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Study of liver restorative therapy for a murine nonalcoholic steatohepatitis model by the administration of immune-suppressive fractions of autologous adipose tissue-derived stromal cells

研究課題

研究課題/領域番号 20K08327
研究種目

基盤研究(C)

配分区分基金
応募区分一般
審査区分 小区分53010:消化器内科学関連
研究機関金沢大学

研究代表者

Nasti Alessandro  金沢大学, 医薬保健学総合研究科, 特任准教授 (20830871)

研究分担者 関 晃裕  金沢大学, 附属病院, 助教 (00733859)
酒井 佳夫  金沢大学, 医学系, 協力研究員 (80401925)
研究期間 (年度) 2020-04-01 – 2025-03-31
研究課題ステータス 交付 (2023年度)
配分額 *注記
4,420千円 (直接経費: 3,400千円、間接経費: 1,020千円)
2022年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円)
2021年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円)
2020年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円)
キーワードNASH / SS / ADSC / uncultured ADSCs / SVF / Immune therapy / adipose tissue (AT)
研究開始時の研究の概要

Nonalcoholic steatohepatitis (NASH) is a liver disease with no established treatment. Adipose tissue-derived stromal cells (ADSCs) are able to repair damaged tissues by means of immunomodulation and secretive ability; we will study the repairing of NASH cirrhosis by using NASH mice-derived ADSCs.

研究実績の概要

Non-alcoholic fatty liver disease (NAFLD) affects millions of people worldwide, often leading to non-alcoholic steatohepatitis (NASH), fibrosis, and eventually cirrhosis. Despite its prevalence, effective treatments remain elusive due to limited understanding of the complex molecular mechanisms driving NAFLD progression. Adipose-derived stem cells (ADSCs) is a candidate for treating liver diseases, since ADSCs promote tissue repair and modulate immune responses. We established a murine model of NASH using high-fat diet feeding and assessed the effect of ADSC administration on liver histopathology and gene expression profiles. We discovered that ADSCs activated Notch signaling in the cirrhotic liver of NASH mice, resulting in enhanced HES1 expression - a downstream target of Notch - and increased numbers of HES1-expressing hepatocytes. To corroborate these findings, we performed immunohistochemistry analyses, revealing robust Notch receptor and ligand induction upon ADSC exposure. Given the known roles of Notch signaling in regulating cellular functions such as proliferation, differentiation, and apoptosis, we confirmed that ADSC-mediated Notch activation might influence liver regeneration and cell survival during NASH progression. Indeed, ADSC treatment promoted liver regeneration, evidenced by increased alpha-fetoprotein (AFP) expression - a marker of hepatic progenitor cells - in the livers of NASH animals. Furthermore, we showed that ADSCs mitigated apoptosis in NASH-cirrhotic liver tissue, marked by substantially fewer TUNEL-positive cells following ADSC intervention.

現在までの達成度 (区分)
現在までの達成度 (区分)

2: おおむね順調に進展している

理由

Overall, this data provides novel insight into the therapeutic potential of ADSC therapy in managing NASH-associated liver injury. Notch signaling, as a critical mediator of ADSC-driven benefits, offers exciting prospects for refining current treatment paradigms and developing targeted interventions for patients afflicted by NAFLD and related disorders. Further investigation is warranted to fully understand the intricate interplay between ADSCs and Notch signaling in the context of liver physiology and pathophysiology. Although Covid-19 pandemic and the 2024 Noto Peninsula Earthquake slowed down the progression of the experiments in the FY2020-FY2023 period, the overall project is progressing smoothly.

今後の研究の推進方策

For FY2024, we plan to use ADSCs as treatment for NASH, understanding the proven mechanism of reduced apoptosis in hepatocyte cell line, and how this effect might be dependent on Notch signaling.

報告書

(3件)
  • 2023 実施状況報告書
  • 2021 実施状況報告書
  • 2020 実施状況報告書
  • 研究成果

    (10件)

すべて 2024 2021 2020

すべて 雑誌論文 (3件) (うち国際共著 3件、 査読あり 3件、 オープンアクセス 3件) 学会発表 (7件) (うち国際学会 6件)

  • [雑誌論文] Characterization of adipose tissue-derived stromal cells of mice with nonalcoholic fatty liver disease and their use for liver repair2021

    • 著者名/発表者名
      Yano M, Honda M, Wada T, Kaneko S, Sakai Y.(ほか17名、19番目)
    • 雑誌名

      Regenerative Therapy

      巻: 18 ページ: 497-507

    • DOI

      10.1016/j.reth.2021.11.005

    • 関連する報告書
      2021 実施状況報告書
    • 査読あり / オープンアクセス / 国際共著
  • [雑誌論文] Restorative effect of adipose tissue-derived stem cells on impaired hepatocytes through Notch signaling in non-alcoholic steatohepatitis mice2021

    • 著者名/発表者名
      Ishida Kosuke、Seki Akihiro、Kawaguchi Kazunori、Nasti Alessandro、Yamato Masatoshi、Inui Hiiro、Komura Takuya、Yamashita Taro、Arai Kuniaki、Yamashita Tatsuya、Mizukoshi Eishiro、Honda Masao、Wada Takashi、Harada Kenichi、Kaneko Shuichi、Sakai Yoshio
    • 雑誌名

      Stem Cell Research

      巻: 54 ページ: 102425-102425

    • DOI

      10.1016/j.scr.2021.102425

    • 関連する報告書
      2021 実施状況報告書
    • 査読あり / オープンアクセス / 国際共著
  • [雑誌論文] Regenerative Therapy for Liver Cirrhosis Based on Intrahepatic Arterial Infusion of Autologous Subcutaneous Adipose Tissue-Derived Regenerative (Stem) Cells: Protocol for a Confirmatory Multicenter Uncontrolled Clinical Trial.2020

    • 著者名/発表者名
      Y Sakai, S Fukunishi, M Takamura, O Inoue, S Takashima, S Usui, A Seki, A Nasti, T Ho, K Kawaguchi, A Asai, Y Tsuchiimura, T Muraymoto, T Yamashita, T Yamashita, E Mizukoshi, M Honda, Y Imai, K Yoshama, T Wada, K Harada, K Higuchi, S Kaneko
    • 雑誌名

      JMIR Res Protoc

      巻: 9 号: 3 ページ: e17904-e17904

    • DOI

      10.2196/17904

    • 関連する報告書
      2020 実施状況報告書
    • 査読あり / オープンアクセス / 国際共著
  • [学会発表] Mesenchymal stromal cells improves liver function in NASH by reducing the ER stress induced by hepatic stellate cells in hepatocytes.2024

    • 著者名/発表者名
      Akihiro Seki, Norihiko Ogawa, Alessandro Nasti, Tuyen Thuy Bich Ho, Yoshio Sakai, Taro Yamashita.
    • 学会等名
      The 33rd Annual Meeting of the Asian Pacific Association for the Study of the Liver (APASL)
    • 関連する報告書
      2023 実施状況報告書
  • [学会発表] Jagged1 ON ADIPOSE TISSUE-DERIVED STROMAL / STEM CELLS IS INVOLVED IN THE RESTORATIVE EFFECT ON MURINE NON-ALCOHOLIC STEATOHEPATITIS.2021

    • 著者名/発表者名
      Kosuke Ishida, Yoshio Sakai, Akihiro Seki, Kazunori Kawaguchi, Alessandro Nasti, Takashi Wada and Shuichi Kaneko
    • 学会等名
      AASLD, The Liver Meeting 2021
    • 関連する報告書
      2021 実施状況報告書
    • 国際学会
  • [学会発表] Restorative effect of adipose tissue-derived mesenchymal stem cells towards impaired hepatocytes via Notch signaling in a murine model of non-alcoholic steatohepatitis mice2021

    • 著者名/発表者名
      Kosuke Ishida, Yoshio Sakai, Akihiro Seki, Kazunori Kawaguchi, Alessandro Nasti, Hiiro Inui, Takashi Wada, Shuichi Kaneko
    • 学会等名
      The 44th Annual Meeting of the Molecular Biology Society of Japan
    • 関連する報告書
      2021 実施状況報告書
    • 国際学会
  • [学会発表] Therapy with adipose tissue-derived mesenchymal stromal/stem cells for NASH mice enhance the activation of Notch signaling and alleviate apoptosis in hepatocytes.2020

    • 著者名/発表者名
      Kosuke Ishida, Yoshio Sakai, Akihiro Seki, Kazunori Kawaguchi, Alessandro Nasti, Hiiro Inui, Takashi Wada, Shuichi Kaneko
    • 学会等名
      AASLD, The Liver Meeting 2020
    • 関連する報告書
      2020 実施状況報告書
    • 国際学会
  • [学会発表] Adipose tissue-derived stromal cells of steatohepatitis mice are useful for treatment of fibrosis-progressive NASH2020

    • 著者名/発表者名
      Akihiro Seki, Yoshio Sakai, Alessandro Nasti, Masatoshi Yamato, Kosuke Ishida, Hiiro Inui, Tuyen Thuy Bich Ho, Kazunori Kawaguchi, Takashi Wada, Shuichi Kaneko
    • 学会等名
      AASLD, The Liver Meeting 2020
    • 関連する報告書
      2020 実施状況報告書
    • 国際学会
  • [学会発表] Investigator-initiated clinical trial of autologous adipose tissue-derived regenerative (stem) cells therapy for steatohepatitis-related cirrhosis.2020

    • 著者名/発表者名
      Yoshio Sakai, Shinya Fukunishi, Masayuki Takamura, Oto Inoue, Soichiro Usui, Shinichiro Takashima, Kazunori Kawaguchi, Akihiro Seki, Akira Asai, Yusuke Tsuchimoto, Alessandro Nasti, Tuyen Thuy Bich Ho, Kazuhide Higuchi, Shuichi Kaneko
    • 学会等名
      AASLD, The Liver Meeting 2020
    • 関連する報告書
      2020 実施状況報告書
    • 国際学会
  • [学会発表] Adipose tissue derived stromal/stem cells suppress the hepatocyte apoptosis by restoring the Atf6 pathway activity in NASH mice.2020

    • 著者名/発表者名
      Masatoshi Yamato, Yoshio Sakai, Hiiro Inui, Akihiro Seki, Alessandro Nasti, Kosuke Ishida, Tuyen Thuy Bich Ho, Kazunori Kawaguchi, Takashi Wada, Shuichi Kaneko
    • 学会等名
      AASLD, The Liver Meeting 2020
    • 関連する報告書
      2020 実施状況報告書
    • 国際学会

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公開日: 2020-04-28   更新日: 2024-12-25  

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