Homeostasis and regeneration of intestinal epithelium regulated by goblet cell lineage

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08001
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Kurokawa Ken 東京大学, 医学部附属病院, 助教 (40868999)
• Co-Investigator(Kenkyū-buntansha): 早河 翼 東京大学, 医学部附属病院, 講師 (60777655)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 消化管上皮恒常性 / 粘膜再生 / 幹細胞 / 前駆細胞 / Wnt / Rspondin / Lgr

Outline of Final Research Achievements

Recent studies have suggested that Rspondin3 (Rspo3) secreted from stem cell niches plays an important role in mucosal injury and regeneration. In this study, we focused on Lgr4, one of the receptors for Rspo3 expressed in the gastrointestinal epithelium. We generated transgenic mice that overexpress Rspo3 specifically in the gastrointestinal epithelium or lack Lgr4, and analyzed the importance of the Rspo3-Lgr4 signaling pathway in the activation of gastrointestinal stem cells and the maintenance of epithelial homeostasis. We also examined the role of the stem cell niche, including goblet cells and Paneth cells. Furthermore, by combining these transgenic mice with reporter mice for stem cells and progenitor cells, we suggested that the Rspo3-Lgr4 signaling pathway contributes to gastrointestinal epithelial homeostasis through the activation of progenitor cells.

Free Research Field

消化器内科

Academic Significance and Societal Importance of the Research Achievements

炎症性腸疾患は、近年多くの薬剤が臨床応用され、以前は外科的切除されていた重症例や難治例においても長期に腸管を温存することができるようになった。一方で、特に発症後に長期間慢性炎症が持続した症例では、粘膜リモデリングや炎症発癌が問題となっている。消化管上皮恒常性の破綻は、炎症や発癌に大きな影響があると考えられるが、その詳細は不明な点が多かった。今回、粘膜障害・再生時にRspo3-Lgr4シグナルが重要な働きをもつことが明らかになり、今後、新たな炎症・発癌メカニズムの解明に繋がることが期待される。