝硬変に至ると、その根本的治療は困難です。本研究では、この肝の線維化に伴う細胞外基質の変化が、そこに生着する肝細胞機能へシグナルを送り上皮間葉転換という変化を通して肝細胞機能を低下させていることを明らかにしました。また、そのインテグリン―FAKシグナル・シグナルを薬剤でブロックすることにより肝細胞機能の回復することが確認され、治療手段の限られる肝硬変の新たな治療選択肢となりうる可能性が示されました。

Research Products

• [Journal Article] A Novel Three-Dimensional Culture System: Decellularized-Tissue Obtained from Cirrhotic Livers Enhances an Epithelial-Mesenchymal Transition Phenotype in Hepatocellular Carcinoma Cells (2017)
  • Author(s): Miyauchi Yuya、Yasuchika Kentaro、Fukumitsu Ken、Ishii Takamichi、Ogiso Satoshi、Kojima Hidenobu、Yamaoka Ryoya、Katayama Hokahiro、Kawai Takayuki、Uemoto Shinji
  • Journal Title: Journal of the American College of Surgeons Volume: 225
  • DOI: 10.1016/j.jamcollsurg.2017.07.455
  • Peer Reviewed
• [Presentation] 細胞外基質による微小環境は肝細胞癌の不均一性に寄与する (2018)
  • Author(s): 宮内 雄也
  • Organizer: 第54回肝癌研究会
• [Presentation] A novel culture system preserving natural scaffolds of fibrotic livers accelerates progression of hepatocellular carcinoma cells (2018)
  • Author(s): Yuya Miyauchi
  • Organizer: APASL Single Topic Conference 2018 on HCC
• [Presentation] A novel three-dimensional culture system, decellularized-tissue obtained from cirrhotic livers, enhances an epithelial-mesenchymal transition phenotype in HCC cells (2017)
  • Author(s): Yuya Miyauchi, Kentaro Yasuchika, Ken Fukumitsu, Takamichi Ishii, Satoshi Ogiso, Hidenobu Kojima, Ryoya Yamaoka, Hokahiro Katayama, Takayuki Kawai, Shinji Uemoto
  • Organizer: American collage of Surgeons, Clinical Congress 2017
  • Int'l Joint Research