Development of the novel therapy for NAFLD by Engineering Fatty Liver from iPS cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H03004
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyushu University
• Principal Investigator: Kazuki Takeishi 九州大学, 大学病院, 特別教員 (50733713)
• Co-Investigator(Kenkyū-buntansha): 三森 功士 九州大学, 大学病院, 教授 (50322748) ; 吉住 朋晴 九州大学, 医学研究院, 教授 (80363373)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: iPS細胞 / 脂肪性肝炎 / 肝硬変

Outline of Final Research Achievements

PNPLA3 variant was reported to be related with metabolic associated fatty liver disease. However, the mechanism has not been unveiled yet. The aim of this study is to generate iPSC-derived hepatic stellate cells (iHSC) from human-induced pluripotent stem cells (iPSC) with PNPLA3 single nucleotide polymorphism (SNP) and to clarify the mechanism of liver fibrosis caused by PNPLA3 SNP. Two types of iPSC (Wild, Variant) were differentiated into iHSC. TGF-β stimulation resulted in significantly higher secretion of the liver fibrosis markers, αSMA and Col1A1 in Variant-iHSCs than in Wild-iHSC. Variant-iHSC secreted significantly more PDGF and TGF-β, and had significantly higher cell proliferative and migration ability. AMIGO2 knockdown using siRNA in variant-iHSC significantly reduced migration and proliferation ability. The staining for AMIGO2 in cirrhotic liver and normal liver samples showed that AMIGO2 protein expression was observed in PNPLA3-variant samples.

Free Research Field

肝再生医療

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪性肝疾患(NAFLD)の一部は非アルコール性脂肪肝炎(nonalcoholic steatohepatitis; NASH)を発症し、肝硬変や肝細胞癌へと進展する。本邦におけるNAFLD の有病率は年々増え続けており、NAFLD/NASH への対策が急務であることは明らかであるが、現在まで有効な治療法は確立されていない。
今回の研究にて、PNPLA３　SNPを認める症例では、肝星細胞の活性化が惹起しやすく、AMIGO２遺伝子発現を介して起こっていることがわかった。このAMIGO2をターゲットとして、今後、治療法の確立につながる可能性が非常に高い。