Regulation of intestinal stem cells in inflammatory bowel disease

• Project/Area Number: 18K15759
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Nagoya City University
• Principal Investigator: Katano Takahito 名古屋市立大学, 医薬学総合研究院(医学), 助教 (50768372)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 幹細胞 / KLF / 消化管幹細胞 / 炎症性腸疾患

Outline of Final Research Achievements

Kruppel-like factor 4 (KLF4) is a zinc-finger transcription factor, expressed in villus cells of the intestinal epithelium, that promotes cellular differentiation and tissue homeostasis. The aim of this study was to investigate how KLF4 contributes to crypt regeneration originated from BMI1＋ intestinal stem cell (ISC) lineage during homeostasis. KLF4 is positively correlated with goblet cell differentiation in BMI+ ISC derived lineage. Irradiate to single sorted BMI1-YFP+ cell derived organoid model reconstitute in vivo response following γ-irradiation . These results suggest that KLF4 regulates goblet cell differentiation during homeostasis and plays a radio-protective role.

Academic Significance and Societal Importance of the Research Achievements

本研究では、転写因子KLF4が消化管幹細胞機能を制御し、組織恒常性維持・粘膜傷害時の再生に関与していることを明らかにした。KLF4はとくに組織恒常性維持においては杯細胞分化を制御していることが示唆され、炎症時の消化管バリア機能の制御においても重要な役割を持つことが示唆される。また、オルガノイドを用いて、放射線照射後の粘膜傷害後の生体内の再生の過程を、ex-vivoで再現することを可能とし、これは正常時のみならず粘膜傷害時の小腸上皮の幹細胞機能制御機構の解明のために有用な研究モデルとなる。

Research Products

• [Journal Article] KLF4 Regulates Goblet Cell Differentiation in BMI1＋ Reserve Intestinal Stem Cell Lineage during Homeostasis (2020)
  • Author(s): Katano Takahito、Bialkowska Agnieszka B.、Yang Vincent W.
  • Journal Title: International Journal of Stem Cells Volume: 13 Issue: 3 Pages: 424-431
  • DOI: 10.15283/ijsc20048
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interplay among p21Waf1/Cip1, MUSASHI-1 and Kruppel-like factor 4 in activation of Bmi1-CreER reserve intestinal stem cells after gamma radiation-induced injury (2020)
  • Author(s): Orzechowska Emilia J.、Katano Takahito、Bialkowska Agnieszka B.、Yang Vincent W.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 18300-18300
  • DOI: 10.1038/s41598-020-75171-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacies of first and second tumor necrosis factor inhibitors in refractory ulcerative colitis patients in real-world practice, (2020)
  • Author(s): Marutani, Y., Mizoshita, T., Sugiyama, T., Togawa, S., Katano, T., Yamada, T., Hirata, Y., Kimura, Y., Miyaki, T., Inoue, Y., Suzuki, E., Sasaki, M., and Kataoka, H.
  • Journal Title: Indian J Gastroenterol. Volume: 39 Issue: 6 Pages: 565-575
  • DOI: 10.1007/s12664-020-01092-1
  • Peer Reviewed
• [Presentation] KRUPPEL-LIKE FACTOR 4 MODULATES GOBLET CELL DIFFERENTIATION AND PLAYS A RADIO-PROTECTIVE ROLE IN THE BMI1+ INTESTINAL RESERVE STEM CELL LINEAGE (2020)
  • Author(s): Takahito Katano, Emilia J. Orzechowska, Agnieszka B. Bialkowska, Vincent W. Yang
  • Organizer: Digestive Disease Week 2020
  • Int'l Joint Research
• [Presentation] KRUPPEL-LIKE FACTOR 4 REGULATES BMI1+ INTESTINAL RESERVE STEM CELLS DURING HOMEOSTASIS AND INJURY (2019)
  • Author(s): Takahito Katano, Chang-Kyung Kim, Emilia J. Orzechowska, Agnieszka B. Bialkowska, Vincent W. Yang
  • Organizer: Digestive Disease Week 2019
  • Int'l Joint Research