Elucidating the Molecular Mechanism of Liver Fibrosis Improvement with Implantation of Adipose Stem Cells Cultured on Discs

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07970
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kanazawa Medical University
• Principal Investigator: OZAKI Kazuaki 金沢医科大学, 医学部, 准教授 (20329379)
• Co-Investigator(Kenkyū-buntansha): 飯田 安保 金沢医科大学, 一般教育機構, 准教授 (10337173)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ヒト脂肪由来幹細胞 / 脂肪由来幹細胞付きシート / 肝硬変モデルラット / 肝線維化改善

Outline of Final Research Achievements

Culturing human adipose tissue-derived stem cells (ADSCs) on a specialized disc and applying it to cirrhotic livers in rats resulted in the improvement of hepatic fibrosis and suppression of TGF-β1 and α-SMA expression even in distant liver lobes. This suggests that factors produced by ADSCs might have diffused systemically through the bloodstream. ADSCs administration led to dose-dependent improvements in serum AST, ALT, total protein, and albumin levels. Immunostaining revealed an increase in the cell proliferation marker PCNA, indicating liver function improvement through hepatocyte regeneration. When rat hepatocytes and ADSCs were co-cultured and exposed to carbon tetrachloride, cell death was not suppressed even with a 0.03 μm filter that prevents exosome passage, suggesting that the factors produced by ADSCs might not be exosomal.

Free Research Field

肝臓病学

Academic Significance and Societal Importance of the Research Achievements

肝移植に代わる肝硬変の根治療法が模索されている状況で、我々は脂肪由来幹細胞（ADSCs）をシート上で培養しそのまま硬変肝に貼付する方法で肝線維化が改善することを見出していたが、その詳細な機序は不明であった。本研究で示唆された「移植したADSCsから放出されるある種の因子が血行性に拡散して作用し、TGF-β1の発現を抑制することにより肝星細胞の活性化が低下する結果、肝線維化が抑制される」という機序は、今後の臨床試験へ向けてのプロトコール開発に寄与するものであり、学術的意義および社会的意義が高いものと考える。