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Identification of stem cells that maintain and regenerate lingual keratinized epithelial cells


Lingual keratinized epithelial cells, which constitute the filiform papillae of the tongue, have one of the most rapid tissue turnover rates in the mammalian body and are thought to be the source of squamous cell carcinoma of the tongue. However, the mechanism of tissue maintenance and regeneration is largely unknown for these cells. Here, we show that stem cells positive for Bmi1, keratin 14 and keratin 5 are present in the base but not at the very bottom of the interpapillary pit (observed most frequently in the second or third layer (position +2 or +3) from the basal cells). Using a multicolour lineage tracing method1,2, we demonstrated that one stem cell per interpapillary pit survives long-term. The cells were shown to be unipotent stem cells for keratinized epithelial cells but not for taste bud cells, and were found to usually be in a slow-growing or resting state; however, on irradiation-induced injury, the cells rapidly entered the cell cycle and regenerated tongue epithelium. The elimination of Bmi1-positive stem cells significantly suppressed the regeneration. Taken together, these results suggest that the stem cells identified in this study are important for tissue maintenance and regeneration of the lingual epithelium.

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Figure 1: Identification of stem cells of lingual epithelial cells.
Figure 2: Position of Bmi1-positive stem cells.
Figure 3: Bmi1-positive stem cells are slow-growing cells in the lingual epithelium.
Figure 4: Regeneration of lingual epithelial cells from Bmi1-positive stem cells observed after irradiation-induced injury.
Figure 5: Deletion of Bmi1-positive stem cells suppresses tissue regeneration after irradiation-induced injury.


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The authors thank P. Soriano (Mount Sinai School of Medicine, USA), R. Y. Tsien (UCSD, USA), J. Miyazaki (Osaka University, Japan), I. L. Weissman (Stanford University School of Medicine, USA) and H. Clevers (Hubrecht Institute, The Netherlands) for the materials, S. Sawada, T. Iwasaka and T. Kinoshita for generous support for the experiments, S. Maeda for statistical analyses, M. Yamamoto and N. Nishida for animal care and technical assistance, and members of the Department of Stem Cell Pathology, Kansai Medical University for helpful discussions. We acknowledge financial support from the following sources: Funding Program for Next Generation World-Leading Researchers, The Mochida Memorial Foundation, The Naito Memorial Foundation, The Cell Science Research Foundation, The Uehara Memorial Foundation, The Mitsubishi Foundation and The Yasuda Memorial Foundation to H.U.

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Authors and Affiliations



T.T. mainly performed the experiments, Y.K., Y.T., H.Y., S.O. and K.O. helped with the experiments and preparing samples. H.U. generated mice and supervised the project. T.T. and H.U. interpreted the results and wrote the manuscript.

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Correspondence to Hiroo Ueno.

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The authors declare no competing financial interests.

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Three-dimensional movie of the image shown in Fig. 2c, right panel.

Single Bmi1-positive stem-cell-derived areas observed 84 days after tamoxifen injection. Usually, a single Bmi1-positive stem cell supplies keratinized epithelial cells towards the tip of three (or, less frequently, four) surrounding filiform papillae. (MOV 4341 kb)

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Tanaka, T., Komai, Y., Tokuyama, Y. et al. Identification of stem cells that maintain and regenerate lingual keratinized epithelial cells. Nat Cell Biol 15, 511–518 (2013).

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