Treatment for metabolic liver diseases using human iPS-derived hepatic stem-like cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08808
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kansai Medical University
• Principal Investigator: Shirouzu Yasumasa 関西医科大学, 医学部, 講師 (20279186)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ヒトiPS細胞 / 肝細胞

Outline of Final Research Achievements

The hepatocyte transplantation has been less effective in curing the metabolic liver disease probably due to including few hepatic stem cells. We produced the hepatic stem-like cell (HSLC) expressing the hepatic stem cell marker X from human induced pluripotent stem cell (iPSC). And an iPSC (ALB-iPS) that contains an albumin allele linked to a Green Fluorescent Protein (GFP）gene was established for monitoring the differentiation toward the hepatic lineage. The ALB-iPS could be differentiated into the hepatocyte-like cell (HLC) expressing albumin accompanied by GFP, and cultivated continuously as the HSLC. The adjustment of chemicals made the ALB-iPS-derived HSLC more matured, and the expression of enzymes related with urea cycle and cytochrome P 450 specific to the loaded drug were confirmed with the GFP expression. Moreover, the HSLC could repopulate in the liver of immune-deficient mice. The HSLC was suggested to be a useful cell source for treating the metabolic liver disease.

Free Research Field

肝臓

Academic Significance and Societal Importance of the Research Achievements

代謝異常性肝疾患は臓器移植に比べてより低侵襲な細胞移植での治療が可能と考えられているが、その効果は限定的である。移植した細胞の生体内での長期生着が困難なことが原因の一つと考えられ、臨床応用のハードルになっている。肝臓には自己複製能と分化能を併せ持ち組織再構築に寄与する組織幹細胞が存在する。本研究ではヒトiPS細胞から肝幹細胞様細胞を誘導する技術が開発され、免疫不全マウスに移植後肝臓内に生着することが確認された。現在肝臓移植以外に治療法のない、特に小児の代謝異常性肝疾患に対し、本研究で開発された肝幹細胞様細胞を用いた移植治療が、新たな標準治療になりうる可能性が示された。