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Development of colitic mucosa repair therapy by the induction of regeneration-specific stem cell niche formation

Research Project

Project/Area Number 25293170
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Okamoto Ryuichi  東京医科歯科大学, 再生医療研究センター, 教授 (50451935)

Co-Investigator(Kenkyū-buntansha) Tsuchiya Kiichiro  東京医科歯科大学, 医学部附属病院消化器内科, 准教授 (40376786)
Nakamura Tetsuya  東京医科歯科大学, 医歯学総合研究科, 寄附講座教授 (70265809)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2013: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Keywords腸管上皮 / 炎症性腸疾患 / Notchシグナル / オルガノイド / ニッチ / 幹細胞ニッチ
Outline of Final Research Achievements

Through the studies of the current project, results were acquired in the following areas: 1) Identification of Dll1+ve or Dll4+ve cells in inflamed and non-inflamed intestinal epithelium, and the functional relevance of those cells, 2) Comprehensive analysis of gene expression in Notch and TNF-α pathway activated cells, which constitute the regenerative epithelium inbt he colitic mucosa and 3) Identification of a distinct intestinal stem cell population that appears at the recovery phase of colitis.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report

Research Products

(38 results)

All 2016 2015 2014 2013 Other

All Journal Article Presentation

  • [Journal Article] Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease.2016

    • Author(s)
      Ryuichi Okamoto, Mamoru Watanabe
    • Journal Title

      J. Gastroenterol

      Volume: 51 Pages: 11-21

    • DOI

      10.1007/s00535-015-1098-4

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Co-culture with intestinal epithelial organoids allows efficient expansion and motility analysis of intraepithelial lymphocytes.2016

    • Author(s)
      Nozaki K, Mochizuki W, Matsumoto Y, Matsumoto T, Fukuda M, Mizutani T, Watanabe M, Nakamura T
    • Journal Title

      J Gastroenterol.

      Volume: 51 Pages: 206-213

    • DOI

      10.1007/s00535-016-1170-8

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells.2016

    • Author(s)
      Otani S, Kakinuma S, Kamiya A, Goto F, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Kawai-Kitahata F, Nitta S, Nakata T, Okamoto R, Itsui Y, Nakagawa M, Azuma S, Asahina Y, Yamaguchi T, Koshikawa N, Seiki M, Nakauchi H, Watanabe M.
    • Journal Title

      Biochem. Biophys. Res. Commun

      Volume: 469 Pages: 1062-1068

    • DOI

      10.1016/j.bbrc.2015.12.105

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Perspectives for Regenerative Medicine in the Treatment of Inflammatory Bowel Diseases.2015

    • Author(s)
      Ryuichi Okamoto, Mamoru Watanabe
    • Journal Title

      Digestion

      Volume: 92 Pages: 73-77

    • DOI

      10.1159/000438663

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy.2015

    • Author(s)
      Matsuzawa Y, Oshima S, Takahara M, Maeyashiki C, Nemoto Y, Kobayashi M, Nibe Y, Nozaki K, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Averil Ma, Watanabe M
    • Journal Title

      Autophagy

      Volume: 11 Pages: 1052-1062

    • DOI

      10.1080/15548627.2015.1055439

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line.2015

    • Author(s)
      Keita Fukushima, Kiichiro Tsuchiya,Okamoto Ryuichi, Mamoru Watanabe,et al
    • Journal Title

      Cancer Sci.

      Volume: 106 Pages: 1000-1007

    • DOI

      10.1111/cas.12703

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Reduced human α-defensin 6 in non-inflamed jejunal tissue of Crohn’s disease patients2015

    • Author(s)
      Hayashi R , Tsuchiya K, Okamoto R, Watanabe M.et al.
    • Journal Title

      Inflammatory Bowel Diseases

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RIPK3 regulates p62- LC3 complex formation via the caspase-8-dependent cleavage of p622015

    • Author(s)
      Y. Matsuzawa , S. Oshima, Y. Nibe, M.Kobayashi, C. Maeyashiki, Y. Nemoto, T. Nagaishi, R. Okamoto R, K. Tsuchiya, T. Nakamura, M. Watanabe.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 456(1) Pages: 298-304

    • DOI

      10.1016/j.bbrc.2014.11.075

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Fluorescent labelling of intestinal epithelial cells reveals independent long-lived intestinal stem cells in a crypt.2014

    • Author(s)
      N. Horita, K. Tsuchiya, R. Hayashi, K. Fukushima, S. Hibiya, M. Fukuda, Y. Kano, T. Mizutani, Y. Nemoto, S. Yui, R. Okamoto, T. Nakamura, M. Watanabe
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 454 Pages: 493-499

    • DOI

      10.1016/j.bbrc.2014.10.091

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis2014

    • Author(s)
      Suzuki M, Nagaishi T, Yamazaki M, Onizawa M, Watabe T, Sakamaki Y, Ichinose S, Totsuka M, Oshima S, Okamoto R, Shimonaka M, Yagita H, Nakamura T, Watanabe M.
    • Journal Title

      PLoS One.

      Volume: 9

    • DOI

      10.1371/journal.pone.0088369

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Distinct expression patterns of Notch ligands, Dll1 and Dll4, in normal and inflamed mice intestine.2014

    • Author(s)
      Shimizu H, Okamoto R, Ito G, Nakata T, Suzuki K, Murano T, Mizutani T, Tsuchiya K, Nakamura T, Hozumi K, Watanabe M.
    • Journal Title

      2014

      Volume: 2

    • DOI

      10.7717/peerj.370

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells.2014

    • Author(s)
      Murano T, Okamoto R, Ito G, Nakata T, Hibiya S, Shimizu H, Fujii S, Kano Y, Mizutani T, Yui S, Akiyama-Morio J, Nemoto Y, Tsuchiya K, Nakamura T, Watanabe M
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 443 Pages: 840-6

    • DOI

      10.1016/j.bbrc.2013.12.061

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Lineage-specific expression of bestrophin-2 and bestrophin-4 in human intestinal epithelial cells2013

    • Author(s)
      Ito G, Okamoto R, Nakamura T, Watanabe M et al
    • Journal Title

      PLoS One.

      Volume: 8

    • DOI

      10.1371/journal.pone.0079693

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4+ T cells in chronic colitis mice2013

    • Author(s)
      Takahara M, Nemoto Y, Oshima S, Matsuzawa Y, Kanai T, Okamoto R, Tsuchiya K, Nakamura T, Yamamoto K, Watanabe M.
    • Journal Title

      Immunol Lett

      Volume: 156 Pages: 82-93

    • DOI

      10.1016/j.imlet.2013.09.001

    • NAID

      120005468269

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells2013

    • Author(s)
      Nemoto Y, Nakamura T, Watanabe M et al
    • Journal Title

      Gut

      Volume: 62 Pages: 1142-1152

    • DOI

      10.1136/gutjnl-2012-302029

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Th1/Th17-mediated interstitial pneumonia in chronic colitis mice independent of intestinal microbiota2013

    • Author(s)
      Nemoto Y, Watanabe M et al
    • Journal Title

      J Immunol

      Volume: 190 Pages: 6616-25

    • DOI

      10.4049/jimmunol.1202930

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] Establishment of a 3D cell culture-based screening platform to identify natural products that can regulate transepithelial water transport of the human gastrointestinal tract.2015

    • Author(s)
      Satoru Fujii, Ryuichi Okamoto, Toru Nakata, Kohei Suzuki, Fumiaki Ishibashi, Ami Kawamoto,Sayaka Ohashi Segawa, Tomohiro Mizutani, Kiichiro Tsuchiya, Tetsuya Nakamura, Mamoru Watanabe.
    • Organizer
      Pacifichem2015
    • Place of Presentation
      ハワイ(米国)
    • Year and Date
      2015-12-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] TNF-α stabilizes atoh1 protein in colitis-associated colorectal cancer resulting in enhanced malignant potential.2015

    • Author(s)
      Tomoaki Shirasaki, Keita Fukushima, Kiichiro Tsuchiya, Shuuji Hibiya, Ryohei Hayashi, Nobukatsu Horita, Ryuichi Okamoto, Tetsuya Nakamura, Mamoru Watanabe.
    • Organizer
      UEGW2015
    • Place of Presentation
      バルセロナ(スペイン)
    • Year and Date
      2015-10-28
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Contiuous stimulation with cytokines leads to irreversible activation of NF-γb signaling in colonic epithelial cells by organoid culture.2015

    • Author(s)
      Shuji Hibiya, Kiichiro Tsuchiya, Tomoaki Shirasaki, Keita Fukushima, Ryohei Hayashi, Nobukatsu Horita, Shigeru Oshima ,Ryuichi Okamoto, Tetsuya Nakamura,Mamoru Watanabe
    • Organizer
      UEGW2015
    • Place of Presentation
      バルセロナ(スペイン)
    • Year and Date
      2015-10-27
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Atoh1 protein stabilized by TNF-α acquires enhanced malignant potential in colitis-associated colorectal cancer.2015

    • Author(s)
      Tomoaki Shirasaki, Keita Fukushima, Kiichiro Tsuchiya, Shuuji Hibiya, Ryohei Hayashi, Nobukatsu Horita, Ryuichi Okamoto, Tetsuya Nakamura, Mamoru Watanabe.
    • Organizer
      AOCC2015
    • Place of Presentation
      北京(中国)
    • Year and Date
      2015-06-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A novel fluorescent labelling system into small intestinal organoid reveals independent long-lived intestinal stem cells in a crypt.2015

    • Author(s)
      Horita N,Tsuchiya K,Hayashi R,Fukushima K,Hibiya S,Fukuda M,Mizutani T,Okamoto R,Nakamura T and Watanabe M.
    • Organizer
      AOCC2015
    • Place of Presentation
      北京(中国)
    • Year and Date
      2015-06-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Enrichment of Intestinal Stem Cells by the 3D-Culture of IBD Patient Derived Intestinal epithelium.2015

    • Author(s)
      Kohei Suzuki,Satoru Fujii,Toru Nakata,Ami Kawamoto,Fumiaki Ishibashi,Sayaka Ohashi Segawa, Tomohiro Mizutani, Kiichiro Tsuchiya,Kazuo Otsuka,Tetsuya Nakamura,Ryuichi Okamoto,Mamoru Watanabe.
    • Organizer
      AOCC2015
    • Place of Presentation
      北京(中国)
    • Year and Date
      2015-06-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Continuous Stimulation With Cytokines Leads to Irreversible Accumulation of NF-kB Signaling in Colonic Epithelial Cells.2015

    • Author(s)
      Shuji Hibiya, Kiichiro Tsuchiya, Keita Fukushima, Ryohei Hayashi, Nobukatsu Horita, Shigeru Oshima, Ryuichi Okamoto, Tetsuya Nakamura, Mamoru Watanabe.
    • Organizer
      DDW 2015
    • Place of Presentation
      ワシントン(米国)
    • Year and Date
      2015-05-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Distinct Role of Notch Ligands, DLL1 and Dll4, in Normal and in Tumor Intestinal Epithelium.2015

    • Author(s)
      Toru Nakata, Hiromichi Shimizu, Kohei Suzuki, Satoru Fujii, Go Ito, Kiichiro Tsuchiya, Tetsuya Nakamura, Ryuichi Okamoto, Katsuto Hozumi, Mamoru Watanabe.
    • Organizer
      DDW 2015
    • Place of Presentation
      ワシントン(米国)
    • Year and Date
      2015-05-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Atoh1 Protein Expression by TNF-a and the Acquisition of Malignant Potential in Colitis- Associated Colorectal Cancer.2015

    • Author(s)
      Keita Fukushima, Kiichiro Tsuchiya, Shuji Hibiya, Ryohei Hayashi, Nobukatsu Horita, Yoshihito Kano, Ryuichi Okamoto, Tetsuya Nakamura, Mamoru Watanabe.
    • Organizer
      DDW 2015
    • Place of Presentation
      ワシントン(米国)
    • Year and Date
      2015-05-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Notch Ligands DLL1 and Dll4 Are Expressed by Distinct Population of Epithelial Cells in the Mice Intestine.2015

    • Author(s)
      Hiromichi Shimizu, Kohei Suzuki, Satoru Fujii, Toru Nakata, Go Ito, Tatsuro Murano, Kiichiro Tsuchiya, Tetsuya Nakamura, Ryuichi Okamoto, Katsuto Hozumi, Mamoru Watanabe.
    • Organizer
      DDW 2015
    • Place of Presentation
      ワシントン;米国
    • Year and Date
      2015-05-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Live imaging analysis of intraepithelial lymphocytes (IELs) co-cultured with intestinal epithelial organoids.2015

    • Author(s)
      Nozaki K, Mochizuki W, Matsumoto Y, Matsumoto T, Fukuda M, Mizutani T, Watanabe M, Nakamura T
    • Organizer
      Cold Spring Harbor Meeting "Fundamental Immunology and Its Therapeutic Applications"
    • Place of Presentation
      ニューヨーク(米国)
    • Year and Date
      2015-04-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Notch signaling and TNF-α synergistically up-regulates expression of OLFM4 in human intestinal epithelial cells.2014

    • Author(s)
      Go Ito, Ryuichi Okamoto, Tasturo Murano, Hiromichi Shimizu, Satoru Fujii, Toru Nakata, Kiichiro Tsuchiya, Tetsuya Nakamura, Mamoru Watanabe .
    • Organizer
      第8回Japan-US Collabaration Conference in Gastroenterology
    • Place of Presentation
      Intercontinental TOKYO BAY (東京都港区海岸1-16-2)
    • Year and Date
      2014-11-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] Notch signaling regulates expression of gelsolin superfamily genes, gelsolim and scinderin and promotes re-assembly of action cytoskeleton in human intestinal epithelial cells.2014

    • Author(s)
      Ryuichi Okamoto, Go Ito, Hiromichi Shimizu, Satoru Fujii , Toru Nakata, Kohei Suzuki, Mamoru Watanabe.
    • Organizer
      UEGW2014
    • Place of Presentation
      Vienna (Austria)
    • Year and Date
      2014-10-22
    • Related Report
      2014 Annual Research Report
  • [Presentation] Notch Signaling and TNF-alpha synergistically promotes intracellular protein accumulation of olfm4 in the inflamed mucosa of ulcerative colitis.2014

    • Author(s)
      Go Ito, Ryuichi Okamoto, Hiromichi Shimizu, Satoru Fujii, Toru Nakata, Kohei Suzuki, Kiichiro Tsuchiya, Tetsuya Nakamura, Mamoru Watanabe.
    • Organizer
      UEGW2014
    • Place of Presentation
      Vienna (Austria)
    • Year and Date
      2014-10-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] Notch signaling and TNF-α synergistically promotes intracellular protein expression of OLFM4 in human intestinal epithelial cells.2014

    • Author(s)
      Go Ito, Ryuichi Okamoto, Hiromichi Shimizu, Satoru Fujii, Toru Nakata, Kohei Suzuki, Kiichiro Tsuchiya, Tetsuya Nakamura, Mamoru Watanabe.
    • Organizer
      The 2nd Annual Meeting of Asian Organization for Crohn's and Colitis
    • Place of Presentation
      Seoul (Korea)
    • Year and Date
      2014-06-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] Distinct Expression Patterns of Notch Ligands, DLL1 and DLL4, in Normal and Inflamed Mice Intestine.2014

    • Author(s)
      Hiromichi Shimizu, Ryuichi Okamoto, Go Ito, Satoru Fujii, Toru Nakata, Kohei Suzuki, Tatsuro Murano, Tomohiro Mizutani, Kiichiro Tsuchiya, Tetsuya Nakamura, Katsuto Hozumi, Mamoru Watanabe.
    • Organizer
      The 2nd Annual Meeting of Asian Organization for Crohn's and Colitis
    • Place of Presentation
      Seoul (Korea)
    • Year and Date
      2014-06-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] Complete conversion of crypt progenitor cells into Atoh1-positive cells by targeted deletion of Dll1 and Dll4 in Lgr5-positive intestinal stem cells

    • Author(s)
      Hiromichi Shimizu, Ryuichi Okamoto, Satoru Fujii, Go Ito, Tatsuro Murano, Kiichiro Tsuchiya, Tetsuya Nakamura, Mamoru Watanabe
    • Organizer
      DDW 2013
    • Place of Presentation
      オーランド、米国
    • Related Report
      2013 Annual Research Report
  • [Presentation] Notch signaling regulates expression of Bestrophin-4, a novel enterocyte-specific HCO3-/Cl- channel, in human intestinal epithelial cells.

    • Author(s)
      Go Ito, Ryuichi Okamoto, Satoru Fujii, Hiromichi Shimizu, Tatsuro Murano, Kiichiro Tsuchiya, Tetsuya Nakamura, Mamoru Watanabe
    • Organizer
      DDW 2013
    • Place of Presentation
      オーランド、米国
    • Related Report
      2013 Annual Research Report
  • [Presentation] Hes1 promotes IL-22-mediated antimicrobial response through enhancement of STAT3-dependent transcription in human intestinal epithelial cells

    • Author(s)
      Ryuichi Okamoto, Tatsuro Murano, Hiromichi Shimizu, Go Ito, Satoru Fujii, Kiichiro Tsuchiya, Tetsuya Nakamura, and Mamoru Watanabe
    • Organizer
      The 1st Annual Meeting of Asian Organization for Crohn's and Colitis
    • Place of Presentation
      東京、ラフォーレ東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] COMPLETE CONVERSION OF CRYPT PROGENITOR CELLS INTO ATOH1-POSITIVE CELLS BY TARGETED DELETION OF DLL1 AND DLL4 IN LGR5-POSITIVE INTESTINAL STEM CELLS

    • Author(s)
      H. Shimizu, R. Okamoto, T. Nakata, S. Fujii, G. Ito, T. Murano, K. Tsuchiya, T. Nakamura, M. Watanabe
    • Organizer
      UEGW 2013
    • Place of Presentation
      ベルリン、ドイツ
    • Related Report
      2013 Annual Research Report
  • [Presentation] IL-22-MEDIATED ANTIMICROBIAL RESPONSE IS REGULATED BY HES1 VIA STAT3-DEPENDENT TRANSCRIPTION IN HUMAN INTESTINAL EPITHELIAL CELLS

    • Author(s)
      R. Okamoto, T. Murano, H. Shimizu, G. Ito, S. Fujii, T. Nakata, K. Tsuchiya, T. Nakamura, M. Watanabe
    • Organizer
      UEGW 2013
    • Place of Presentation
      ベルリン、ドイツ
    • Related Report
      2013 Annual Research Report
  • [Presentation] LINEAGE-SPECIFIC EXPRESSION OF BESTROPHIN-2 AND BESTROPHIN-4 IS REGULATED BY NOTCH SIGNALING IN HUMAN INTESTINAL EPITHELIAL CELLS

    • Author(s)
      G. Ito , R. Okamoto, T. Murano, H. Shimizu, K. Tsuchiya, T. Nakamura, M. Watanabe
    • Organizer
      UEGW 2013
    • Place of Presentation
      ベルリン、ドイツ
    • Related Report
      2013 Annual Research Report

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Published: 2013-05-21   Modified: 2019-07-29  

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