Progenitor cells and initiation of squamous metaplasia focused on club cell fate conversion

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08655
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Kumamoto University
• Principal Investigator: MATSUO Akira 熊本大学, 大学院生命科学研究部(医), 特別研究員 (50735074)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 運命転換 / Club細胞 / 基底細胞 / 扁平上皮化生

Outline of Final Research Achievements

Tracheobronchial squamous metaplasia is a precursor lesion to squamous carcinoma in smokers. However, the cell of origin of squamous metaplasia and the mechanisms that underlie the development of squamous metaplasia remain largely unknown. Here, we show that inhibition of Notch signaling can induce lineage conversion of club cells into basal stem cells, which can generate squamous cells. Using lineage tracing and single-cell transcriptomics, we find that club cells can convert into basal cells by inactivating Notch signaling. Induced basal (iB) cells show heterogeneity in the cell population. A subset of iB cells expresses squamous makers Krt4 and Krt13. Following the neoplastic process, we also reveal that iB cells can generate squamous-like cells expressing Krt13 in the mouse trachea. Our study provides new avenues for the understanding of club cell plasticity and novel cancer therapy based on the prevention of squamous metaplasia by club cell-derived basal cells.

Free Research Field

幹細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究の知見は、恒常性及び発癌(扁平上皮化生及び扁平上皮癌)におけるclub細胞の運命転換の理解と扁平上皮化生予防に着目した新規癌治療の基盤形成につながる。