ヒト体外複合臓器モデルによる生体維持機構解析

2021 Fiscal Year Annual Research Report

• Project/Area Number: 19H01050
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 渡辺 守 東京医科歯科大学, 高等研究院, 特別栄誉教授 (10175127)
• Co-Investigator(Kenkyū-buntansha): 油井 史郎 東京医科歯科大学, 統合研究機構, 准教授 (00383886) ; 柿沼 晴 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30372444) ; 鬼澤 道夫 福島県立医科大学, 医学部, 助教 (30783352) ; 土屋 輝一郎 筑波大学, 医学医療系, 教授 (40376786)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ヒトオルガノイド / 臓器間制御機構 / 臓器共培養

Outline of Annual Research Achievements

炎症性腸疾患（IBD）は本邦で患者が急増している難病であり、持続性の腸管炎症及び粘膜障害により重篤な症状を呈する疾患である。また、若年者に多く、再燃を繰り返す難治性であることが課題である。これまでIBDの病態は炎症ではなく上皮細胞機能不全による粘膜障害が原因であることを、上皮細胞のみを単離して分子機構を解析することで解明した。さらに、病態の根幹である上皮幹細胞塑性は生体環境と密接に関与することを発見し、生体環境と腸管との相互作用機構の解明が新たに必要であると着想した。そこで本研究では独自に構築してきたヒト細胞体外臓器モデルをさらに発展させ、腸管と肝胆臓器の共培養による複合モデルを作成し、臓器間関係を単純化することで新規の臓器間制御因子を同定することを目的とする。既に小腸・大腸オルガノイド及びiPS由来肝臓胆管細胞の共培養系の構築を行った。同一ウェル内にそれぞれの臓器細胞をマトリゲルに封入した状態で培養するものであるが、個々の培養液成分が異なるため、共通培地で培養可能な条件を決定した。また既にヒト腸管オルガノイドにLPS,Flagellin の腸内細菌コンポーネントを添加し、腸内細菌応答腸管オルガノイドを作成することでヒト体外腸内環境モデルを構築した。炎症応答ヒト大腸オルガノイドのマウス大腸への移植を行い、キメラマウスを作成したところ、炎症性腸疾患の特徴的腺管を認め、正常なヒト大腸腺管から人工的にIBD腺管を作成することに成功した。本年度はヒト腸管・肝胆ダブルキメラマウスを構築し、臓器間制御機構を確認した。臓器間制御機構及び疾患特異的機構をヒトサンプルで解析中である。また複数の臓器間因子を同定しており、臓器間に大きく影響を与える因子を選択している。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results. (2022)
  • Author(s): Panes J,Colombel JF,D’Hanes GR,Schreiber S,Panaccione R,Peyrin-Biroulet L,Loftus EV Jr,Danese S,Tanida S,Okuyama Y,Louis E,Armuzzi A,Ferrante M,Vogelsang H,Hibi T,Watanabe M,Lefebve J,Finney-Hayward T,Gonzalez YS,Doan TT,Mostafa NM,Ikeda K,Xie W,Huang B,Petersson J,Kalabic J,Robinson AM,Sandborn WJ
  • Journal Title: Gastroenterology Volume: - Pages: -
  • DOI: 10.1053/j.gastro.2022.02.033.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] AJM300(carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled phase 3 study. (2022)
  • Author(s): Matsuoka K, Watanabe M, Ohmori T, Nakajima K, Ishida T, Ishiguro Y, Kanke K, Kobayashi K, Hirai F, Watanabe K, Mizusawa H, Kishida S, Miura Y, Ohta A, Kajioka T, Hibi T
  • Journal Title: Lancet Gastroenterol Hepatol Volume: - Pages: -
  • DOI: 10.1016/S2468-1253(22)00022-X.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nickel particles are present in Crohn’s disease tissue and exacerbate intestinal inflammation in IBD susceptible mice. (2022)
  • Author(s): Matsuda H, Nibe-Shirakihara Y, Tamura A, Aonuma E, Arakawa S, Otsubo K, Nemoto Y, Nagaishi T, Tsuchiya K, Shimizu S, Ma A, Watanabe M, Uo M, Okamoto R, Oshima S
  • Journal Title: Biochem Biophys Res Commun. Volume: 592 Pages: 74-80
  • DOI: 10.1016/j.bbrc.2021.12.111.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transplantation of intestinal Organoids into a mouse model of colitis. (2022)
  • Author(s): Watanabe S, Kobayashi S, Ogasawara N, Okamoto R, Nakamura T, Watanabe M, Kim BJ, Yui S
  • Journal Title: Nat Protoc. Volume: 17 Pages: 649-671
  • DOI: 10.1038/s41596-021-00658-3.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Deep neural network for video colonoscopy of ulcerative colitis: a cross-sectional study. (2022)
  • Author(s): Takenaka K, Fujii T, Kawamoto A, Suzuki K, Shimizu H, Maeyashiki C, Yamaji O, Motobayashi M, Igarashi A, Hanazawa R, Hibiya S, Nagahori M, Saito E, Okamoto R, Ohtsuka K, Watanabe M
  • Journal Title: Lancet Gastroenterol Hepatol. Volume: 7 Pages: 230-237
  • DOI: 10.1016/S2468-1253(21)00372-1.
  • Peer Reviewed
• [Journal Article] Immunoglobulin A-specific deficiency induces spontaneous inflammation specifically in the ileum. (2022)
  • Author(s): Nagaishi T, Watabe T, Kotake K, Kumazawa T, Aida T, Tanaka K, Ono R, Ishino F, Usami T, Miura T, Hirakata S, Kawasaki H, Shinkura R, Tsugawa N, Yamada D, Hirayama K, Yoshikawa S, Karasuyama H, Okamoto R, Watanabe M, Blumberg RS, Adachi T
  • Journal Title: Gut Volume: 71 Pages: 487-496
  • DOI: 10.1136/gutjnl-2020-322873.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Activated Mucosal-associated Invariant T Cells Have a Pathogenic Role in a Murine Model of Inflammatory Bowel Disease. (2022)
  • Author(s): Yasutomi Y, Chiba A, Haga K, Murayama G, Makiyama A, Kuga T, Watanabe M, Okamoto R, Nagahara A, Nagaishi T, Miyakae S
  • Journal Title: Cell Mol Gastroenterol Hepatol. Volume: 13 Pages: 81-93
  • DOI: 10.1016/j.jcmgh.2021.08.018.
  • Peer Reviewed
• [Journal Article] Importance of telomere shortening in the pathogenesis of ulcerative colitis: A new treatment from the aspect of telomeres in intestinal epithelial cell. (2022)
  • Author(s): Watanabe S, Hibiya S, Katsukura N, Kitagawa S, Sato A, Okamoto R, Watanabe M, Tsuchiya K
  • Journal Title: J Crohns Colitis. Volume: 16 Pages: 109-121
  • DOI: 10.1093/ecco-jcc/jjab115.
  • Peer Reviewed
• [Journal Article] A potent endocytosis inhibitor Ikarugamycin up-regulates TNF production. (2021)
  • Author(s): Minamidate A, Onizawa M, Saito C, Hikichi R, Mochimaru T, Murakami M, Sakuma C, Asakawa T, Hiraoka Y, Oshima S, Nagaishi T, Tsuchiya K, Ohira H, Okamoto R, Watanabe M
  • Journal Title: Biochem Biophys Res. Volume: - Pages: -
  • DOI: 10.1016/j.bbrep.2021.101065.
  • Peer Reviewed
• [Journal Article] Serum leucine-rich α-2 glycoprotein; a novel biomarker for small bowel mucosal activity in Crohn’s Disease. (2021)
  • Author(s): Kawamoto T, Takenaka K, Hibiya S, Ohtsuka K, Okamoto R, Watanabe M
  • Journal Title: Clin Gastroenterol Hepatol. Volume: 20 Pages: e1196-e1200
  • DOI: 10.1016/j.cgh.2021.06.036.
  • Peer Reviewed
• [Journal Article] Oral administration of D-serine prevents the onset and progression of colitis in mice. (2021)
  • Author(s): Asakawa T, Onizawa M, Saito C, Hikichi R, Yamada D, Minamidate A, Mochimaru T, Asahara SI, Kido Y, Oshima S, Nagaishi T, Tsuchiya K, Ohira H, Okamoto R, Watanabe M
  • Journal Title: J Gastroenterol. Volume: 56 Pages: 732-745
  • DOI: 10.1007/s00535-021-01792-1.
  • Peer Reviewed
• [Journal Article] Influence of chronic inflammation on the malignant phenotypes and the plasticity of colorectal cancer cells. (2021)
  • Author(s): Watanabe S, Hibiya S, Katsukura N, Kitagawa S, Sato A, Okamoto R, Watanabe M, Tsuchiya K
  • Journal Title: Biochem Biophys Rep. Volume: - Pages: -
  • DOI: 10.1016/j.bbrep.2021.101031.
  • Peer Reviewed
• [Journal Article] Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA)： a multicentre, open-label, randomised controlled trial. (2021)
  • Author(s): Kobayashi T, Motoya S, Nakamura S, Yamamoto T, Nagahori M, Tanaka S, Hisamatsu T, Hirai F, Nakase H, Watanabe K, Matsumoto T, Tanaka M, Abe T, Suzuki Y, Watanabe M, Hibi T; HAYABUSA Study Group
  • Journal Title: Lancet Gastroenterol Hepatol. Volume: 6 Pages: 429-437
  • DOI: 10.1016/S2468-1253(21)00062-5.
  • Peer Reviewed
• [Journal Article] Filgotinib as induction and maintenance therapy for ulcerative colitis(SELECTION) t: a phase 2b/3 double-blind, randomised, placebo-controlled trial. (2021)
  • Author(s): Feagan BG,Danese S,Loftus EV Jr,Vermeire S,Schreiber S,Ritter T,Fogel R,Mehta R,Nijhawan S,Kempinski R,Filip R,Hospodarskyy I,Seidler U,Seibold F,Beales ILP,Kim HJ,McNally J,Yun C,Zhao S,Liu X,Hsueh CH,Tasset C,Besuyen R,Watanabe M,Sandborn WJ,Rogler G,Hibi T,Peyrin-Biroulet L
  • Journal Title: Lancet Volume: 397 Pages: 2372-2384
  • DOI: 10.1016/S0140-6736(21)00666-8.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Schlafen 11 is a novel target for mucosal regeneration in Ulcerative Colitis. (2021)
  • Author(s): Watanabe S, Nishimura R, Shirasaki T, Katsukura N, Hibiya S, Kirimura S, Negi M, Okamoto R, Matsumoto Y, Nakamura T, Watanabe M, Tsuchiya K
  • Journal Title: J Crohns Colitis. Volume: 25 Pages: 1558-1572
  • DOI: 10.1093/ecco-jcc/jjab032.
  • Peer Reviewed
• [Journal Article] Deep neural network accurately predicts prognosis of ulcerative colitis using endoscopic images. (2021)
  • Author(s): Takenaka K, Ohtsuka K, Fujii T, Oshima S, Okamoto R, Watanabe M
  • Journal Title: Gastroenterology Volume: 160 Pages: 2175-2177
  • DOI: 10.1053/j.gastro.2021.01.210.
  • Peer Reviewed
• [Presentation] 特別講演：腸からヒト全身を繙く新しい時代の到来 (2021)
  • Author(s): 渡辺 守
  • Organizer: 第76回日本大腸肛門病学会学術集会
  • Invited
• [Presentation] Machine learning to synthesize endoscopy findings in ulcerative colitis (2021)
  • Author(s): Mamoru Watanabe
  • Organizer: IOBD Satellite Meeting
  • Int'l Joint Research / Invited
• [Presentation] 基調講演：再生医療研究・応用を目指す次世代の消化器臨床医へ (2021)
  • Author(s): 渡辺 守
  • Organizer: JDDW2021（第63回日本消化器病学会大会）
  • Invited
• [Presentation] 特別講演：IBD診療における温故知新 (2021)
  • Author(s): 渡辺 守
  • Organizer: 第39回日本大腸検査学会総会
  • Invited
• [Presentation] AJM300, an Oral Antagonist of α4-Integrin, as induction therapy for patients with Moderately Active Ulcerative Colitis: A Phase 3, randomized, double-blind, placebo-controlled induction study. (2021)
  • Author(s): Mamoru Watanabe, Katsuyoshi Matsuoka, Toshihide Ohmori, Koichi Nakajima, Tetsuya Ishida ,Yoh Ishiguro, Kazunari Kanke, Kiyonori Kobayashi, Fumihito Hirai, Kenji Watanabe, Toshifumi Hibi
  • Organizer: ECCO2021
  • Int'l Joint Research
• [Presentation] 本邦におけるIBD治療の変遷とIBD研究班 (2021)
  • Author(s): 渡辺 守
  • Organizer: 25周年記念web講演会
  • Invited
• [Presentation] 招待講演：再生医療おける内視鏡の役割 (2021)
  • Author(s): 渡辺 守
  • Organizer: 第101回日本消化器内視鏡学会総会
  • Invited