Progenitor cells and initiation of squamous metaplasia focused on club cell fate conversion
| Project/Area Number |
19K08655
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Kumamoto University |
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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)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 運命転換 / Club細胞 / 基底細胞 / 扁平上皮化生 / 細胞へ運命転換 / 細胞系譜解析 / 単１細胞遺伝子発現解析 / 扁平上皮細胞 / 脱分化 / 可塑性 / 呼吸器 / 扁平上皮癌 / 肺癌 / 器官形成 |
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| Outline of Research at the Start |
癌の発生母地である扁平上皮化生は、分化細胞が別の分化細胞へ運命転換する現象であるが、その起源細胞及び発生機序は不明瞭である。私達は、マウス生体内で、Notchシグナル標的遺伝子の不活性化により、気管Club細胞が基底細胞へ運命転換することを見出した。そこで、本研究では、Club細胞の基底細胞への運命転換が、扁平上皮化生及び化生病変による発癌（扁平上皮癌）に関与するかを細胞系譜解析と単１細胞遺伝子発現解析を用いて検証することを目的とした。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。
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| 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.
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| 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。
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Report
(4 results)
Research Products
(8 results)
