Development of the novel therapy for Liver Failure by Engineering Liver Graft from iPS cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18152
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyushu University
• Principal Investigator: Kazuki Takeishi 九州大学, 大学病院, 助教 (50733713)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: iPS細胞 / 人工肝臓 / 肝不全 / 肝硬変

Outline of Final Research Achievements

We have established an optimized differentiation protocol . Most important transcription factors (HNF4alpha and FOXA2 etc) related to liver regeneration are expressed in the resulting cells at the same levels as human adult hepatocytes. In order to establish an animal model for liver repopulation and generate sufficient number of highly functional iPSCs-Heps,　we transplanted five million iPSCs-Heps into SCID rats. At 90d after transplantation both iPSCs-Heps engrafted and started to form colonies of growing human liver tissue implying that repopulation of iPSCs-Heps in rat's liver succeeded. We tried to isolate human iPSCs-Heps from rats livers, but the cells still contained rat's cells. We are making the new SCID rat which has Cris-Cas9 genes. We are trying to delete the rat cells by induction of suicide genes in rat livers.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

肝不全に対する唯一の治療は肝移植であるがドナー不足は深刻で拒絶反応も問題となる。本人の細胞から人工肝臓が作成できればこれらの問題を解決できる。iPS細胞は再生医療への応用が期待されているが、人工肝臓の作成には至っていない。この原因は、iPS細胞から肝細胞を大量に作成できないからである。今回、我々はiPS細胞から肝細胞を作成し、免疫抑制ラットに移植することで、ラットの肝臓内で大量のiPS細胞由来肝細胞を作成することに成功した。このことにより臨床に必要な大量の肝細胞を作成でき、iPS由来肝細胞が生体内でも十分に機能することが証明され、今後、肝不全への臨床応用に向けてブレイクスルーとなり得る。