Elucidation of hepatocarcinogenesis mechanism using gene-edited iPSCs and iPSC-derived hepatic organoid system

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15942
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Masato Miyoshi 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20844385)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: iPS由来肝細胞 / オルガノイド / 肝細胞癌 / HBVインテグレーション

Outline of Final Research Achievements

The two aims of this study are to establish a culture system of human induced pluripotent stem cell (iPSC)-derived hepatocyte organoids with high phenotype of hepatocyte and to investigate the process of hepatocarcinogenesis using gene-edited iPSCs.
Through optimization of the hepatocyte induction method from iPSCs and subsequent 3D culture conditions, we successfully developed a culture system that maintains proliferation and hepatic phenotype. Additionally, iPSC lines were generated that replicate the HBV integration identified in hepatocellular carcinomas in our in-house database. After differentiation into the hepatocyte lineage, these established iPSC-derived hepatic cells exhibited enhanced proliferative capacity. As a result, a pathological model was successfully created that partially mimics the mechanism of hepatocarcinogenesis. Our research team is currently identifying therapeutic targets based on the elucidation of the mechanism underlying this enhanced proliferation.

Free Research Field

肝再生、肝細胞癌

Academic Significance and Societal Importance of the Research Achievements

本研究では、従来では不可能であった肝細胞性を高く保持しながら維持培養が可能である新規ヒトiPS細胞由来肝細胞オルガノイド培養系を構築することができた。増殖する肝細胞という新規プラットフォームの有用性の高さから、学術集会で主題演題としての発表を行うなど高い評価を得た。また、HBVインテグレーションを再現したiPS細胞を解析することで肝細胞癌におけるHBVインテグレーションのメカニズムの解明を行った。同様に複数の学会で発表し、学会賞を受賞するなど高い評価を得た。