短腸症候群モデルを用いた新規移植療法の開発

2022 Fiscal Year Annual Research Report

• Project/Area Number: 21K19540
• Research Institution: Keio University
• Principal Investigator: 杉本 真也 慶應義塾大学, 医学部(信濃町), 助教 (20626387)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 短腸症候群 / 小腸移植 / 幹細胞 / 腸管不全 / GLP-2アナログ

Outline of Annual Research Achievements

重症の短腸症候群に対する唯一の根治療法となりうる小腸移植は，小腸の他の臓器に比して強い拒絶反応のため移植後の管理に難渋しており，実施例はごく少数に限られているのが現状である．十分な治療法がなく，予後不良である重症の短腸症候群に対する新規治療法開発へのニーズは大きい．本研究では，自己の小腸由来細胞を移植細胞として用いることによって，生涯の免疫抑制を要さない新規移植療法の開発を目指し，短腸症候群モデル動物における知見の創出とヒトへの応用へ向けた研究基盤の構築を目的とした．
これまでに開発してきた致死的な短腸症候群モデルラットの切除する腸管長の改変や，周術期における経腸栄養剤の併用を含めた術後管理の改善によって，解析効率の上昇へとつながった．また，teduglutideなどのGLP-2アナログ製剤の効果を検証し，絨毛伸長への有効性を確認した．小動物レベルから大動物レベルへの移行に先立って，小動物レベルにおける移植先組織の移植前処置の条件をex vivo，in vivoで検証し，組織障害を低減しつつ効率的な処置が可能となった．この手法を大動物へと応用し，同様にex vivo，in vivoでの課題抽出から，従来は困難であった大動物レベルでの上皮剥離効率向上へとつながっている．大動物における腸管切除を含む手術も生存実験として実施可能となり，本研究によって，ヒトへの応用へ向けた研究基盤が構築された．

Research Products

• [Journal Article] Usefulness of texture and color enhancement imaging in assessing mucosal healing in patients with ulcerative colitis (2023)
  • Author(s): Hayashi Yukie、Takabayashi Kaoru、Kato Motohiko、Tojo Anna、Aoki Yasuhiro、Hagihara Yuya、Yoshida Kosuke、Yoshimatsu Yusuke、Kiyohara Hiroki、Sugimoto Shinya、Nanki Kosaku、Mikami Yohei、Sujino Tomohisa、Mutaguchi Makoto、Kawaguchi Takaaki、Hosoe Naoki、Yahagi Naohisa、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Gastrointestinal Endoscopy Volume: 97 Pages: 759～766.e1
  • DOI: 10.1016/j.gie.2022.11.019
  • Peer Reviewed
• [Journal Article] Water Does Not Mix with Lipids: Water-assisted Colonoscopy (2023)
  • Author(s): Sugimoto Shinya、Takabayashi Kaoru、Kanai Takanori
  • Journal Title: Internal Medicine Volume: 62 Pages: 665～666
  • DOI: 10.2169/internalmedicine.0053-22
  • Peer Reviewed / Open Access
• [Journal Article] 浸水法を用いた大腸内視鏡検査の開発と応用 (2023)
  • Author(s): 水上 健、杉本 真也
  • Journal Title: 日本消化器内視鏡学会雑誌 Volume: 65 Pages: 19～28
  • DOI: 10.11280/gee.65.19
  • Peer Reviewed
• [Journal Article] Efficacy of Calcineurin Inhibitors for Induction of Remission in Intestinal Behcet’s Disease (2022)
  • Author(s): Kawaguchi Takaaki、Fukata Masayuki、Omori Teppei、Kiyohara Hiroki、Sugimoto Shinya、Nanki Kosaku、Sujino Tomohisa、Mikami Yohei、Kanai Takanori
  • Journal Title: Crohn's & Colitis 360 Volume: 4 Pages: otac017
  • DOI: 10.1093/crocol/otac017
  • Peer Reviewed / Open Access
• [Journal Article] Effectiveness and Durability of Ustekinumab Therapy With or Without Immunomodulators for Ulcerative Colitis Patients in Japan (2022)
  • Author(s): Aoki Yasuhiro、Sujino Tomohisa、Kawaguchi Takaaki、Sugimoto Shinya、Shimada Fumie、Yoshimatsu Yusuke、Kiyohara Hiroki、Nanki Kosaku、Mikami Yohei、Takabayashi Kaoru、Hosoe Naoki、Ogata Haruhiko、Iwao Yasushi、Kanai Takanori
  • Journal Title: Crohn's & Colitis 360 Volume: 4 Pages: otac010
  • DOI: 10.1093/crocol/otac010
  • Peer Reviewed / Open Access
• [Journal Article] In Vivo Intestinal Research Using Organoid Transplantation (2022)
  • Author(s): Sugimoto Shinya、Kobayashi Eiji、Kanai Takanori、Sato Toshiro
  • Journal Title: The Keio Journal of Medicine Volume: 71 Pages: 73～81
  • DOI: 10.2302/kjm.2022-0019-IR
  • Peer Reviewed / Open Access
• [Journal Article] CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis (2022)
  • Author(s): Cui Yanmei、Wu Haiyong、Liu Zhihang、Ma Tenghui、Liang Wenfeng、Zeng Qingzhi、Chen Daici、Qin Qiyuan、Huang Binjie、Wang Michael Hu、Huang Xiaoyan、He Yanjiong、Kuang Yingyi、Sugimoto Shinya、Sato Toshiro、Wang Lei
  • Journal Title: The Journal of Pathology Volume: 259 Pages: 180～193
  • DOI: 10.1002/path.6031
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of Quiescent LGR5+ Stem Cells in the Human Colon (2022)
  • Author(s): Ishikawa Keiko、Sugimoto Shinya、Oda Mayumi、Fujii Masayuki、Takahashi Sirirat、Ohta Yuki、Takano Ai、Ishimaru Kazuhiro、Matano Mami、Yoshida Kosuke、Hanyu Hikaru、Toshimitsu Kohta、Sawada Kazuaki、Shimokawa Mariko、Saito Megumu、Kawasaki Kenta、Ishii Ryota、Taniguchi Koji、Imamura Takeshi、Kanai Takanori、Sato Toshiro
  • Journal Title: Gastroenterology Volume: 163 Pages: 1391～1406.e24
  • DOI: 10.1053/j.gastro.2022.07.081
  • Peer Reviewed / Open Access
• [Journal Article] Texture and color enhancement imaging in combination with indigo carmine dye spraying to highlight the border of flat ulcerative colitis-associated neoplasia (2022)
  • Author(s): Takabayashi Kaoru、Kato Motohiko、Sugimoto Shinya、Yahagi Naohisa、Kanai Takanori
  • Journal Title: Gastrointestinal Endoscopy Volume: 95 Pages: 1273～1275
  • DOI: 10.1016/j.gie.2022.02.011
  • Peer Reviewed
• [Journal Article] 潰瘍性大腸炎関連発がんの臨床 (2022)
  • Author(s): 杉本真也, 金井隆典
  • Journal Title: 別冊Bio Clinica Volume: 11 Pages: 47～52
• [Journal Article] 直腸扁平上皮化と潰瘍性大腸炎関連腫瘍の領域拡大における上皮置換の寄与 (2022)
  • Author(s): 杉本 真也, 岩男 泰, 金井 隆典
  • Journal Title: 消化器病学サイエンス Volume: 6 Pages: 186～191
• [Journal Article] 潰瘍性大腸炎に伴うdysplasiaに対する内視鏡治療はどのように考えるのか? (2022)
  • Author(s): 高林 馨, 杉本 真也, 吉松 裕介, 清原 裕貴, 三上 洋平, 筋野 智久, 河口 貴昭, 加藤 元彦, 細江 直樹, 岩男 泰, 矢作 直久, 金井 隆典, 緒方 晴彦
  • Journal Title: 消化器・肝臓内科 Volume: 12 Pages: 158～164
• [Journal Article] 【内視鏡データリファレンスブック2022】臓器別 大腸 潰瘍性大腸炎関連腫瘍 (2022)
  • Author(s): 岩男 泰, 杉本 真也, 高林 馨, 三上 洋平, 金井 隆典
  • Journal Title: 消化器内視鏡 Volume: 34 Pages: 735～740
• [Presentation] 小腸移植と再生医療のクロストーク (2023)
  • Author(s): 杉本 真也
  • Organizer: 第22回日本再生医療学会総会
  • Invited
• [Presentation] 潰瘍性大腸炎関連腫瘍の自然史の観察に基づくサーベイランス内視鏡戦略 (2023)
  • Author(s): 脇坂悠介, 杉本真也, 高林馨, 高田祐明, 細江直樹, 緒方晴彦, 金井隆典
  • Organizer: 第19回日本消化管学会総会学術集会 (GI Week 2023)
• [Presentation] Dose escalation of oral 5-aminosalicylic acid for ulcerative colitis with Mayo endoscopic subscore of one improves long-term prognosis: a one-year multicentre, open-label, randomized controlled trial (2023)
  • Author(s): Yasuhiro Aoki, Tomohiro Fukuda, Hiroki Kiyohara, Ayumi Yokoyama, Atsushi Nakazawa, Yusuke Yoshimatsu, Shinya Sugimoto, Kosaku Nanki, Yohei Mikami, Kayoko Fukuhara, Shinta Mizuno, et al.
  • Organizer: 18th Congress of European Crohn’s and Colitis Organization (ECCO 2023)
  • Int'l Joint Research
• [Presentation] Intestinal research with replacement of colonic epithelium by organoid transplantation (2022)
  • Author(s): Shinya Sugimoto, Takanori Kanai, Toshiro Sato
  • Organizer: The 108th General Meeting of the Japanese Society of Gastroenterology
  • Int'l Joint Research / Invited
• [Presentation] 液流動による細胞分化誘導と小腸絨毛形成への応用 (2022)
  • Author(s): 杉本 真也, 金井 隆典, 佐藤 俊朗
  • Organizer: 第108回日本消化器病学会総会
• [Presentation] 潰瘍性大腸炎合併腫瘍に対するESD前鑑別診断の検討 (2022)
  • Author(s): 髙林 馨, 岩男 泰, 杉本 真也, 三上 洋平, 細江 直樹, 緒方 晴彦, 金井 隆典
  • Organizer: 第１回Interventional IBD研究会
• [Presentation] Generation of Functional Small Intestine Tissue by Organoid Transplantation (2022)
  • Author(s): Shinya Sugimoto
  • Organizer: The 10th Annual Meeting of Asian Organization for Crohn’s & Colitis
  • Int'l Joint Research / Invited
• [Presentation] Investigation of endoscopic chronological evolution of ulcerative colitis-associated neoplasia (2022)
  • Author(s): Yusuke Wakisaka, Shinya Sugimoto, Yasushi Iwao, Kaoru Takabayashi, Yusuke Yoshimatsu, Hiroki Kiyohara, Takaaki Kawaguchi, Tomohisa Sujino, Naoki Hosoe, Haruhiko Ogata, Yohei Mikami, Takanori Kanai
  • Organizer: The 10th Annual Meeting of the Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] Evaluation of diagnostic criteria for Sporadic neoplasm in ulcerative colitis (2022)
  • Author(s): Evaluation of diagnostic criteria for Sporadic neoplasm in ulcerative colitis
  • Organizer: The 10th Annual Meeting of the Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] Successful Combination Therapy with Infliximab and Cyclosporine A for Refractory Myelodysplastic Syndrome associated Small Intestinal Ulcers: A case report (2022)
  • Author(s): Shogo Sunaga, Hiroki Kiyohara, Kurato Miyazaki, Ryosuke Kasuga, Kaoru Takabayashi, Naoki Hosoe, Takaaki Kawaguchi, Yohei Mikami, Kosaku Nanki, Yusuke Yoshimatsu, Shinya Sugimoto, Tomohisa Sujino, Yasushi Iwao, Haruhiko Ogata, Takanori Kanai
  • Organizer: The 10th Annual Meeting of the Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] Effectiveness and Durability of Ustekinumab Therapy With or Without Immunomodulators for Ulcerative Colitis Patients (2022)
  • Author(s): Yasuhiro Aoki, Tomohisa Sujino, Takaaki Kawaguchi, Shinya Sugimoto, Fumie Shimada, Yusuke Yoshimatsu, Hiroki Kiyohara, Kosaku Nanki, Yohei Mikami, Kaoru Takabayashi, Naoki Hosoe, Haruhiko Ogata, Yasushi Iwao, Takanori Kanai
  • Organizer: The 10th Annual Meeting of the Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] Short-term Efficacy of Calcineurin Inhibitors for Intestinal Behcet’s Disease (2022)
  • Author(s): Takaaki Kawaguchi, Masayuki Fukata, Teppei Omori, Hiroki Kiyohara, Shinya Sugimoto, Kosaku Nanki, Tomohisa Sujino, Yohei Mikami, Takanori Kanai
  • Organizer: The 10th Annual Meeting of the Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] Serum LRG as a novel biomarker of disease and endoscopic activity in patients with Crohn’s disease (2022)
  • Author(s): Yoshiaki Takada, Hiroki Kiyohara, Yohei Mikami, Fumie Shimada, Yuta Matsubara, Ryoya Sakakibara, Yasuhiro Aoki, Masataka Ichikawa, Yusuke Wakisaka, Yuya Hagihara, Shun Tanemoto, Satoko Umeda, Yusuke Yoshimatsu, Keiko Ono, Emi Irie, Shinya Sugimoto, Kosaku Nanki, et al.
  • Organizer: The 10th Annual Meeting of the Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] Hematologic features in thiopurine treated patients with heterozygote of NUDT15 R139C (2022)
  • Author(s): Ryoya Sakakibara, Hiroki Kiyohara, Yusuke Yoshimatsu, Shinya Sugimoto, Yohei Mikami, Takaaki Kawaguchi, Takanori Kanai
  • Organizer: The 10th Annual Meeting of the Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] Prognosis in the treatment of the 2nd line anti-TNF inhibitor in patients with ulcerative colitis (2022)
  • Author(s): Hiroki Kiyohara, Takaaki Kawaguchi, Yohei Mikami, Yusuke Yoshimatsu, Shinya Sugimoto, Tomohisa Sujino, Kaoru Takabayashi, Naoki Hosoe, Yasushi Iwao, Haruhiko Ogata, Takanori Kanai
  • Organizer: The 10th Annual Meeting of the Asian Organization for Crohn's & Colitis
  • Int'l Joint Research
• [Presentation] 消化管オルガノイド移植の新潮流 (2022)
  • Author(s): 杉本 真也
  • Organizer: 第43回日本炎症・再生医学会
  • Invited
• [Presentation] UC関連腫瘍診療における肛門直腸移行部観察の意義 (2022)
  • Author(s): 杉本真也, 高林馨, 金井隆典
  • Organizer: 第64回日本消化器病学会大会（JDDW 2022）
• [Presentation] 内視鏡Mayoスコア1の臨床的寛解潰瘍性大腸炎患者に対する経口5-ASA製剤の増量は臨床的再燃を抑制する (2022)
  • Author(s): 福田知広, 青木康浩, 清原裕貴, 横山 歩, 吉松裕介, 杉本真也, 南木康作, 三上洋平, 福原佳代子, 水野慎大, 筋野智久, 牟田口 真, 高林 馨, 諸星雄一, 中澤 敦, 細田泰雄, 緒方晴彦, 岩男 泰, 長沼 誠, 金井隆典
  • Organizer: 第13回日本炎症性腸疾患学会学術集会
• [Presentation] 平坦型潰瘍性大腸炎関連腫瘍の色素散布内視鏡像の特徴 (2022)
  • Author(s): 高林 馨, 岩男 泰, 杉本 真也, 緒方 晴彦, 金井 隆典
  • Organizer: 第115 回日本消化器内視鏡学会関東支部例会
• [Presentation] 自然整復した成人の特発性小腸重積症の一例 (2022)
  • Author(s): 韓可, 吉松裕介, 杉本真也, 清原裕貴, 三上洋平, 筋野智久, 河口貴昭, 高林馨, 細江直樹, 緒方晴彦, 金井隆典
  • Organizer: 日本消化器病学会 関東支部第372回例会
• [Presentation] 潰瘍性大腸炎に対する Texture and Color Enhancement Imaging（TXI）併用内視鏡的活動性評価の有用性 (2022)
  • Author(s): 林 由紀恵, 高林 馨, 吉松 裕介, 清原 裕貴, 杉本 真也, 三上 洋平, 筋野 智久, 細江 直樹, 緒方 晴彦, 金井 隆典
  • Organizer: 第40回日本大腸検査学会総会