Title of Research Project

• Project/Area Number: 20K21610
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Hokkaido University
• Principal Investigator: Teshima Takanori 北海道大学, 医学研究院, 教授 (40284096)
• Co-Investigator(Kenkyū-buntansha): 坂本 直哉 北海道大学, 医学研究院, 教授 (10334418) ; 冨塚 一磨 東京薬科大学, 生命科学部, 教授 (40444640)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: GVHD / TGF-beta / 肝幹細胞 / オーガノイド / 胆管上皮幹細胞 / 造血幹細胞移植 / マクロファージ / 肝GVHD / VOD/SOS / R-Spondin

Outline of Research at the Start

造血幹細胞移植は白血病・リンパ腫や造血・免疫不全症の根治的治療であるが、移植後肝合併症の代表である肝移植片対宿主病(GVHD)や肝中心静脈閉塞症(VOD)は難治性の合併症で、有効な治療法開発が喫緊の課題である。本研究では移植後肝傷害におけるLgr5+肝幹細胞の動態をレポーターマウスを用いて解析、肝幹細胞を標的とした新たな治療法を開発する。我々R-spondin1がLgr5+腸上皮幹細胞への増殖促進作用を有すことを見出しており、Lgr5+肝幹細胞増殖促進作用と病態改善効果を検討する。さらにR-spondin1を肝組織移行性抗体と連結し、より組織指向性の高い次世代型バイオロジクス医療の開発を目指す。

Outline of Final Research Achievements

We investigated fate of liver stem cells in liver GVHD after allogeneic hematopoietic stem cell transplantation (allo-SCT). After allo-SCT, donor T cells and macrophages infiltrated in the portal area of the liver with apoptosis of the adjunct bile duct epithelial cells. Using Lgr5-eGFP-reporter mice, Lgr5+ cells isolated from the liver after allo-SCT were cultured to generate liver organoids. Number of the organoids was significantly decreased after allo-SCT. PCR analysis showed an upregulated expression of IFN-gamma, TGF, and TNF in the liver. Addition of TGF-beta suppressed the organoid formation in culture. Addition of TGF-beta inhibitor SB-431552 abrogated inhibitory effect of TGF-beta on the organoid formation. Administration of SB-431552 to mice after allo-SCT restored the organoid formation. These results indicated that macrophage-derived TGF-beta damage liver stem cells in GVHD.

Academic Significance and Societal Importance of the Research Achievements

同種造血幹細胞移植の組織傷害はドナーT細胞が組織幹細胞を標的とすることによる組織恒常性、修復、細菌叢などの破綻によるものであることを我々は、腸、皮膚で明らかにしてきた。残るのは肝臓GVHDであったが、ここでも同様に胆管上皮幹細胞が標的となることを世界で最初に明らかにすることができた。さらにマクロファージ由来のTGF-betaがその原因であることを明らかにできたことで、将来的な新たな治療開発への展開が期待される。

Research Products

• [Int'l Joint Research] University of Southern California(米国)
• [Int'l Joint Research] Zurich University/Novartis Institute, Biomedical Research/Piothera SAS(スイス)
• [Int'l Joint Research] Regensburg University/University of Cologne/University of Freiburg(ドイツ)
• [Int'l Joint Research] University of Paris(フランス)
• [Journal Article] Mocravimod, a Selective Sphingosine-1-Phosphate Receptor Modulator, in Allogeneic Hematopoietic Stem Cell Transplantation for Malignancy (2023)
  • Author(s): Dertschnig Simone、Gergely Peter、Finke Jurgen、Schanz Urs、Holler Ernst、Holtick Udo、Socie Gerard、Medinger Michael、Passweg Jakob、Teshima Takanori、Stylianou Christos、Oehen Stephan、Heim Dominik、Bucher Christoph
  • Journal Title: Transplantation and Cellular Therapy Volume: 29 Issue: 1 Pages: 41.e1-41.e9
  • DOI: 10.1016/j.jtct.2022.10.029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Decreased Paneth cell α-defensins promote fibrosis in a choline-deficient L-amino acid-defined high-fat diet-induced mouse model of nonalcoholic steatohepatitis via disrupting intestinal microbiota (2023)
  • Author(s): Nakamura Shunta、Nakamura Kiminori、Yokoi Yuki、Shimizu Yu、Ohira Shuya、Hagiwara Mizu、Song Zihao、Gan Li、Aizawa Tomoyasu、Hashimoto Daigo、Teshima Takanori、Ouellette Andre J.、Ayabe Tokiyoshi
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 3953-3953
  • DOI: 10.1038/s41598-023-30997-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reactive granulopoiesis depends on T-cell production of IL-17A and neutropenia-associated alteration of gut microbiota (2022)
  • Author(s): Chen Xuanzhong、Hashimoto Daigo、Ebata Ko、Takahashi Shuichiro、Shimizu Yu、Shinozaki Ryuga、Hasegawa Yuta、Kikuchi Ryo、Senjo Hajime、Yoneda Kazuki、Zhang Zixuan、Harada Shinpei、Hayase Eiko、Ara Takahide、Ohigashi Hiroyuki、Iwakura Yoichiro、Nakamura Kiminori、Ayabe Tokiyoshi、Teshima Takanori
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 119 Issue: 48 Pages: 1-10
  • DOI: 10.1073/pnas.2211230119
  • Peer Reviewed / Open Access
• [Journal Article] Gilteritinib enhances graft-versus-leukemia effects against FLT3-ITD mutant leukemia after allogeneic hematopoietic stem cell transplantation (2022)
  • Author(s): Zhang Zixuan、Hasegawa Yuta、Hashimoto Daigo、Senjo Hajime、Kikuchi Ryo、Chen Xuanzhong、Yoneda Kazuki、Sekiguchi Tomoko、Kawase Tatsuya、Tsuzuki Hirofumi、Ishio Takashi、Ara Takahide、Ohigashi Hiroyuki、Nakagawa Masao、Teshima Takanori
  • Journal Title: Bone Marrow Transplantation Volume: - Issue: 5 Pages: 775-780
  • DOI: 10.1038/s41409-022-01619-4
  • Peer Reviewed / Open Access
• [Journal Article] The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models (2021)
  • Author(s): Teshima T, Hill GR
  • Journal Title: Front Immunol Volume: 12 Pages: 715424-715424
  • DOI: 10.3389/fimmu.2021.715424
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Graft-versus-host disease: a disorder of tissue regeneration and repair (2021)
  • Author(s): Chakraverty R, Teshima T
  • Journal Title: Blood Volume: 138 Issue: 18 Pages: 1657-1665
  • DOI: 10.1182/blood.2021011867
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nonclassical manifestations of acute GVHD (2021)
  • Author(s): Zeiser R, Teshima T
  • Journal Title: Blood Volume: 138 Issue: 22 Pages: 2165-2172
  • DOI: 10.1182/blood.2021012431
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8 (2020)
  • Author(s): Ara Takahide、Hashimoto Daigo、Hayase Eiko、Noizat Clara、Kikuchi Ryo、Hasegawa Yuta、Matsuda Kana、Ono Shoko、Matsuno Yoshihiro、Ebata Ko、Ogasawara Reiki、Takahashi Shuichiro、Ohigashi Hiroyuki、Yokoyama Emi、Matsuo Keitaro、Sugita Junichi、Onozawa Masahiro、Okumura Ryu、Takeda Kiyoshi、Teshima Takanori
  • Journal Title: Science Translational Medicine Volume: 12 Issue: 550
  • DOI: 10.1126/scitranslmed.aaw0720
  • Peer Reviewed / Open Access
• [Presentation] GVHD Targets Organoid-forming Biliary Epithelial Stem Cells via a TGF-b-Dependent Manner (2022)
  • Author(s): Yuta Hasegawa, Daigo Hashimoto, Ryo Kikuchi, Zixuan Zhang, Hajime Senjo, Tomoko Sekiguchi, Eiko Hayase, Takahiro Tateno, Emi Yokoyama, Shuichiro Takahashi, Xuanzhong Chen, Kazuki Yoneda, Hiroyuki Ohigashi, Takahide Ara, and Takanori Teshima
  • Organizer: 第84回日本血液学会学術集会 (福岡, 10月15日): Plenary
• [Presentation] Novel insights into biology and treatment of acute GVHD (2022)
  • Author(s): Teshima T
  • Organizer: The 3rd Annual Meeting of Indian Society for Blood & Marrow Transplantation． 2022年4月8日．Web
  • Invited
• [Presentation] Tales from the intestinal crypt (2022)
  • Author(s): Teshima T
  • Organizer: Tandem Meetings 2022: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR． 2022年4月23日．Salt lake city
  • Invited
• [Presentation] Tissue stem cell injury in graft vs host disease (2022)
  • Author(s): Teshima T
  • Organizer: Australia Centre for Blood Transplant and Cell Therapies Webinar Series． 2022年6月14日．Web
  • Invited
• [Presentation] Treatment for steroid-refractory chronic GVHD (2022)
  • Author(s): Teshima T
  • Organizer: The International Congress of BMT 2022． 2022年9月2日．Busan
  • Invited
• [Presentation] Novel insights in biology and treatment of acute GVHD (2022)
  • Author(s): Teshima T
  • Organizer: The 27th Congress of Asia-Pacific Blood and Marrow Transplantation． 2022年10月8日．Kochi, India
  • Invited
• [Presentation] Novel approach in GVHD prophylaxis (2021)
  • Author(s): Teshima T
  • Organizer: 26th Annual Meeting of Asian Pacific Blood and Marrow Transplantation
  • Int'l Joint Research / Invited
• [Presentation] Intestinal goblet cell and IL-25 in intestinal GVHD (2021)
  • Author(s): Teshima T
  • Organizer: International Congress of Bone Marrow Transplantation 2021
  • Int'l Joint Research / Invited
• [Presentation] Pathogensis of GVHD -from bench to bedside- (2021)
  • Author(s): Teshima T
  • Organizer: 中日血液専門家検討会
  • Int'l Joint Research / Invited
• [Presentation] Gilteritinib Enhances Graft-Versus-Leukemia Effects Against FLT3-ITD+ Leukemia after Mouse Allogeneic HSCT (2021)
  • Author(s): Hasegawa Y, Zhang Z, Kikuchi R, Chen X, Yoneda Y, Senjo H, Sekiguchi T, Kawase T, Tsuzuki H, Ishio T, Ohigashi H, Nakagawa M, Hashimoto D, Teshima T
  • Organizer: Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR 2021
  • Int'l Joint Research
• [Presentation] ギルテリチニブはマウスFLT3-ITD陽性白血病に対する移植片対白血病効果を促進する (2021)
  • Author(s): 張紫, 長谷川祐太, 菊池遼, 陳炫仲, 米田和樹, 千丈創, 関口智子, 川瀬竜也, 續啓史, 石尾崇, 大東寛幸, 中川雅夫, 橋本大吾, 豊嶋崇徳
  • Organizer: 第43回日本造血免疫細胞療法学会総会
• [Presentation] GVHD targets organoid-forming Biliary Epithelial Stem Cells Via a TGF-β-Dependent Manner (2021)
  • Author(s): Hasegawa Y, Hashimoto D, Kikuchi R, Zhang Z, Senjo H, Sekiguchi S, Eiko Hayase E, Tateno T, Yokoyama E, Takahashi S, Chen X, Yoneda K, Ohigashi H, Ara T, and Teshima T
  • Organizer: 63nd American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Gut microbiome and its relevance to immunology of transplantation (2020)
  • Author(s): Takanori Teshima
  • Organizer: The 25th Annual Congress of APBMT-2020
  • Int'l Joint Research / Invited
• [Presentation] 大腸杯細胞は抗菌分子Lypd8依存性に同種造血幹細胞移植後の移植片対宿主病を予防する (2020)
  • Author(s): 荒隆英、橋本大吾、早瀬英子、Clara Noizat、菊池遼、長谷川祐太、奥村龍、竹田潔、豊嶋崇徳
  • Organizer: 第24回腸内細菌学会学術集会