| Project/Area Number |
18K08589
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 55010:General surgery and pediatric surgery-related
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| Research Institution | Shinshu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
増田 雄一 信州大学, 学術研究院医学系(医学部附属病院), 准教授 (60467149)
小山 誠 信州大学, 医学部附属病院, 助教(特定雇用) (80712778)
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| Project Period (FY) |
2018-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | iPS細胞 / 胆管細胞 / 胆汁鬱滞 / organ on chip / 3D biliary tube / iPS cell / cholangiocyte / Primary cilia / 肝内胆管 / シングルセルRNA解析 / 肝細胞 / オルガノイド / 一次繊毛 / Mechano-sensor / Ca2+シグナル / ヒトiPS細胞 / 3次元培養 / 薬剤スクリーニング / 再生医療 / 肝臓 / 胆管 / 胆汁酸合成 / Organ on chip |
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| Outline of Final Research Achievements |
Observing the interaction between cholangiocytes and bile flow under static conditions using conventional organoid technology has proven challenging. To address this, we established a method for obtaining functional cholangiocytes from iPS cells to create 3D bile duct tubes. By bypassing traditional 3D culture techniques, we successfully differentiated a substantial number of functional cholangiocytes through the use of chemical compounds, cytokines, and retinoic acid.
The differentiated cholangiocytes exhibited functional primary cilia and has demonstrated the capability to transport chloride ions. Additionally, we were able to differentiate cholangiocytes from cystic fibrosis patients iPS cells derived from, thereby creating for modeling disease in vitro. Utilizing 3D printing technology, we measured the function of these cholangiocytes in association with bile flow, providing a new insight for studying cholangiocyte-bile flow interactions and related liver functions in vitro.
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| Academic Significance and Societal Importance of the Research Achievements |
胆道上皮細胞は炎症、線維化などに起因する胆管障害により最終的には肝不全に至る。胆汁酸の過度の蓄積は胆管細胞や肝細胞への毒性を引き起こし、炎症プロセスの蓄積により重篤な肝不全を発症する。重症胆汁鬱滞性肝疾患に対する現在の唯一の有効な治療法は肝移植である。胆汁鬱滞性肝疾患の進行における基礎となる病態生理学的メカニズムは、未だに十分に理解されておらず、臨床使用可能な薬剤の胆汁クリアランスを決定することは非常に困難である。ヒトiPS細胞の技術的進歩は、胆汁を排出することができるヒト肝組織をiPS細胞から工学的に作製し、最終的には胆汁性肝疾患を治療するための細胞治療戦略の開発に応用することが可能になる。
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