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Oligopotent stem cells are distributed throughout the mammalian ocular surface

Abstract

The integrity of the cornea, the most anterior part of the eye, is indispensable for vision. Forty-five million individuals worldwide are bilaterally blind and another 135 million have severely impaired vision in both eyes because of loss of corneal transparency1; treatments range from local medications to corneal transplants, and more recently to stem cell therapy2. The corneal epithelium is a squamous epithelium that is constantly renewing, with a vertical turnover of 7 to 14 days in many mammals3. Identification of slow cycling cells (label-retaining cells) in the limbus of the mouse has led to the notion that the limbus is the niche for the stem cells responsible for the long-term renewal of the cornea4; hence, the corneal epithelium is supposedly renewed by cells generated at and migrating from the limbus, in marked opposition to other squamous epithelia in which each resident stem cell has in charge a limited area of epithelium5,6. Here we show that the corneal epithelium of the mouse can be serially transplanted, is self-maintained and contains oligopotent stem cells with the capacity to generate goblet cells if provided with a conjunctival environment. Furthermore, the entire ocular surface of the pig, including the cornea, contains oligopotent stem cells (holoclones)7,8 with the capacity to generate individual colonies of corneal and conjunctival cells. Therefore, the limbus is not the only niche for corneal stem cells and corneal renewal is not different from other squamous epithelia. We propose a model that unifies our observations with the literature and explains why the limbal region is enriched in stem cells.

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Figure 1: The limbus does not contribute to steady-state corneal renewal, but to corneal repair.
Figure 2: The cornea of the mouse has extensive self-renewal capacity and contains oligopotent stem cells.
Figure 3: The cornea of mammals contains clonogenic keratinocytes.
Figure 4: A unifying model of ocular surface renewal.

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Acknowledgements

We are grateful to F. Radtke and S. Vauclair for Notch1lox/lox K14Cre ROSA26R mice, to A. Smith for critical reading of the manuscript, to T. Hoang-Xuan, L. Zografos, F. Munier and S. Kinoshita for continuous support and to L. Schnell, J. Vannod and S. Vermot for excellent technical help. The work was supported by grants to Y.B. from the Swiss National Science Foundation (grant 3100A0-104160), the EPFL, the CHUV and EuroStemCell. The early part of the work was supported by grants to Y.B. from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association pour la Recherche contre le Cancer and the Association Française contre les Myopathies. F.M. was supported by fellowships from the Fédération des Aveugles et Handicapés Visuels de France, the INSERM and then the CHUV.

Author Contributions F.M., A.R. and M.N. performed and assisted in the design of the experiments and the interpretation of results, A.R. and G.A.J. made the figures and G.A.J. and Y.B. contributed the new concept. Y.B. designed the experiments and wrote the paper.

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Correspondence to Yann Barrandon.

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Majo, F., Rochat, A., Nicolas, M. et al. Oligopotent stem cells are distributed throughout the mammalian ocular surface. Nature 456, 250–254 (2008). https://doi.org/10.1038/nature07406

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