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Epithelial Defense Force

The nature of the cells that maintain and heal the epithelium lining the esophagus has been controversial. Doupéet al. (p. 1091, published online 19 July; see the Perspective by Kushner) show that, unlike many other tissues, mouse esophagus is devoid of slow cycling stem cells. Instead, the epithelium is maintained and repaired by a single population of proliferating cells that can switch rapidly from homeostatic behavior into “repair mode” in the vicinity of a wound.

Abstract

Diseases of the esophageal epithelium (EE), such as reflux esophagitis and cancer, are rising in incidence. Despite this, the cellular behaviors underlying EE homeostasis and repair remain controversial. Here, we show that in mice, EE is maintained by a single population of cells that divide stochastically to generate proliferating and differentiating daughters with equal probability. In response to challenge with all-trans retinoic acid (atRA), the balance of daughter cell fate is unaltered, but the rate of cell division increases. However, after wounding, cells reversibly switch to producing an excess of proliferating daughters until the wound has closed. Such fate-switching enables a single progenitor population to both maintain and repair tissue without the need for a “reserve” slow-cycling stem cell pool.

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Supplementary Material

Summary

Materials and Methods
Figs. S1 to S13
Table S1
References (29, 30)

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References and Notes

1
Tumbar T., et al., Defining the epithelial stem cell niche in skin. Science 303, 359 (2004).
2
Barker N., et al., Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6, 25 (2010).
3
Barker N., et al., Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003 (2007).
4
Jaks V., et al., Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat. Genet. 40, 1291 (2008).
5
Goetsch E., The structure of the mammalian oesophagus. Am. J. Anat. 10, 1 (1910).
6
Messier B., Leblond C. P., Cell proliferation and migration as revealed by radioautography after injection of thymidine-H3 into male rats and mice. Am. J. Anat. 106, 247 (1960).
7
Marques-Pereira J. P., Leblond C. P., Mitosis and differentiation in the stratified squamous epithelium of the rat esophagus. Am. J. Anat. 117, 73 (1965).
8
Seery J. P., Watt F. M., Asymmetric stem-cell divisions define the architecture of human oesophageal epithelium. Curr. Biol. 10, 1447 (2000).
9
Croagh D., Phillips W. A., Redvers R., Thomas R. J., Kaur P., Identification of candidate murine esophageal stem cells using a combination of cell kinetic studies and cell surface markers. Stem Cells 25, 313 (2007).
10
Kalabis J., et al., A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. J. Clin. Invest. 118, 3860 (2008).
11
Croagh D., Thomas R. J., Phillips W. A., Kaur P., Esophageal stem cells: A review of their identification and characterization. Stem Cell Rev. 4, 261 (2008).
12
Dent J., El-Serag H. B., Wallander M. A., Johansson S., Epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut 54, 710 (2005).
13
Jemal A., et al., Global cancer statistics. CA Cancer J. Clin. 61, 69 (2011).
14
Kanda T., Sullivan K. F., Wahl G. M., Histone-GFP fusion protein enables sensitive analysis of chromosome dynamics in living mammalian cells. Curr. Biol. 8, 377 (1998).
15
Hochedlinger K., Yamada Y., Beard C., Jaenisch R., Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121, 465 (2005).
16
Snippert H. J., et al., Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134 (2010).
17
Braun K. M., et al., Manipulation of stem cell proliferation and lineage commitment: Visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130, 5241 (2003).
18
Clayton E., et al., A single type of progenitor cell maintains normal epidermis. Nature 446, 185 (2007).
19
Doupé D. P., Klein A. M., Simons B. D., Jones P. H., The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. Dev. Cell 18, 317 (2010).
20
Klein A. M., Doupé D. P., Jones P. H., Simons B. D., Kinetics of cell division in epidermal maintenance. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 76, 021910 (2007).
21
Klein A. M., Simons B. D., Universal patterns of stem cell fate in cycling adult tissues. Development 138, 3103 (2011).
22
Lopez-Garcia C., Klein A. M., Simons B. D., Winton D. J., Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822 (2010).
23
Chapellier B., et al., Physiological and retinoid-induced proliferations of epidermis basal keratinocytes are differently controlled. EMBO J. 21, 3402 (2002).
24
Collins C. A., Watt F. M., Dynamic regulation of retinoic acid-binding proteins in developing, adult and neoplastic skin reveals roles for beta-catenin and Notch signalling. Dev. Biol. 324, 55 (2008).
25
Potten C. S., Allen T. D., The fine structure and cell kinetics of mouse epidermis after wounding. J. Cell Sci. 17, 413 (1975).
26
Gurtner G. C., Werner S., Barrandon Y., Longaker M. T., Wound repair and regeneration. Nature 453, 314 (2008).
27
Martin P., et al., Wound healing in the PU.1 null mouse: Tissue repair is not dependent on inflammatory cells. Curr. Biol. 13, 1122 (2003).
28
Jacinto A., Martinez-Arias A., Martin P., Mechanisms of epithelial fusion and repair. Nat. Cell Biol. 3, E117 (2001).
29
Gonzalez M. A., et al., Geminin is essential to prevent endoreduplication and to form pluripotent cells during mammalian development. Genes Dev. 20, 1880 (2006).
30
Klein A. M., Doupé D. P., Jones P. H., Simons B. D., Mechanism of murine epidermal maintenance: Cell division and the voter model. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 77, 031907 (2008).

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Published In

Science
Volume 337 | Issue 6098
31 August 2012

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Submission history

Received: 6 January 2012
Accepted: 10 July 2012
Published in print: 31 August 2012

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Acknowledgments

We thank E. Choolun and the staff at ARES and CBS Cambridge for technical assistance; D. Winton and D. Adams (Cambridge) for mice; and M. Gonzalez (London) for the Geminin antibody. We acknowledge the support of the MRC, EPSRC (Engineering and Physical Sciences Research Council), the NC3Rs (National Centre for the Replacement, Refinement and Reduction of Animals in Research), the Wellcome Trust, Sidney Sussex College, Cambridge (D.P.D.), European Union Marie Curie Fellowship PIEF-LIF-2007-220016 (M.P.A.), the Royal College of Surgeons of England (A.R.), and Cambridge Cancer Centre (A.R.). This work uses methods included in the patent WO2009010725 (A2), a method of detecting altered behavior in a population of cells; inventors were P.H.J., B.D.S., and A.M.K.

Authors

Affiliations

David P. Doupé*
Medical Research Council (MRC) Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge CB2 0XZ, UK.
The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Maria P. Alcolea*
Medical Research Council (MRC) Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge CB2 0XZ, UK.
Amit Roshan
Medical Research Council (MRC) Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge CB2 0XZ, UK.
Gen Zhang
Cavendish Laboratory, Department of Physics, J. J. Thomson Avenue, University of Cambridge, Cambridge CB3 0HE, UK.
Allon M. Klein
Cavendish Laboratory, Department of Physics, J. J. Thomson Avenue, University of Cambridge, Cambridge CB3 0HE, UK.
Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Benjamin D. Simons
Cavendish Laboratory, Department of Physics, J. J. Thomson Avenue, University of Cambridge, Cambridge CB3 0HE, UK.
The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Philip H. Jones [email protected]
Medical Research Council (MRC) Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge CB2 0XZ, UK.

Notes

*
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: [email protected]

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