Elucidation of stem cell pathogenesis in inflammatory bowel disease using primary intestinal epithelial stem cells culture and development of new therapeutic agent

• Project/Area Number: 17K15930
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NISHIMURA Ryu 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (60778132)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 幹細胞機能評価 / 初代培養 / 炎症性腸疾患

Outline of Final Research Achievements

We have established in vitro UC model using human colonic organoid. Microarray analysis showed a significant induction of inflammatory-related genes in colonic organoids whereas cell differentiation was suppressed. Treatment with the investigational drug showed reciprocal dynamics of gene expression to inflammatory stimulation. We by focused a series of genes that were upregulated in an antagonistic response to inflammation by treatment with the investigational drug, and identified the molecular target.
Further maturation of this system might be more efficient to predict the effect on UC for the development of new drugs.

Academic Significance and Societal Importance of the Research Achievements

体外でのヒト大腸上皮細胞でも潰瘍性大腸炎モデルの作成に成功し、潰瘍性大腸炎における大腸上皮細胞の病態の一部が明らかになった。このモデルを用いて新規治療候補薬の効果や作用機序を明らかにすることができた。このモデルを用いて治療候補薬のスクリーニングや安全性の評価することが期待できるものと考えられる。

Research Products

• [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, Shirasaki T, Tsuchiya K, Miyake Y, Watanabe Y, Hibiya S, Watanabe S, Nakamura T, Watanabe M
  • Journal Title: J Gastroenterol. Volume: in press Issue: 7 Pages: 608-620
  • DOI: 10.1007/s00535-018-01540-y
  • Peer Reviewed / Open Access
• [Journal Article] Long-term inflammation transforms intestinal epithelial cells of colonic organoids. (2017)
  • Author(s): Hibiya S, Tsuchiya K, Hayashi R, Horita N, Watanabe S, Shirasaki T, Nishimura R, Kimura N, Nishimura T, Gotoh N, Oshima S, Okamoto R, Nakamura T, Watanabe M
  • Journal Title: J Crohns Colitis. Volume: 61 Pages: 621-630
  • DOI: 10.1093/ecco-jcc/jjw186
  • Peer Reviewed / Acknowledgement Compliant
• [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] 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] 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: DDW2018
  • 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: DDW2018
  • Int'l Joint Research
• [Presentation] Establishment of in vitro human model for Ulcerative Colitis by using human colon organoid culture. (2018)
  • Author(s): Shuji Hibiya, Kiichiro Tsuchiya, Sho Watanabe, Ryu Nishimura, Tomoaki Shirasaki, Shigeru Oshima, Ryuichi Okamoto, Tetsuya Nakamura, Mamoru Watanabe.
  • Organizer: 13th Congress of ECCO
  • Int'l Joint Research
• [Presentation] The identification of lesion-specific gene expression in intestinal epithelial cells of Ulcerative Colitis by comparing colonic organoids from lesion and non-lesion parts of same patients. (2018)
  • Author(s): Ryu Nishimura, Kiichiro Tsuchiya, Tomonori Shirasaki, Syo Watanabe, Syuji Hibiya, Ryuichi Okamoto, Tetsuya Nakamura, and Mamoru Watanabe.
  • Organizer: 13th Congress of ECCO
  • Int'l Joint Research
• [Presentation] ヒト大腸オルガノイドを用いた炎症性腸疾患擬似モデルの構築による薬効評価システムへの応用 (2017)
  • Author(s): 西村 龍、土屋 輝一郎、白﨑 友彬、渡辺 翔、日比谷 秀爾、岡本 隆一、中村 哲也、渡辺 守
  • Organizer: 第54回日本消化器免疫学会総会
• [Presentation] TP53 mutation acquires higher malignant potential in human colon cancer cells. (2017)
  • Author(s): Sho Watanabe, Kiichiro Tsuchiya, Tomoaki Shirasaki, Shuji Hibiya, Shigeru Oshima, Ryu Nishimura, Tetsuya Nakamura, Ryuichi Okamoto, Mamoru Watanabe.
  • Organizer: UEGW2017
  • Int'l Joint Research