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2018 Fiscal Year Annual Research Report

The elucidation of homeostasis regulated by intestinal epithelial stem cells

Research Project

Project/Area Number 26221307
Research InstitutionTokyo Medical and Dental University

Principal Investigator

渡辺 守  東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10175127)

Co-Investigator(Kenkyū-buntansha) 土屋 輝一郎  東京医科歯科大学, 医学部附属病院, 准教授 (40376786)
中村 哲也  東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (70265809)
Project Period (FY) 2014-05-30 – 2019-03-31
Keywords腸内環境 / 共培養 / 幹細胞機能評価 / 疑似モデル構築 / 全身制御
Outline of Annual Research Achievements

炎症性腸疾患では腸管上皮細胞の機能不全による腸内環境破綻が難治性の原因と示唆される。申請者は腸管上皮幹細胞運命を人為的に制御し、腸内環境を改善させることが生体恒常性までもリセットすることにより炎症性腸疾患を根本的に解決できると着想した。申請者らが独自に確立した「腸管上皮幹細胞初代培養」と「幹細胞移植モデル」をさらに発展させ、擬似腸管環境モデル構築による腸管上皮幹細胞の運命制御及び腸管免疫・内分泌制御を含めた腸内環境・生体恒常性への関与を解明する。最終的には腸管上皮幹細胞による腸内環境、生体恒常性リセットという新たな機序を創成し臨床応用への基盤を構築するだけでなく、腸疾患に留まらず生活習慣病などの全身疾患を制御できるという新しい概念を提唱するものである。
本年度は昨年度のマウスでの系を発展させ、ヒトでの系を樹立した。ヒト内視鏡生検検体、もしくは手術検体より、腸上皮オルガノイド・上皮間リンパ球の初代培養を施行した。ヒト大腸オルガノイドを用いてサイトカイン、細菌菌体成分添加による上皮応答を確認した。添加のみでも十分な免疫応答が得られることを確認し、最大限の炎症応答が得られる条件を最適化した。潰瘍性大腸炎患者生検検体の網羅的遺伝子発現プロファイルと炎症刺激オルガノイドのプロファイルを比較検討したところ、類似性を確認した。さらに持続刺激を1年間以上行い、IBDの罹患状態を模倣している。マイクロアレイ解析により、1年以上の長期刺激により始めて発現誘導される遺伝子群を発見した。以上より、炎症性腸疾患の体外擬似モデルを構築し、長期炎症特異的発現遺伝子がIBD病態と密接に関与することが示唆された。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

  • Research Products

    (36 results)

All 2019 2018

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Open Access: 2 results) Presentation (27 results) (of which Int'l Joint Research: 25 results,  Invited: 3 results)

  • [Journal Article] TP53 mutation by CRISPR system enhances the malignant potential of colon cancer.2019

    • Author(s)
      Watanabe S, Tsuchiya K, Nishimura R, Shirasaki T, Katsukura N, Hibiya S, Okamoto R, Nakamura T, Watanabe M
    • Journal Title

      Mol Cancer Res.

      Volume: in press Pages: in press

    • DOI

      10.1158/1541-7786.MCR-18-1195.

    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of a system to evaluate the therapeutic effect and the dynamics of an investigational drug on ulcerative colitis using human colonic organoids.2019

    • Author(s)
      Nishimura R, Shirasakai T, Tsuchiya K, Miyake Y, Watanabe Y, Hibiya S, Watanabe S, Nakamura T, Watanabe M
    • Journal Title

      J Gastroenterol.

      Volume: in press Pages: in press

    • DOI

      10.1007/s00535-018-01540-y.

    • Peer Reviewed
  • [Journal Article] Ubiquitin D is up-regulated by synergy of Notch signaling and TNF-α in the inflamed intestinal epithelia of IBD patients.2018

    • Author(s)
      Kawamoto A, Nagata S, Anzai S, Takahashi J, Kawai M, Hama M, Nogawa D, Yamamoto K, Kuno R, Suzuki K, Shimizu H, Hiraguri Y, Yui S, Ohshima S, Tsuchiya K, Nakamura T, Ohtsuka K, Kitagawa M, Okamoto R, Watanabe M
    • Journal Title

      J Crohns Colitis.

      Volume: 13 Pages: 495-509

    • DOI

      10.1093/ecco-jcc/jjy180.

    • Peer Reviewed
  • [Journal Article] Genetic and environmental factors drive personalized medicine for Crohn’s disease.2018

    • Author(s)
      Oshima S, Watanabe M:
    • Journal Title

      J Clin Invest.

      Volume: 128 Pages: 4758-4760

    • DOI

      10.1172/JCI124303.

    • 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 K, Murano T, Shimizu M, Ito G, Nakata T, Fujii S, Ishibashi F, Kawamoto A, Anzai S, Kuno R, Kuwabara K, Takahashi J, Hama M, Nagata S, Hiraguri Y, Takenaka K, Yui S, Tsuchiya K, Nakamura T, Ohtsuka K, Watanabe M, Okamoto R:
    • Journal Title

      J Gastroenterol.

      Volume: 53 Pages: 1035-1047

    • DOI

      10.1007/s00535-018-1437-3.

    • Peer Reviewed
  • [Journal Article] B cell activation in the cecal patches during the development of an experimental colitis model.2018

    • Author(s)
      Watabe T, Nagaishi T, Tsugawa M, Kojima Y, Jose N, Hosoya A, Onizawa M, Nemoto Y, Oshima S, Nakamura T, Karasuyama H, Adachi T, Watanabe M
    • Journal Title

      Biochem Biophys res Commun.

      Volume: 496 Pages: 367-373

    • DOI

      10.1016/j.bbrc.2018.01.053.

    • Peer Reviewed
  • [Journal Article] YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration.2018

    • Author(s)
      Yui S, Azzolin L, Maimets M, Pedersen M, Fordham R, Hansen S, Guiu J, Alves M, Rundsen C, Johansen J, Li Y, Madsen C, Nakamura T, Wanatabe M, Nielsen O, Schweiger P, Piccolo S, Jensen K
    • Journal Title

      Cell Stem Cell

      Volume: 22 Pages: 35-49

    • DOI

      10.1016/j.stem.2017.11.001.

    • Peer Reviewed
  • [Journal Article] Contribution of ATOH1+ cells to the homeostasis, repair and tumorigenesis of the colonic epithelium.2018

    • Author(s)
      Ishibashi F, Shimizu H, Nakata T, Fujii S, Suzuki K, Kawamoto A, Anzai S, Kuno R, Nagata S, Ito G, Murano T, Mizutani T, Oshima S, Tsuchiya K, Nakamura T, Watanabe M, Okamoto R
    • Journal Title

      Stem Cell Rep.

      Volume: 10 Pages: 27-42,

    • DOI

      10.1016/j.stemcr.2017.11.006.

    • Peer Reviewed / Open Access
  • [Journal Article] Novel polyubiquitin imaging system, PolyUb-FC, reveals that K33-linked polyubiquitin is recruited by p62/SQSTM1.2018

    • Author(s)
      Nibe Y, Oshima S, Kobayashi M, Maeyashiki C, Matsuzawa Y, Otsubo K, Matsuda H, Aonuma E, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Nakada S, Watanabe M
    • Journal Title

      Autophagy

      Volume: 24 Pages: 347-358

    • DOI

      10.1080/15548627.2017.1407889.

    • Peer Reviewed
  • [Presentation] TP53 mutation in human colonic organoids acquires resistance to in vitro long-term inflammation.2019

    • Author(s)
      Tsuchiya K, Watanabe S, Shirasaki T, Nishimura R, Katsukura N, Hibiya S, Okamoto R, Nakamura T, Watanabe M
    • Organizer
      ECCO2019
    • Int'l Joint Research
  • [Presentation] Synergy of Notch signalling and TNF-α 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, Takahashi J, Kawai M, Hama M, Nogawa D, Yamamoto K, Kuno R, Suzuki K, Shimizu H, Hiraguri Y, Yui S, Oshima S, Tsuchiya K, Nakamura T, Ohtsuka K, Kitagawa M, Okamoto R, Watanabe M
    • Organizer
      ECCO2019
    • Int'l Joint Research
  • [Presentation] UC-related and segment-specific properties of patientderived colonic organoids.2019

    • Author(s)
      Suzuki K, Shimizu H, Kawai M, Takahashi J, Anzai S, Kawamoto A, Nagata S, Hiraguri Y, Yui S, Tsuchiya K, Nakamura T, Ohtsuka K, Okamoto R, Watanabe M
    • Organizer
      ECCO2019
    • Int'l Joint Research
  • [Presentation] Introduction to IBD Centre at Tokyo Medical and Dental University.2018

    • Author(s)
      Watanabe M
    • Organizer
      IBD Center of Excellence
    • Invited
  • [Presentation] Intestinal Epithelial Stem Cell Organoid and IBD.2018

    • Author(s)
      Watanabe M
    • Organizer
      第55回日本消化器免疫学会 シンポジウム
    • Invited
  • [Presentation] Regeneration of intestinal epithelial cell and IBD2018

    • Author(s)
      Watanabe M
    • Organizer
      Falk symposium2018
    • Int'l Joint Research / Invited
  • [Presentation] Downregulated APL expression in T cells in the setting of chronic colitis.2018

    • Author(s)
      Kojima Y, Nagaishi T, Watabe T, Yamada D, Tsugawa N, Jose N, Hosoya A, Shimizu M, Onizawa M, Watanabe M
    • Organizer
      第47回日本免疫学会学術集会
    • Int'l Joint Research
  • [Presentation] Mice overexpressing MKL1 in macrophages experience fulminant colitis.2018

    • Author(s)
      An J, Nagaishi T, Watabe T, Naruse TK., Watanabe M, Kimura A
    • Organizer
      UEGW 2018
    • Int'l Joint Research
  • [Presentation] B cell-mediated ileocecal immune response is activated in the early phase of colitis development.2018

    • Author(s)
      Kojima Y, Nagaishi T, Watabe T, Tsugawa N, Jose N, Yamada D, Hosoya A, Adachi T, Watanabe M
    • Organizer
      UEGW 2018
    • Int'l Joint Research
  • [Presentation] Lesion-specific gene expression in the Epithelial cells of Crohn’s disease by comparing Small intestinal organoids from active and inactive Lesion in the same patient.2018

    • Author(s)
      Hibiya S, Tsuchiya K, Nishimura R, Shirasaki T, Watanabe S, Katsukura N, Okamoto R, Nakamura T, Watanabe M
    • Organizer
      UEGW 2018
    • Int'l Joint Research
  • [Presentation] Tp53 mutation enhances cell proliferation and stemness in human colon epithelial organoids and promotes a resistance against long-term inflammation.2018

    • Author(s)
      Watanabe S, Tsuchiya K, Shirasaki T, Hibiya S, Nishimura S, Katsukura N, Oshima S, Okamoto R, Tetsuya N, Watanabe M
    • Organizer
      UEGW 2018
    • Int'l Joint Research
  • [Presentation] Long-lived secretory cells residing in the mouse proximal colon serve as reserve stem cells under DNA damage-induced mucosal injury.2018

    • Author(s)
      Kuwabara K, Ishibashi F, Kawamoto A, Anzai S, Takahashi J, Nagata S, Shimizu H, Yui S, Oshima S, Tsuchiya K, Nakamura T, Watanabe M, Okamoto R
    • Organizer
      UEGW 2018
    • Int'l Joint Research
  • [Presentation] Ectopic expression of reg3a in the mice distal Colon is mediated by interactions between notch and Il-22 signaling pathways, and promotes tissue repair By the augmentation of EGFR signaling.2018

    • Author(s)
      Ishibashi F, Kuwabara K, Kawamoto A, Anzai S, Takahashi J, Nagata S, Shimizu H, Yui S, Oshima S, Tsuchiya K, Nakamura T, Watanabe M, Okamoto R
    • Organizer
      UEGW 2018
    • Int'l Joint Research
  • [Presentation] Regenerative medicine for the treatment of inflammatory bowel disease.2018

    • Author(s)
      Okamoto R, Watanabe M
    • Organizer
      5th TERMIS World Congress 2018
    • Int'l Joint Research
  • [Presentation] Crohn’s disease patient-derived small intestinal organoids reveal diseasestatus related modification of stem cell properties.2018

    • Author(s)
      Suzuki K, Takahashi J, Hiraguri Y, Yui S, Shimizu H, Tsuchiya K, Nakamura T, Ohtsuka K, Okamoto R, Watanabe M
    • Organizer
      5th TERMIS World Congress 2018
    • Int'l Joint Research
  • [Presentation] Crohn’s disease patient-derived small intestinal organoids reveal disease-status related modification of stem cell properties. 52018

    • Author(s)
      Suzuki K, Murano T, Hiraguri Y, Takahashi J, Shimizu H,Anzai S, Kuwabara K, Kawamoto A, Ishibashi F, Yui S, Tsuchiya K, Nakamura T, Ohtsuka K, Watanabe M, Okamoto R
    • Organizer
      5th TERMIS World Congress 2018
    • Int'l Joint Research
  • [Presentation] Development of a new mouse model of short bowel syndrome that may allow for the assessment of therapeutic efficacy of heterotopic transplantation of small intestinal organoids.2018

    • Author(s)
      Matsumoto Y, Watanabe M, Nakamura T
    • Organizer
      5th TERMIS World Congress 2018
    • Int'l Joint Research
  • [Presentation] Overexpression of MKL1 in Macrophages leads to the development of murine colitis.2018

    • Author(s)
      An J, Nagaishi T, Watabe T, Naruse TK., Watanabe M, Kimura A
    • Organizer
      MICS 2018
    • Int'l Joint Research
  • [Presentation] Mice overexpressing MKL1 in macrophages are susceptible to DSS-induced colitis.2018

    • Author(s)
      An J, Nagaishi T, Watabe T, Naruse TK., Watanabe M, Kimura
    • Organizer
      FOCIS 2018
    • Int'l Joint Research
  • [Presentation] Analysis of cecal immune response in a murine model of colitis using intravital imaging.2018

    • Author(s)
      Nagaishi T, Watabe T, Tsugawa N, Kojima Y, Jose N, Yamada D, Adachi T, Watanabe M
    • Organizer
      FOCIS 2018
    • Int'l Joint Research
  • [Presentation] Mouse colonic secretory cells de-differentiate into intestinal stem cells and promote mucosal repair through activation of NF-KB signaling.2018

    • Author(s)
      Ishibashi F, Shimizu H, Kawamoto A, Suzuki K, Anzai S, Kuwabara K, Takahashi J, Nagata S, Oshima S, Tsuchiya K, Nakamura T, Watanabe M, Okamoto R
    • Organizer
      ISSCR2018
    • Int'l Joint Research
  • [Presentation] Mice overexpressing MKL1 in macrophages are susceptible to the development of colitis.2018

    • Author(s)
      An J, Nagaishi T, Watabe T, Naruse TK., Watanabe M, Kimura A
    • Organizer
      DDW 2018
    • Int'l Joint Research
  • [Presentation] Human colonic organoid treated with inflammatory factors might mimic the pathophysiology of epithelial cells in ulcerative colitis.2018

    • Author(s)
      Hibiya S, Tsuchiya K, Watanabe S, Nishimura R, Shirasaki T, Oshima S, Okamoto R, Nakamura T, Watanabe M
    • Organizer
      DDW 2018
    • Int'l Joint Research
  • [Presentation] Identification of lesion-specific epithelial function of ulcerative colitis by comparing colonic organoids from lesion and non-lesion parts of same patients.2018

    • Author(s)
      Shirasaki T, Tsuchiya K, Nishimura R, Watanabe S, Hibiya S, Katsukura N, Okamoto R, Nakamura T, Watanabe M
    • Organizer
      DDW 2018
    • Int'l Joint Research
  • [Presentation] Analysis of ileocecal immune response in an animal model of colitis using intra-vital imaging.2018

    • Author(s)
      Watabe T, Nagaishi T, Tsugawa N, Kojima Y, Jose N, Hosoya A, Adachi T, Watanabe M
    • Organizer
      DDW 2018
    • Int'l Joint Research
  • [Presentation] Single-cell level analysis of organoids derived from CD patients reveals disease-status related modifications of small intestinal stem cells.2018

    • Author(s)
      Suzuki K, Kuwabara K, Takahashi J, Anzai S, Kuno R, Kawamoto A, Ishibashi F, Nagata S, Hiraguri Y, Yui S, Tsuchiya K, Nakamura T, Ohtsuka K, Okamoto R, Watanabe M
    • Organizer
      DDW 2018
    • Int'l Joint Research
  • [Presentation] Fetalization of colonic epithelium medicated by YAP/TAZ links ECM remodeling to tissue regeneration.2018

    • Author(s)
      Yui S, Okamoto R, Tsuchiya K, Nakamura T, Watanabe M
    • Organizer
      GI Research Academy2018
    • Int'l Joint Research

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Published: 2019-12-27  

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