Analysis and therapeutic application of intestinal epithelial cell plasticity in inflammatory bowel disease

• Project/Area Number: 16H05284
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Okamoto Ryuichi 東京医科歯科大学, 統合研究機構, 教授 (50451935)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 炎症性腸疾患 / 腸上皮幹細胞 / 分泌型上皮細胞 / 可塑性 / 潰瘍性大腸炎 / オルガノイド / 幹細胞 / 粘膜再生 / 腸管上皮幹細胞 / 消化器内科学

Outline of Final Research Achievements

Through our current research project focused on mucosal damage in inflammatory bowel diseases, we found and confirmed a novel endogenous tissue repair system supported by a secretory-type cell population (Atoh1-positive cells) distinct from the genuine intestinal stem cells. In addition, we successfully identified a novel genetic marker, UBD, for the prediction of favorable clinical outcome in response to anti-TNF-a therapy. Expression of UBD was regulated by a synergistic enhancement between the TNF-a pathway and the Notch signaling pathway, as confirmed by experiments using patient-derived intestinal epithelial cells.

Academic Significance and Societal Importance of the Research Achievements

炎症性腸疾患において幹細胞とは異なる上皮細胞分画による新たな組織修復機構の存在を明らかにしたことにより、同細胞の機能を活用した新たな粘膜再生・修復治療に繋がる成果を提示した。同疾患における抗TNF-a抗体治療の効果予測指標となり得る遺伝子UBDの同定については、当該治療を実施した患者における治療の有効性を早期に予測し、より適切な治療の選択が可能となることに貢献することが期待できる。

Research Products

• [Journal Article] Ubiquitin D is up-regulated by synergy of Notch signaling and TNF-α in the inflamed intestinal epithelia of IBD patients. (2019)
  • Author(s): Kawamoto Ami、Nagata Sayaka、Anzai Sho、Takahashi Junichi、Kawai Mao、Hama Minami、Nogawa Daichi、Yamamoto Kouhei、Kuno Reiko、Suzuki Kohei、Shimizu Hiromichi、Hiraguri Yui、Yui Shiro、Oshima Shigeru、Tsuchiya Kiichiro、Nakamura Tetsuya、Ohtsuka Kazuo、Kitagawa Masanobu、Okamoto Ryuichi、Watanabe Mamoru
  • Journal Title: J Crohns Colitis Volume: 13 Pages: 495-509
  • DOI: 10.1093/ecco-jcc/jjy180
  • Peer Reviewed
• [Journal Article] Single cell analysis of Crohn’s disease patient-derived small intestinal organoids reveals disease activity-dependent modification of stem cell properties. (2018)
  • Author(s): Suzuki Kohei、Murano Tatsuro、Shimizu Hiromichi、Ito Go、Nakata Toru、Fujii Satoru、Ishibashi Fumiaki、Kawamoto Ami、Anzai Sho、Kuno Reiko、Kuwabara Konomi、Takahashi Junichi、Tsuchiya Kiichiro、Nakamura Tetsuya、Ohtsuka Kazuo、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: J Gastroenterol. Volume: 印刷中 Pages: 1035-1047
  • DOI: 10.1007/s00535-018-1437-3
  • Peer Reviewed / Open Access
• [Journal Article] Novel polyubiquitin imaging system, PolyUb-FC, reveals that K33-linked polyubiquitin is recruited by SQSTM1/p62. (2018)
  • Author(s): Yoichi Nibe, Shigeru Oshima, Masanori Kobayashi, Chiaki Maeyashiki, Yu Matsuzawa, Kana Otsubo, Hiroki Matsuda, Emi Aonuma, Yasuhiro Nemoto, Takashi Nagaishi, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Shinichiro Nakada, Mamoru Watanabe
  • Journal Title: Autophagy Volume: 22 Pages: 347-358
  • DOI: 10.1080/15548627.2017.1407889
  • Peer Reviewed / Open Access
• [Journal Article] Contribution of ATOH1+ cells to the homeostasis, repair and tumorigenesis of the colonic epithelium. (2018)
  • Author(s): Ishibashi Fumiaki、Shimizu Hiromichi、Nakata Toru、Fujii Satoru、Suzuki Kohei、Kawamoto Ami、Anzai Sho、Kuno Reiko、Nagata Sayaka、Ito Go、Murano Tatsuro、Mizutani Tomohiro、Oshima Shigeru、Tsuchiya Kiichiro、Nakamura Tetsuya、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Stem Cell Rep. Volume: 10 Pages: 27-42
  • DOI: 10.1016/j.stemcr.2017.11.006
  • Peer Reviewed / Open Access
• [Journal Article] New Notch inhibitors from Calotropis gigantea that induce neuronal differentiation of neural stem cells (2017)
  • Author(s): Yoneyama Tatsuro、Arai Midori A.、Akamine Ryuta、Koryudzu Kazune、Tsuchiya Anna、Sadhu Samir K.、Ahmed Firoj、Itoh Motoyuki、Okamoto Ryuichi、Ishibashi Masami
  • Journal Title: J. Nat. Prod. Volume: 80 Pages: 2453-2461
  • DOI: 10.1021/acs.jnatprod.7b00282
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Data showing proliferation and differentiation of intestinal epithelial cells under targeted depletion of Notch ligands in mouse intestine. (2017)
  • Author(s): Nakata T, Shimizu H, Nagata S, Ito G, Fujii S, Suzuki K, Kawamoto A, Ishibashi F, Kuno R, Anzai S, Murano T, Mizutani T, Oshima S, Tsuchiya K, Nakamura T, Hozumi K, Watanabe M, Okamoto R
  • Journal Title: Data in Brief Volume: 10 Pages: 551-556
  • DOI: 10.1016/j.dib.2016.12.045
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors. (2017)
  • Author(s): Nakata T, Shimizu H, Nagata S, Ito G, Fujii S, Suzuki K, Kawamoto A, Ishibashi F, Kuno R, Anzai S, Murano T, Mizutani T, Oshima S, Tsuchiya K, Nakamura T, Hozumi K, Watanabe M, Okamoto R
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 482 Pages: 1296-1303
  • DOI: 10.1016/j.bbrc.2016.12.031
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Synergy of Notch Signaling and TNF-alpha Leads to Up-regulation of UBD in the Inflamed Intestinal Epithelia of IBD Patients (2019)
  • Author(s): Kawamoto A, Nagata S, Anzai S, Okamoto R, Mamoru Watanabe et al.
  • Organizer: AOCC 2019
  • Int'l Joint Research
• [Presentation] Synergy of Notch signalling and TNF-alpha in the inflamed intestinal epithelia of IBD patients leads to up-regulation of UBD, a ubiquitin-like protein. (2019)
  • Author(s): Kawamoto A, Nagata S, Anzai S, Okamoto R, Mamoru Watanabe et al.
  • Organizer: 14th ECCO
  • Int'l Joint Research
• [Presentation] クローン病由来の小腸上皮オルガノイド構築による幹細胞形質の解析 (2018)
  • Author(s): 鈴木康平, 村野竜朗, 平栗優衣, 高橋純一, 河本亜美, 石橋史明 , 安斎 翔, 久野玲子, 桒原小の実, 川井麻央, 永田紗矢香, 油井史郎, 土屋輝一郎, 中村哲也, 大塚和朗, 渡辺 守, 岡本隆一
  • Organizer: 第17回再生医療学会総会
• [Presentation] Jagged1 is indispensable for the maintenance of tumor stem cell niche in APC-Deficient intestinal adenomas (2016)
  • Author(s): Toru Nakata, Go Ito, Hiromichi Shimizu, Satoru Fujii, Kohei Suzuki, Fumiaki Ishibashi, Ami Kawamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Katsuto Hozumi, Ryuichi Okamoto, Mamoru Watanabe
  • Organizer: DDW2016
  • Place of Presentation: サンディエゴ（米国）
  • Int'l Joint Research
• [Presentation] Single-cell level analysis reveals heterogeneous expression of stem-cell specific genes in human small intestinal organoids (2016)
  • Author(s): Kohei Suzuki, Satoru Fujii, Ami Kawamoto, Fumiaki Ishibashi, Toru Nakata, Go Ito, Hiromichi Shimizu, Kiichiro Tsuchiya, Tetsuya Nakamura, Kazuo Otsuka, Ryuichi Okamoto, Mamoru Watanabe
  • Organizer: ion of stem-cell specific genes in human small intestinal organoidsDDW2016
  • Place of Presentation: サンディエゴ（米国）
  • Int'l Joint Research