Simultaneous lineage tracing of multiple gastric stem cells and their paracrine regulation by stem cell niche

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19474
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Hayakawa Yoku 東京大学, 医学部附属病院, 講師 (60777655)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 胃 / 幹細胞 / マウスモデル

Outline of Final Research Achievements

To examine Rspondin signaling to stem cells, we analyzed Tff1-Cre;tetO-Rspo3;R26-LSL-rtTA mice and conditional knockout mice of its receptors Lgr4 and Lgr5. As a result, Rspo3 induced differentiation into chief cells via Lgr4 expressed in stem cells and mucous neck cells. Furthermore, as a result of a lineage tracing experiment in mice in which intermediate cells located in the middle of differentiation from mucous neck cells to chief cells were selectively labeled, this intermediate cell population was divided into two fractions. The more differentiated cell type cells do not have the ability to divide, while the progenitor type cells have the function of gradual differentiation towards chief cells.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

消化管上皮の腺管底部に存在するLgr5陽性幹細胞が同定されて以降、消化管幹細胞研究はLgr5陽性細胞の動態解析を中心に進められてきた。しかし申請者の精密かつ詳細な観察によって、胃上皮ではLgr5陽性幹細胞よりもその上方に位置するLgr5陰性（Lgr4陽性）幹細胞の方がより活発に腺管構成細胞を供給していることが明らかとなった。本研究は「これまでのLgr5=胃上皮の主たる幹細胞」という学説を覆す、大きな成果を輩出した。また、胃の基礎研究領域で簡易的な脱分化マーカーとして汎用されている主細胞・頸細胞間の中間細胞について世界で初めて選択的な細胞標識を実現し、分裂・分化様式を可視化することに成功した。