Identification of critical factor to generate human colon from small intestine

• Project/Area Number: 17K19513
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Biomedical structure and function and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Watanabe Mamoru 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10175127)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 炎症性腸疾患 / 再生医療 / 幹細胞運命制御 / 大腸オルガノイド / 体性幹細胞 / 運命転換

Outline of Final Research Achievements

The aim of this study is to elucidate the mechanism of the transformation from the stem cell in human small intestine to the stem cell in colon. We therefore collected biopsy specimens from both small intestine and colon in a same patient. We then assessed the difference of gene expression between small intestine and colon, resulting in the identification of a gene specifically expressed only in colon.
Further analysis for the function of this gene might help to understand the mechanism of stem cell fate to generate human colon.

Academic Significance and Societal Importance of the Research Achievements

炎症性腸疾患、中でも潰瘍性大腸炎は若年者に多く、日本でも患者数が増加している難治性の病気です。潰瘍性大腸炎では粘膜の再生が治療のゴールとなっており、大腸上皮細胞を体外で培養し移植する治療も将来的に考えられています。しかし、潰瘍性大腸炎では病変が大腸全域に渡るため、大腸再生医療では培養するべき正常大腸上皮細胞が確保できないことも心配されます。そのため、小腸細胞を大腸細胞に変換させることで、再生医療の移植に使用できるのではと考えています。

Research Products

• [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 Issue: 7 Pages: 1459-1467
  • 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, 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] Ubiquitin D is Upregulated by Synergy of Notch Signalling and TNF-α in the Inflamed Intestinal Epithelia of IBD Patients (2018)
  • 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: Journal of Crohn's and Colitis Volume: 13 Issue: 4 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 Shigeru、Watanabe Mamoru
  • Journal Title: Journal of Clinical Investigation Volume: 128 Issue: 11 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 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: Journal of Gastroenterology Volume: 印刷中 Issue: 9 Pages: 1035-1047
  • DOI: 10.1007/s00535-018-1437-3
  • Peer Reviewed / Open Access
• [Journal Article] B cell activation in the cecal patches during the development of an experimental colitis model. (2018)
  • Author(s): Taro Watabe, Takashi Nagaishi, Naoya Tsugawa, Yudai Kojima, Nisha Jose, Akinori Hosoya, Michio Onizawa, Yasuhiro Nemoto, Shigeru Oshima, Tetsuya Nakamura, Hajime Karasuyama, Takahiro Adachi, Mamoru Watanabe
  • Journal Title: Biochem Biophys Res Commun. Volume: 496 Issue: 2 Pages: 367-373
  • DOI: 10.1016/j.bbrc.2018.01.053
  • Peer Reviewed / Open Access
• [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 MT、Fordham RP、Hansen SL、Larsen HL、Guiu Jordi、Alves MRP、Rundsten CF、Johansen JV、Li Y、Madsen CD、Nakamura T、Watanabe M、Nielsen OH、Schweiger PJ、Piccolo S、Jensen KB
  • Journal Title: Cell Stem Cell Volume: 22 Issue: 1 Pages: 35-49
  • DOI: 10.1016/j.stem.2017.11.001
  • 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 Reports Volume: 10 Issue: 1 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. (2017)
  • 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 Issue: 2 Pages: 1-43
  • DOI: 10.1080/15548627.2017.1407889
  • Peer Reviewed / Open Access
• [Journal Article] Distinct intestinal adaptation for vitamin B12 and bile acid absorption revealed in a new mouse model of massive ileocecal resection. (2017)
  • Author(s): Matsumoto Y, Mochizuki W, Akiyama S, Matsumoto T, Nozaki K, Watanabe M, Nakamura T
  • Journal Title: Biol Open. Volume: 15 Pages: 1364-1374
  • DOI: 10.1242/bio.024927
  • Peer Reviewed / Open Access
• [Journal Article] <i>CCN3</i> Expression Marks a Sulfomucin-nonproducing Unique Subset of Colonic Goblet Cells in Mice (2017)
  • Author(s): Akiyama S, Mochizuki W, Nibe Y, Matsumoto Y, Sakamoto K, Oshima S, Watanabe M, Nakamura T
  • Journal Title: ACTA HISTOCHEMICA ET CYTOCHEMICA Volume: 50 Issue: 6 Pages: 159-168
  • DOI: 10.1267/ahc.17027
  • NAID: 130006285159
  • ISSN: 0044-5991, 1347-5800
  • 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総会 シンポジウム
  • Invited
• [Presentation] Regeneration of intestinal epithelial cell and IBD (2018)
  • 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. (2018)
  • 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 A
  • 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 Academy 2018
  • Int'l Joint Research
• [Presentation] Organoids as a therapy resource from clinical trial in a dish to engraftment. (2018)
  • Author(s): Watanabe M
  • Organizer: International Cluster Symposium
  • Int'l Joint Research / Invited
• [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): Nishimura R, Tsuchiya K, Shirasaki T, Watanabe S, Hibiya S, Okamoto R, Nakamura T, Watanabe M
  • Organizer: The 13th Congress of ECCO
  • Int'l Joint Research
• [Presentation] Long-chain fatty acid regulates autophagy and polyubiquitination in intestinal epithelial cells. (2018)
  • Author(s): Otsubo K, Maeyashiki C, Aonuma E, Matsuda H, Nibe Y, Kobayashi M, Matsuzawa Y, Watanabe M, Oshima S
  • Organizer: Keystone Symposia - Ubiquitin Signaling (A8)
  • Int'l Joint Research
• [Presentation] Stem Cell Therapy for IBD: Promise and Challenge. (2017)
  • Author(s): Watanabe M
  • Organizer: GZDDW2017
  • Int'l Joint Research / Invited
• [Presentation] Intestinal Epithelial Stem Cells for the Treatment of GI Disease. (2017)
  • Author(s): Watanabe M
  • Organizer: Digestive and Liver Diseases Conference
  • Int'l Joint Research / Invited
• [Presentation] Analysis of ileocecal immune response in an experimental colitis model using intra-vital imaging. (2017)
  • Author(s): Watabe T, Nagaishi T, Hosoya A, Jose N, Tsugawa N, Kojima Y, Yoshikawa S, Karasuyama H, Adachi T, Watanabe M
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Reprogrammed Atoh1+ intestinal epithelial cells contribute to regenerate damaged colonic mucosa in DSS-induced colitis. (2017)
  • Author(s): shibashi F, Shimizu H, Nakata T, Fujii S, Suzuki K, Kawamoto A, Anzai S, Kuno R, Nagata S, Ito G, Murano T, Oshima S, Tsuchiya K, Nakamura T, Okamoto R, Watanabe M
  • Organizer: UEGW2017
  • Int'l Joint Research
• [Presentation] Lineage tracing reveals contribution of Atoh1+ cell-derived stem cells in the homeostasis, repair, and carcinogenesis of the intestinal epithelium. (2017)
  • Author(s): Ishibashi F, Shimizu H, Nakata T, Fujii S, Suzuki K, Kawamoto A, Anzai S, Kuno R, Nagata S, Ito G, Murano T, Oshima S, Tsuchiya K, Nakamura T, Okamoto R, Watanabe M
  • Organizer: DDW2017
  • Int'l Joint Research