Liver organoid-based study of macrophage-induced injury of liver stem cells in GVHD

• Project/Area Number: 21K08409
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Hokkaido University
• Principal Investigator: 橋本 大吾 北海道大学, 医学研究院, 准教授 (20419576)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 同種造血細胞移植 / 移植片対宿主病 / GVHD / 組織幹細胞 / オルガノイド / 肝臓オルガノイド / マクロファージ / 胆管上皮幹細胞 / 同種造血幹細胞移植 / TGF-beta / 胆管上皮

Outline of Research at the Start

近年、様々な疾患で組織恒常性の維持や、組織修復に、組織幹細胞が関与することが示されている。同種造血細胞移植後のGVHDにおいて、皮膚や腸管の組織肝細胞障害の重要性が指摘されてきたが、肝臓GVHDにおける組織幹細胞の役割は解明されていない。本研究では、マウスモデルおよび肝臓オルガノイド培養系を用いて、肝臓GVHDにおける肝臓の組織幹細胞の傷害の有無を検討し、そのメカニズムを解明する。さらに、肝臓組織幹細胞を標的とする治療法の開発を行いたい。

Outline of Annual Research Achievements

移植片対宿主病 (graft-versus-host disease: GVHD)は、同種造血細胞移植 (allogeneic hematopoietic cell trasplantation: allo-HCT)後に起こる生命を脅かす主要な合併症である。組織幹細胞が皮膚GVHDや腸管GVHDの標的となって、GVHDの難治化につながることが示されているが、肝臓GVHDにおける組織幹細胞の役割は明らかではない。本研究では、allo-HCT後の肝臓GVHD中において、肝臓オルガノイドを生成する能力を持つ細胞を胆管幹細胞(bile duct stem cells: BDSCs)として定量し、GVHDでの役割を検討した。Allo-HCT後早期に胆管上皮細胞 (BECs)の顕著な増殖が観察され、胆管からのオルガノイド形成効率もallo-HCT直後に著しく増加した。その後、胆管からのオルガノイド形成効率は顕著に減少し、BECsの減少や血漿ビリルビン濃度の上昇と関連することが示され、GVHDがBDSCsを標的とし、BECsの回復力を損なうことで肝臓GVHDが重症化することが示唆された。同種レシピエントから肝浸潤単核細胞を採取して肝オルガノイドと共培養すると、肝臓オルガノイドの成長は、TGF-β依存性に減少した。TGF-βシグナルの阻害剤であるSB-431542を、培養に加えることでこうした抑制は解除された。SB-431542を14日目から28日目まで投与することで、GVHDに対してオルガノイド形成BDSCsを保護し、allo-HCT後の胆管機能障害を軽減できた。これは、BDSCsが肝GVHDのための有望な治療標的であることを示唆している。

Research Products

• [Journal Article] Separation of GVL from GVHD -location, location, location (2023)
  • Author(s): Teshima Takanori、Hashimoto Daigo
  • Journal Title: Frontiers in Immunology Volume: 14 Pages: 1296663-1296663
  • DOI: 10.3389/fimmu.2023.1296663
  • Peer Reviewed / Open Access
• [Journal Article] Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT (2023)
  • Author(s): Senjo Hajime、Harada Shinpei、Kubota Shimpei I.、Tanaka Yuki、Tateno Takahiro、Zhang Zixuan、Okada Satomi、Chen Xuanzhong、Kikuchi Ryo、Miyashita Naoki、Onozawa Masahiro、Goto Hideki、Endo Tomoyuki、Hasegawa Yuta、Ohigashi Hiroyuki、Ara Takahide、Hasegawa Yoshinori、Murakami Masaaki、Teshima Takanori、Hashimoto Daigo
  • Journal Title: Blood Volume: 142 Issue: 5 Pages: 477-492
  • DOI: 10.1182/blood.2023019875
  • 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] Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation (2022)
  • Author(s): Shouval Roni、Hashimoto Daigo、et al. (19番目、他26名)
  • Journal Title: Clinical Cancer Research Volume: 29 Issue: 1 Pages: 165-173
  • DOI: 10.1158/1078-0432.ccr-22-1254
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GVHD: pathophysiology and novel agents (2022)
  • Author(s): 荒 隆英、橋本 大吾
  • Journal Title: Rinsho Ketsueki Volume: 63 Issue: 9 Pages: 1261-1269
  • DOI: 10.11406/rinketsu.63.1261
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Guest editorial: prophylaxis and treatment of relapse after allogeneic hematopoietic stem cell transplantation (2022)
  • Author(s): Hashimoto Daigo
  • Journal Title: International Journal of Hematology Volume: 116 Issue: 3 Pages: 307-308
  • DOI: 10.1007/s12185-022-03407-8
  • Peer Reviewed
• [Journal Article] Intravenous transplantation of amnion-derived mesenchymal stem cells promotes functional recovery and alleviates intestinal dysfunction after spinal cord injury. (2022)
  • Author(s): Takamiya S, Kawabori M, Yamazaki K, Yamaguchi S, Tanimori A, Yamamoto K, Ohnishi S, Seki T, Konno K, Tha KK, Hashimoto D, Watanabe M, Houkin K, Fujimura M.
  • Journal Title: PLoS One Volume: 17 Issue: 7 Pages: e0270606-e0270606
  • DOI: 10.1371/journal.pone.0270606
  • Peer Reviewed / Open Access
• [Journal Article] High CRP-albumin ratio predicts poor prognosis in transplant ineligible elderly patients with newly diagnosed acute myeloid leukemia (2022)
  • Author(s): Senjo Hajime、Onozawa Masahiro、Hidaka Daisuke、Yokoyama Shota、Yamamoto Satoshi、Tsutsumi Yutaka、Haseyama Yoshihito、Nagashima Takahiro、Mori Akio、Ota Shuichi、Sakai Hajime、Ishihara Toshimichi、Miyagishima Takuto、Kakinoki Yasutaka、Kurosawa Mitsutoshi、Kobayashi Hajime、Iwasaki Hiroshi、Hashimoto Daigo、et al.
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 8885-8885
  • DOI: 10.1038/s41598-022-12813-1
  • Peer Reviewed / Open Access
• [Journal Article] Editorial: Mouse Models of Hematopoietic Stem Cell Transplantation (2022)
  • Author(s): Varelias Antiopi、Zhang Ping、Hashimoto Daigo
  • Journal Title: Frontiers in Immunology Volume: 13 Pages: 882592-882592
  • DOI: 10.3389/fimmu.2022.882592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Novel Insights Into the Mechanism of GVHD-Induced Tissue Damage (2021)
  • Author(s): Ara T, Hashimoto D
  • Journal Title: Front Immunol Volume: 12 Pages: 713631-713631
  • DOI: 10.3389/fimmu.2021.713631
  • Peer Reviewed / Open Access
• [Presentation] The role of microbiota in immunity and hematopoiesis after HSCT (2023)
  • Author(s): Daigo Hashimoto
  • Organizer: 28th Annual Meeting of Asia-Pacific Blood and Marrow Transplantation Group
  • Int'l Joint Research / Invited
• [Presentation] GVHDの診断と治療 (2023)
  • Author(s): 橋本 大吾
  • Organizer: 第46回日本造血免疫細胞療法学会
  • Invited
• [Presentation] 分子標的薬による移植片対白血病効果の促進 (2023)
  • Author(s): 橋本 大吾
  • Organizer: 第46回日本造血免疫細胞療法学会
  • Invited
• [Presentation] Delayed Initiation of Calcineurin Inhibitor Is Critical for Tolerance Induction By Posttransplant Cyclophosphamide (2023)
  • Author(s): Hajime Senjo, Daigo Hashimoto, Satomi Okada, Shimpei I Kubota, Ayumu Ito, Takashi Tanaka, Yumika Saito, Toru Miyajima, Wenyu Li, Zixuan Zhang, Shinpei Harada, Yuta Hasegawa, Hiroyuki Ohigashi, Takahide Ara, Yoshinori Hasegawa, Yoshihiro Inamoto, Masaaki Murakami, Takahiro Fukuda, Takanori Teshima
  • Organizer: 65th ASH Annual Meeting & Exposition
  • Int'l Joint Research
• [Presentation] Ferroptosis Inhibition Generates TCF-1+ CAR-T Cells with Enhanced Persistence and Cytotoxicity (2023)
  • Author(s): Shinpei Harada1, Daigo Hashimoto, Yumika Saito, Toru Miyajima, Wenyu Li, Hajime Senjo, Zixuan Zhang, Ryo Kikuchi, Masahiro Chiba, Hiroyuki Ohigashi, Takahide Ara, Masao Nakagawa, Takanori Teshima
  • Organizer: 65th ASH Annual Meeting & Exposition
  • Int'l Joint Research
• [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
• [Presentation] Calcineurin Inhibitors Inhibit Tolerance Induction By Suppressing Terminal Dierentiation of Donor Exhausted T Cells after Allogeneic SCT (2022)
  • Author(s): Hajime Senjo, Daigo Hashimoto, Shinpei Kubota, Yuki Tanaka, Shinpei Harada , Kazuki Yoneda, Zixuan Zhang, Xuanzhong Chen, Ryo Kikuchi, Yuta Hasegawa, Hiroyuki Ohigashi, Takahide Ara, Yoshinori Hasegawa, Masaaki Murakami, DVM., Ph.D. and Takanori Teshima
  • Organizer: 64th ASH Annual Meeting and Exposition
• [Presentation] Intercellular Mitochondrial Transfer Enhances Metabolic Fitness and Anti-Tumor Effects of CAR T Cells (2022)
  • Author(s): Shinpei Harada, Daigo Hashimoto, Hajime Senjo, Kazuki Yoneda, Zixuan Zhang, Xuanzhong Chen, Ryo Kikuchi, Masahiro Chiba, Hiroyuki Ohigashi, Takahide Ara, Masao Nakagawa, Masashi Suganuma, Rick C. Tsai, and Takanori Teshima
  • Organizer: 64th ASH Annual Meeting and Exposition
• [Presentation] Gvhd Targets Organoid-Forming Biliary Epithelial Stem Cells Via a TGF-β-Dependent Manner (2021)
  • 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, Takanori Teshima
  • Organizer: The 63rd ASH Annual Meeting
  • Int'l Joint Research
• [Presentation] Intestinal dysbiosis and GVHD: preclinical and clinical findings (2021)
  • Author(s): Daigo Hashimoto
  • Organizer: The International Congress of BMT 2021
  • Int'l Joint Research / Invited
• [Remarks] 北海道大学血液内科 造血幹細胞移植・免疫療法グループ
  • URL: https://www.hokudai-hematology.jp/research/basic/02/
• [Patent(Industrial Property Rights)] フェロトーシス阻害剤を用いたキメラ抗原受容体遺伝子導入T細胞における過酸化脂質の低減方法 (2023)
  • Inventor(s): 豊嶋 崇徳, 橋本 大吾, 原田 晋平
  • Industrial Property Rights Holder: 豊嶋 崇徳, 橋本 大吾, 原田 晋平
  • Industrial Property Rights Type: 特許
  • Filing Date: 2023