Therapeutic effects and mechanisms of inflammatory bowel disease using immunomodulatory effects of iPS cell-derived mesenchymal stem cells

• Project/Area Number: 19K23983
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0903:Organ-based internal medicine and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Akihiro Seki 金沢大学, 医学系, 特任助教 (00733859)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 間葉系幹細胞 / 炎症性腸疾患 / iPS細胞

Outline of Research at the Start

炎症の関連する消化器疾患である，炎症性腸疾患が急増しているが，完全な治療法は確立されておらず，消化器疾患領域の重要な課題となっている．間葉系幹細胞(MSC)は，炎症修飾作用を有することが知られている．このため，炎症修飾効果を有するMSCを用いる炎症性腸疾患治療への応用の可能性が示唆されている．
本研究では，炎症性腸疾患モデルを用いiPS細胞からのMSCへの分化誘導，培養とiPS由来MSCの炎症性腸疾患に対する治療効果および炎症修飾機序の詳細解明を目的とする．本研究の発展は，炎症性腸疾患に対するiPS細胞を用いる治療のトランスレーショナルリサーチの基盤となる．

Outline of Final Research Achievements

Inflammatory bowel disease (IBD) is one of the most common gastrointestinal diseases caused by inflammation, and its incidence has been increasing in Japan、recent years. Biologics have been developed for the treatment of IBD because of their anti-inflammatory effects, and although they have shown some efficacy, the clinical improvement rate is only about 50%. Mesenchymal stem cells (MSCs), which are part of the mesenchymal stromal cell population, are known to possess not only multipotency but also inflammation modifying properties. In this study, we investigated the effect of MSCs on inflammatory bowel disease. The purpose of this study was to establish the basis for the establishment of a novel therapy for inflammatory bowel disease using MSCs.

Academic Significance and Societal Importance of the Research Achievements

間葉系幹細胞(MSC)の炎症性腸疾患に対する治療効果を確認した．さらに均一な細胞の安定的な供給を目的としてiPS細胞からMSCへの分化誘導と培養を確立した．同様に炎症が疾患を惹起する非アルコール性脂肪肝炎モデルマウスを用い，MSCが肝臓の間質の細胞に対し，抑制的に働くことにより，間質細胞を介した実質細胞障害を回避する新たな機序の詳細を解明し，第107回日本消化器病学会総会の主題演題として報告した．現在は以上の成果を踏まえ，炎症性腸疾患モデルマウスの腸管において間質細胞を介した腸管炎症の軽減機序の解析を行っており，MSCを用いた炎症性腸疾患に対する新規治療確立に向けた基盤の形成が期待される。

Research Products

• [Journal Article] BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma (2021)
  • Author(s): Chen Han、Nio Kouki、Yamashita Taro、Okada Hikari、Li Ru、Suda Tsuyoshi、Li Yingyi、Doan Phuong Thi Bich、Seki Akihiro et.al
  • Journal Title: Molecular Oncology Volume: not available Issue: 8 Pages: 2203-2218
  • DOI: 10.1002/1878-0261.12963
  • Peer Reviewed / Open Access
• [Journal Article] LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH (2021)
  • Author(s): Takata Noboru、Ishii Kiyo-aki、Takayama Hiroaki、Nagashimada Mayumi、Kamoshita Kyoko、Tanaka Takeo、Kikuchi Akihiro、Takeshita Yumie、Matsumoto Yukako、Ota Tsuguhito、Yamamoto Yasuhiko、Yamagoe Satoshi、Seki Akihiro、Sakai Yoshio、Kaneko Shuichi、Takamura Toshinari
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 555-555
  • DOI: 10.1038/s41598-020-80689-0
  • Peer Reviewed / Open Access
• [Journal Article] Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis (2020)
  • Author(s): Ho Tuyen Thuy Bich、Nasti Alessandro、Seki Akihiro、Komura Takuya、Inui Hiiro、Kozaka Takashi、Kitamura Yoji、Shiba Kazuhiro、Yamashita Taro、Yamashita Tatsuya、Mizukoshi Eishiro、Kawaguchi Kazunori、Wada Takashi、Honda Masao、Kaneko Shuichi、Sakai Yoshio
  • Journal Title: Journal for ImmunoTherapy of Cancer Volume: 8 Issue: 2 Pages: e001367-e001367
  • DOI: 10.1136/jitc-2020-001367
  • NAID: 120007185659
  • Peer Reviewed / Open Access
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: JMIR Res Protoc Volume: 9 Issue: 3 Pages: e17904-e17904
  • DOI: 10.2196/17904
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice (2020)
  • Author(s): Torres Joana、Hu Jianzhong、Seki Akihiro, et. al
  • Journal Title: Gut Volume: 69 Issue: 1 Pages: 42-51
  • DOI: 10.1136/gutjnl-2018-317855
• [Presentation] 非アルコール性脂肪肝炎マウスの小胞体ストレスと脂肪組織由来間質細胞投与による治療効果機序の検討 (2021)
  • Author(s): 関 晃裕, 酒井 佳夫, 金子 周一
  • Organizer: 第107回日本消化器病学会 総会
• [Presentation] Regenerative effect of adipose tissue-derived stromal cell administration in non-alcoholic steatohepatitis mice was mediated via Notch signaling system (2020)
  • Author(s): Akihiro Seki, Yoshio Sakai, Kazunori Kawaguchi, Kosuke Ishida, Masatoshi Yamato, Alessandro, Nasti, Takashi Wada, Shuichi Kaneko
  • Organizer: keystone symposia 2020 Stromal Cells in Immunity and Disease
  • Int'l Joint Research
• [Presentation] ADIPOSE TISSUE-DERIVED STROMAL CELLS OF STEATOHEPATITIS MICE ARE USEFUL FOR TREATMENT OF FIBROSIS-PROGRESSIVE NASH (2020)
  • Author(s): Akihiro Seki , Yoshio Sakai , Alessandro Nasti , Dr. Masatoshi Yamato , Kosuke Ishida , Hiiro Inui , Tuyen Thuy Bich Ho , Kazunori Kawaguchi , Takashi Wada and Shuichi Kaneko
  • Organizer: AASLD Liver meeting 2020
• [Presentation] Regenerative effect of adipose tissue-derived stromal cell administration in non-alcoholic steatohepatitis mice was mediated via Notch signaling system (2020)
  • Author(s): Akihiro Seki, Yoshio Sakai, Kazunori Kawaguchi, Kosuke Ishida, Masatoshi Yamato, Alessandro, Nasti, Takashi Wada, Shuichi Kaneko
  • Organizer: 2020 Keystone Symposia Conference Q5: Stromal Cells in Immunity and Disease
  • Int'l Joint Research