In vivo reconstruction of iPS cell-derived human three dimensional hepatic tissue including neural network

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02874
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Yokohama City University
• Principal Investigator: KOIKE Naoto 横浜市立大学, 医学研究科, 客員教授 (50301081)
• Co-Investigator(Kenkyū-buntansha): 田所 友美 横浜市立大学, 医学部, 助教 (20507644) ; 谷口 英樹 東京大学, 医科学研究所, 教授 (70292555) ; 武部 貴則 横浜市立大学, 先端医科学研究センター, 教授 (20612625)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 高次肝組織 / 神経系 / 門脈域 / iPS

Outline of Final Research Achievements

The hepatic nerve fiver was observed to infiltrate into the liver from porta hepatis just before birth under histological examination using pre and postnatal mouse liver. And we speculated the intrahepatic nerve system play important roles in the maintenance of morphogenesis of the portal area of the liver. Therefore, the liver buds prepared from human iPS cell (iPSC)-derived hepatic progenitor cells, vascular endothelial cells, and mesenchymal stem cell, were cultured on nerve fibers obtained from three-dimensional culture of iPSC derived nerve progenitor cells in order to regenerate a micro-hepatic tissue having a portal area consisting of bile ducts, vessels and nerves. In the result, portal area like morphology (CK19-positive biliary epithelial cells formed bile ductal processes accompanied by nerves and blood vessels) were observed in the liver bud. The liver bud was implanted into the cranial window of the mouse and the process of development was observed under the microscope.

Free Research Field

肝胆道外科

Academic Significance and Societal Importance of the Research Achievements

肝内の自律神経は糖代謝、サーカジアンリズム、食欲に関与するほか、肝血流や肝再生に関与しているとも言われている。しかし、神経系の肝発生に関する意義ははっきりしていない。今回の研究で神経線維が肝内門脈域構築やその形態維持に関与している可能性を示唆する新たな知見を得ることができた。今回の方法でできた神経線維を有する高次肝組織が生体内で成熟し長期安定化できれば、本技術は肝疾患に対する再生医療に利用可能であり、本研究の究極の目的である絶対的に不足している移植臓器に取って代わる革新的な医療技術となりうると思われる。