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Regulatory mechanism of gastric differentiation from gastric stem cells

Research Project

Project/Area Number 17H05081
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

Hayakawa Yoku  東京大学, 医学部附属病院, 助教 (60777655)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥25,480,000 (Direct Cost: ¥19,600,000、Indirect Cost: ¥5,880,000)
Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2018: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
Fiscal Year 2017: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
Keywords胃上皮幹細胞 / 萎縮性胃炎 / 粘膜再生 / 腸上皮化生 / 分化 / 胃癌 / アセチルコリン / 遺伝子発現解析 / 内科 / 細胞・組織 / ゲノム / マイクロアレイ / 発生・分化
Outline of Final Research Achievements

We performed gene expression analysis of gastric stem cells, progenitors, and other mature cell types, and identified novel markers specific for each cell population. We generated several mouse lines that mark these specific cell types. We analyzed histological and molecular changes in stem and other cell types during early carcinogenesis, and identified the mechanism of the development of gastric metaplasia and cancer. We also showed that tuft cell-mediated acetylcholine signal is important for stem cell function and mucosal regeneration via ERK pathway, and identified several chemicals that revert the gastric precancerous change, loss of parietal cells.

Academic Significance and Societal Importance of the Research Achievements

新規の胃上皮幹細胞マーカーの同定とその制御機構を解明したことにより、胃発癌や粘膜再生のメカニズムを明らかにすることに貢献した。
胃癌や腸上皮化生は成熟細胞ではなく幹細胞・前駆細胞から発生することが明らかになり、より選択的な治療標的の同定や、発癌予測のバイオマーカーの樹立に役立つ可能性がある。
Tuft細胞や壁細胞の分化制御機構やその粘膜再生における機能を明らかにしたことで、今後の胃癌に対する予防や治療の開発に結びつく可能性がある。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (32 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (19 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 18 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (11 results) (of which Int'l Joint Research: 7 results,  Invited: 5 results) Remarks (1 results)

  • [Int'l Joint Research] Columbia University(米国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis2020

    • Author(s)
      Chang Wenju、Wang Hongshan、Kim Woosook、Liu Yang、Deng Huan、Liu Haibo、Jiang Zhengyu、Niu Zhengchuan、Sheng Weiwei、Napoles Osmel Companioni、Sun Yihong、Xu Jianmin、Sepulveda Antonia、Hayakawa Yoku、Bass Adam J.、Wang Timothy C.
    • Journal Title

      Cell Stem Cell

      Volume: in press Issue: 5 Pages: 739-754.e8

    • DOI

      10.1016/j.stem.2020.01.020

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GRP30-expressing gastric chief cells do not differentiate but are eliminated via PDK-dependent cell competition during development of metaplasia.2020

    • Author(s)
      1.Hata M, Kinoshita H, Hayakawa Y, Konishi M, Tsuboi M, Oya Y, Hayata Y, Nakagawa H, Tateishi K, Fujiwara H, Hirata Y, Worthley DL, Muranishi Y, Furukawa T, Kon S, Tomita H, Wang TC, Koike K.
    • Journal Title

      Gastroenterology

      Volume: 158 Issue: 6 Pages: 1650-1666

    • DOI

      10.1053/j.gastro.2020.01.046

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche2020

    • Author(s)
      Middelhoff Moritz、Nienheiser Henrik、Valenti Giovanni、Maurer H. Carlo、Hayakawa Yoku、Takahashi Ryota、Kim Woosook、Jiang Zhengyu、Malagola Ermanno、Cuti Krystle、Tailor Yagnesh、Zamechek Leah B.、Renz Bernhard W.、Quante Michael、Yan Kelley S.、Wang Timothy C.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 111-111

    • DOI

      10.1038/s41467-019-13850-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of Muscarinic Acetylcholine Signaling in Gastrointestinal Cancers2019

    • Author(s)
      Konishi Mitsuru、Hayakawa Yoku、Koike Kazuhiko
    • Journal Title

      Biomedicines

      Volume: 7 Issue: 3 Pages: 58-58

    • DOI

      10.3390/biomedicines7030058

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Reduction in Gastric Atrophy after Helicobacter pylori Eradication Is Reduced by Treatment with Inhibitors of Gastric Acid Secretion2019

    • Author(s)
      Niikura Ryota、Hayakawa Yoku、Hirata Yoshihiro、Ogura Keiji、Fujishiro Mitsuhiro、Yamada Atsuo、Ushiku Tetsuo、Konishi Mitsuru、Fukayama Masashi、Koike Kazuhiko
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 8 Pages: 1913-1913

    • DOI

      10.3390/ijms20081913

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Three types of metaplasia model through Kras activation, Pten deletion, or Cdh1 deletion in the gastric epithelium.2019

    • Author(s)
      Kinoshita H, Hayakawa Y, Konishi M, Hata M, Tsuboi M, Hayata Y, Hikiba Y, Ihara S, Nakagawa H, Ikenoue T, Ushiku T, Fukayama M, Hirata Y, Koike K.
    • Journal Title

      Journal of Pathology

      Volume: 247 Issue: 1 Pages: 35-47

    • DOI

      10.1002/path.5163

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice2019

    • Author(s)
      Hayakawa Yoku、Tsuboi Mayo、Asfaha Samuel、Kinoshita Hiroto、Niikura Ryota、Konishi Mitsuru、Hata Masahiro、Oya Yukiko、,,,Koike Kazuhiko、Wang Timothy C.
    • Journal Title

      Gastroenterology

      Volume: 156 Issue: 4 Pages: 1066-1081.e16

    • DOI

      10.1053/j.gastro.2018.11.024

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mature gastric chief cells are not required for the development of metaplasia.2018

    • Author(s)
      Kinoshita H, Hayakawa Y, Niu Z, Konishi M, Hata M, Tsuboi M, Hayata Y, Hikiba Y, Ihara S, Nakagawa H, Hirata Y, Wang TC, Koike K.
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol.

      Volume: - Issue: 5 Pages: G583-G596

    • DOI

      10.1152/ajpgi.00351.2017

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Distinct chemopreventive effects of aspirin in diffuse and intestinal-type gastric cancer.2018

    • Author(s)
      Niikura R, Hayakawa Y, Hirata Y, Konishi M, Suzuki N, Ihara S, Yamada A, Ushiku T, Fujishiro M, Fukayama M, Koike K.
    • Journal Title

      Cancer Prev Res (Phila)

      Volume: - Issue: 5 Pages: 279-286

    • DOI

      10.1158/1940-6207.capr-17-0276

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Tuft Cell-ILC2 Circuit Integrates Intestinal Defense and Homeostasis2018

    • Author(s)
      Hayakawa Yoku、Wang Timothy C.
    • Journal Title

      Cell

      Volume: 174 Issue: 2 Pages: 251-253

    • DOI

      10.1016/j.cell.2018.06.037

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gastric Stem Cell and Cellular Origin of Cancer2018

    • Author(s)
      Hata Masahiro、Hayakawa Yoku、Koike Kazuhiko
    • Journal Title

      Biomedicines

      Volume: 6 Issue: 4 Pages: 100-100

    • DOI

      10.3390/biomedicines6040100

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Long-term proton pump inhibitor use is a risk factor of gastric cancer after treatment forHelicobacter pylori: a retrospective cohort analysis2017

    • Author(s)
      Niikura Ryota、Hayakawa Yoku、Hirata Yoshihiro、Yamada Atsuo、Fujishiro Mitsuhiro、Koike Kazuhiko
    • Journal Title

      Gut

      Volume: epub Issue: 10 Pages: 1908-1910

    • DOI

      10.1136/gutjnl-2017-315710

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CXCR4-expressing Mist1+ progenitors in the gastric antrum contribute to gastric cancer development.2017

    • Author(s)
      Sakitani K, Hayakawa Y, Deng H, Ariyama H, Kinoshita H, Konishi M, Ono S, Suzuki N, Ihara S, Niu Z, Kim W, Tanaka T, Liu H, Chen X, Tailor Y, Fox JG, Konieczny SF, Onodera H, Sepulveda AR, Asfaha S, Hirata Y, Worthley DL, Koike K, Wang TC.
    • Journal Title

      Oncotarget.

      Volume: Nov 10;8(67) Issue: 67 Pages: 111012-111012

    • DOI

      10.18632/oncotarget.22451

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nerves switch on angiogenic metabolism.2017

    • Author(s)
      Hayakawa Y, Wang TC
    • Journal Title

      Science

      Volume: Oct 20;358(6361) Issue: 6361 Pages: 305-305

    • DOI

      10.1126/science.aaq0365

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Summary of the 2016 James W. Freston Conference of the American Gastroenterological Association: Intestinal Metaplasia in the Esophagus and Stomach: Origins, Differences, Similarities and Significance.2017

    • Author(s)
      Spechler SJ, Merchant JL, Wang TC, Chandrasoma P, Fox JG, Genta RM, Goldenring JR, Hayakawa Y, Kuipers EJ, Lund PK, McKeon F, Mills JC, Odze RD, Peek RM Jr., Pham T, Que J, Rustgi AK, Shaheen NJ, Shivdasani RA, Souza RF, Storz P, Todisco A, Wang DH, Wright NA.
    • Journal Title

      Gastroenterology.

      Volume: Jul;153(1) Issue: 1 Pages: e6-e13

    • DOI

      10.1053/j.gastro.2017.05.050

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metaplasia in the Stomach-Precursor of Gastric Cancer?2017

    • Author(s)
      Kinoshita H, Hayakawa Y, Koike K.
    • Journal Title

      Int J Mol Sci.

      Volume: Sep 27;18(10) Issue: 10 Pages: 2063-2063

    • DOI

      10.3390/ijms18102063

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dclk1-expressing tuft cells: critical modulators of the intestinal niche?2017

    • Author(s)
      Middelhoff M, Westphalen CB, Hayakawa Y, Yan KS, Gershon MD, Wang TC, Quante M.
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol.

      Volume: Oct 1;313(4) Issue: 4 Pages: G285-G299

    • DOI

      10.1152/ajpgi.00073.2017

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Isthmus Stem Cells Are the Origins of Metaplasia in the Gastric Corpus2017

    • Author(s)
      Yoku Hayakawa, James G. Fox, Timothy C. Wang
    • Journal Title

      Cellular and Molecular Gastroenterology and Hepatology

      Volume: 印刷中 Issue: 1 Pages: 89-94

    • DOI

      10.1016/j.jcmgh.2017.02.009

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Isthmus Progenitors, Not Chief Cells, Are the Likely Origin of Metaplasia in eR1-CreERT; LSL-KrasG12D Mice.2017

    • Author(s)
      Hayakawa Y, Wang TC.
    • Journal Title

      Gastroenterology

      Volume: Jun;152(8) Issue: 8 Pages: 2078-2078

    • DOI

      10.1053/j.gastro.2017.02.043

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] Stem cell origin of gastric metaplasia and cancer2019

    • Author(s)
      Yoku Hayakawa
    • Organizer
      NCI ThinkTank
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Stem cell origin of gastric cancer and their niche2019

    • Author(s)
      Yoku Hayakawa
    • Organizer
      JCA-KCA joint symposium
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Adrenaline-dependent immunogenic reprogramming in endothelial cells regulate tumor immunity in gastric cancers, poster presentation2019

    • Author(s)
      Yoku Hayakawa
    • Organizer
      11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Stem cell origin of gastric cancer2019

    • Author(s)
      Yoku Hayakawa
    • Organizer
      National Cancer Institute Think Tank
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] The role of gastric microbiome in gastric carcinogenesis2018

    • Author(s)
      Yoku Hayakawa
    • Organizer
      2018年日本癌学会総会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] CXCR4シグナルによる胃上皮幹細胞と 発癌の制御機構2018

    • Author(s)
      早河翼
    • Organizer
      2018年日本消化器病学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Mist1+ secretory progenitor cells can give rise to cancer in the intestine and colon2018

    • Author(s)
      Yoku Hayakawa
    • Organizer
      Digestive Disease Week 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Muscarinic acetylcholine receptor subtype 3 regulates gastric stem cell expansion and gastric cancer progression by controlling YAP activation.2017

    • Author(s)
      Yoku Hayakawa
    • Organizer
      AACR annual meeting 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Muscarinic receptor-3 modulates YAP signaling in gastric stem and cancer cells.2017

    • Author(s)
      Konishi M, Hayakawa Y, et al.
    • Organizer
      Digestive Disease Week 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Neural regulation of gastric stem cells and cancer.2017

    • Author(s)
      Yoku Hayakawa
    • Organizer
      GESA AGW 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Gastric stem cell and cancer microenvironment2017

    • Author(s)
      Yoku Hayakawa
    • Organizer
      Intrastellar Initiative (AMED/NYAS)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 【プレスリリース】胃の前がん病変の真の起源を同定~これまでの定説を覆す

    • URL

      https://www.h.u-tokyo.ac.jp/press/20200205.html

    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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