In vitro reconstruction of hepatic tissue

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K19703
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Sapporo Medical University
• Principal Investigator: Mitaka Toshihiro 札幌医科大学, 医学部, 教授 (50231618)
• Co-Investigator(Kenkyū-buntansha): 谷水 直樹 札幌医科大学, 医学部, 准教授 (00333386) ; 吉川 大和 東京薬科大学, 薬学部, 准教授 (20274227) ; 須藤 亮 慶應義塾大学, 理工学部(矢上), 准教授 (20407141) ; 市戸 義久 札幌医科大学, 医学部, 研究員 (80452978)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Keywords: 小型肝細胞 / 胆管上皮細胞 / 毛細胆管 / 胆管 / ヘリング管 / 胆汁 / 組織構築 / 細胞培養

Outline of Final Research Achievements

We developed the method to reconstruct hepatic organoids consisting of mouse hepatocytes and cholangiocytes, which could drain bile juice into bile ducts from bile canaliculi formed by hepatocytes. Cholangiocytes are cultured on collagen gel and then hepatocytes are added. After collagen gel containing Matrigel is overlaid on the cells, hepatic organoids with the connections between bile canaliculi and bile ducts are formed within 2 weeks.
Hepatocytic parental progenitor cells (HPPCs) with self-renewal capability exist in a population of small hepatocytes, which is a subpopulation of mature hepatocytes. HPPCs could be passaged several times with maintaining their abilities of basic hepatic functions and production of progeny. Self-renewal capability of HPPCs is maintained when they are cultured on laminin 111, which transduces the signal via integrin beta1.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

肝細胞中にself-renewal能を有する肝前駆細胞(HPPCs)が存在することが分かり、ヒト肝細胞中からもHPPCsを分離増殖させられる可能性がでてきた。またヒト肝細胞を増殖させ胆管を組み込んだ類肝組織を形成することにより、排泄された胆汁が胆管に流れ、その毒性が軽減され、高分化機能を維持したまま長期培養出来ることが期待される。更に、生体内と同様に代謝され胆汁中に排泄された薬剤代謝物の回収が可能になる。この成果は、これまで動物個体を使うしかなかった創薬研究のkeyになるADMEをin vitroで代替出来る可能性と人工臓器の開発に繋がる可能性を示している。