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Distinct contribution of stem and progenitor cells to epidermal maintenance

Nature volume 489, pages 257–262 (2012)Cite this article

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Abstract

The skin interfollicular epidermis (IFE) is the first barrier against the external environment and its maintenance is critical for survival. Two seemingly opposite theories have been proposed to explain IFE homeostasis. One posits that IFE is maintained by long-lived slow-cycling stem cells that give rise to transit-amplifying cell progeny, whereas the other suggests that homeostasis is achieved by a single committed progenitor population that balances stochastic fate. Here we probe the cellular heterogeneity within the IFE using two different inducible Cre recombinase–oestrogen receptor constructs targeting IFE progenitors in mice. Quantitative analysis of clonal fate data and proliferation dynamics demonstrate the existence of two distinct proliferative cell compartments arranged in a hierarchy involving slow-cycling stem cells and committed progenitor cells. After wounding, only stem cells contribute substantially to the repair and long-term regeneration of the tissue, whereas committed progenitor cells make a limited contribution.

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Figure 1: K14-Cre-ER and Inv-Cre-ER target IFE progenitors with different survival characteristics.
Figure 2: Inv-Cre-ER targets IFE CP cells.
Figure 3: K14-Cre-ER targets IFE SCs.
Figure 4: Molecular signature of K14 SC and Inv CP cells.
Figure 5: Massive and sustained contribution of K14 SC during wound healing.

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Gene Expression Omnibus

Data deposits

The data discussed in this publication have been deposited in the NCBI Gene Expression Omnibus and are accessible through GEO Series accession number GSE36688.

References

  1. Blanpain, C. & Fuchs, E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nature Rev. Mol. Cell Biol. 10, 207–217 (2009)

    Article  CAS  Google Scholar 

  2. Potten, C. S., Saffhill, R. & Maibach, H. I. Measurement of the transit time for cells through the epidermis and stratum corneum of the mouse and guinea-pig. Cell Tissue Kinet. 20, 461–472 (1987)

    CAS  PubMed  Google Scholar 

  3. Potten, C. S. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. Int. Rev. Cytol. 69, 271–318 (1981)

    Article  CAS  Google Scholar 

  4. Potten, C. S., Wichmann, H. E., Loeffler, M., Dobek, K. & Major, D. Evidence for discrete cell kinetic subpopulations in mouse epidermis based on mathematical analysis. Cell Tissue Kinet. 15, 305–329 (1982)

    CAS  PubMed  Google Scholar 

  5. Potten, C. S. & Loeffler, M. Epidermal cell proliferation. I. Changes with time in the proportion of isolated, paired and clustered labelled cells in sheets of murine epidermis. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 53, 279–285 (1987)

    Article  CAS  Google Scholar 

  6. Mackenzie, I. C. Retroviral transduction of murine epidermal stem cells demonstrates clonal units of epidermal structure. J. Invest. Dermatol. 109, 377–383 (1997)

    Article  CAS  Google Scholar 

  7. Kolodka, T. M., Garlick, J. A. & Taichman, L. B. Evidence for keratinocyte stem cells in vitro: long term engraftment and persistence of transgene expression from retrovirus-transduced keratinocytes. Proc. Natl Acad. Sci. USA 95, 4356–4361 (1998)

    Article  ADS  CAS  Google Scholar 

  8. Ghazizadeh, S. & Taichman, L. B. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J. 20, 1215–1222 (2001)

    Article  CAS  Google Scholar 

  9. Ghazizadeh, S. & Taichman, L. B. Organization of stem cells and their progeny in human epidermis. J. Invest. Dermatol. 124, 367–372 (2005)

    Article  CAS  Google Scholar 

  10. Ro, S. & Rannala, B. A stop-EGFP transgenic mouse to detect clonal cell lineages generated by mutation. EMBO Rep. 5, 914–920 (2004)

    Article  CAS  Google Scholar 

  11. Ro, S. & Rannala, B. Evidence from the stop-EGFP mouse supports a niche-sharing model of epidermal proliferative units. Exp. Dermatol. 14, 838–843 (2005)

    Article  Google Scholar 

  12. Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007)

    Article  ADS  CAS  Google Scholar 

  13. 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, 317–323 (2010)

    Article  Google Scholar 

  14. Jones, P. & Simons, B. D. Epidermal homeostasis: do committed progenitors work while stem cells sleep? Nature Rev. Mol. Cell Biol. 9, 82–88 (2008)

    Article  CAS  Google Scholar 

  15. Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004)

    Article  ADS  CAS  Google Scholar 

  16. Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med. 11, 1351–1354 (2005)

    Article  CAS  Google Scholar 

  17. Levy, V., Lindon, C., Zheng, Y., Harfe, B. D. & Morgan, B. A. Epidermal stem cells arise from the hair follicle after wounding. FASEB J. 21, 1358–1366 (2007)

    Article  CAS  Google Scholar 

  18. Snippert, H. J. et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science 327, 1385–1389 (2010)

    Article  ADS  CAS  Google Scholar 

  19. Vasioukhin, V., Degenstein, L., Wise, B. & Fuchs, E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Natl Acad. Sci. USA 96, 8551–8556 (1999)

    Article  ADS  CAS  Google Scholar 

  20. Lapouge, G. et al. Identifying the cellular origin of squamous skin tumors. Proc. Natl Acad. Sci. USA 108, 7431–7436 (2011)

    Article  ADS  CAS  Google Scholar 

  21. Klein, A. M. & Simons, B. D. Universal patterns of stem cell fate in cycling adult tissues. Development 138, 3103–3111 (2011)

    Article  CAS  Google Scholar 

  22. Waghmare, S. K. et al. Quantitative proliferation dynamics and random chromosome segregation of hair follicle stem cells. EMBO J. 27, 1309–1320 (2008)

    Article  CAS  Google Scholar 

  23. Zhang, Y. V., Cheong, J., Ciapurin, N., McDermitt, D. J. & Tumbar, T. Distinct self-renewal and differentiation phases in the niche of infrequently dividing hair follicle stem cells. Cell Stem Cell 5, 267–278 (2009)

    Article  CAS  Google Scholar 

  24. Zhang, Y. V., White, B. S., Shalloway, D. I. & Tumbar, T. Stem cell dynamics in mouse hair follicles: A story from cell division counting and single cell lineage tracing. Cell Cycle 9, 1504–1510 (2010)

    Article  CAS  Google Scholar 

  25. Jones, P. H., Harper, S. & Watt, F. M. Stem cell patterning and fate in human epidermis. Cell 80, 83–93 (1995)

    Article  CAS  Google Scholar 

  26. Lavker, R. M. & Sun, T. T. Heterogeneity in epidermal basal keratinocytes: morphological and functional correlations. Science 215, 1239–1241 (1982)

    Article  ADS  CAS  Google Scholar 

  27. Jones, P. H. & Watt, F. M. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell 73, 713–724 (1993)

    Article  CAS  Google Scholar 

  28. Legg, J., Jensen, U. B., Broad, S., Leigh, I. & Watt, F. M. Role of melanoma chondroitin sulphate proteoglycan in patterning stem cells in human interfollicular epidermis. Development 130, 6049–6063 (2003)

    Article  CAS  Google Scholar 

  29. Tani, H., Morris, R. J. & Kaur, P. Enrichment for murine keratinocyte stem cells based on cell surface phenotype. Proc. Natl Acad. Sci. USA 97, 10960–10965 (2000)

    Article  ADS  CAS  Google Scholar 

  30. Rangarajan, A. et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20, 3427–3436 (2001)

    Article  CAS  Google Scholar 

  31. Blanpain, C., Lowry, W. E., Pasolli, H. A. & Fuchs, E. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev. 20, 3022–3035 (2006)

    Article  CAS  Google Scholar 

  32. Ting, S. B. et al. A homolog of Drosophila grainy head is essential for epidermal integrity in mice. Science 308, 411–413 (2005)

    Article  ADS  CAS  Google Scholar 

  33. Candi, E., Schmidt, R. & Melino, G. The cornified envelope: a model of cell death in the skin. Nature Rev. Mol. Cell Biol. 6, 328–340 (2005)

    Article  CAS  Google Scholar 

  34. Månsson, R. et al. Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors. Immunity 26, 407–419 (2007)

    Article  Google Scholar 

  35. Pina, C. et al. Inferring rules of lineage commitment in haematopoiesis. Nature Cell Biol. 14, 287–294 (2012)

    Article  CAS  Google Scholar 

  36. Langton, A. K., Herrick, S. E. & Headon, D. J. An extended epidermal response heals cutaneous wounds in the absence of a hair follicle stem cell contribution. J. Invest. Dermatol. 128, 1311–1318 (2008)

    Article  CAS  Google Scholar 

  37. Loeffler, M., Potten, C. S. & Wichmann, H. E. Epidermal cell proliferation. II. A comprehensive mathematical model of cell proliferation and migration in the basal layer predicts some unusual properties of epidermal stem cells. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 53, 286–300 (1987)

    Article  CAS  Google Scholar 

  38. Morris, R. J., Fischer, S. M. & Slaga, T. J. Evidence that the centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations. J. Invest. Dermatol. 84, 277–281 (1985)

    Article  CAS  Google Scholar 

  39. Cotsarelis, G., Cheng, S. Z., Dong, G., Sun, T. T. & Lavker, R. M. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 57, 201–209 (1989)

    Article  CAS  Google Scholar 

  40. Cotsarelis, G., Sun, T. T. & Lavker, R. M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329–1337 (1990)

    Article  CAS  Google Scholar 

  41. Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008)

    Article  CAS  Google Scholar 

  42. Foudi, A. et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nature Biotechnol. 27, 84–90 (2009)

    Article  CAS  Google Scholar 

  43. Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M. A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012)

    Article  CAS  Google Scholar 

  44. Bonaguidi, M. A. et al. In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell 145, 1142–1155 (2011)

    Article  CAS  Google Scholar 

  45. Essers, M. A. et al. IFNα activates dormant haematopoietic stem cells in vivo . Nature 458, 904–908 (2009)

    Article  ADS  CAS  Google Scholar 

  46. Takeda, N. et al. Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424 (2011)

    Article  ADS  CAS  Google Scholar 

  47. Youssef, K. K. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nature Cell Biol. 12, 299–305 (2010)

    Article  CAS  Google Scholar 

  48. Diamond, I., Owolabi, T., Marco, M., Lam, C. & Glick, A. Conditional gene expression in the epidermis of transgenic mice using the tetracycline-regulated transactivators tTA and rTA linked to the keratin 5 promoter. J. Invest. Dermatol. 115, 788–794 (2000)

    Article  CAS  Google Scholar 

  49. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001)

    Article  CAS  Google Scholar 

  50. Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004)

    Article  Google Scholar 

  51. McCall, M. N., Bolstad, B. M. & Irizarry, R. A. Frozen robust multiarray analysis (fRMA). Biostatistics 11, 242–253 (2010)

    Article  Google Scholar 

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Acknowledgements

We thank F. Bollet-Quivogne and J.-M. Vanderwinden for their help with confocal imaging. C.B. and P.A.S. are chercheur qualifié, G.M. and S.B. are supported by fellowship of the FRS/FNRS. B.D. is supported by TELEVIE. C.B. is an investigator of WELBIO. This work was supported by the FNRS, the program d’excellence CIBLES of the Wallonia Region, a research grant from the Fondation Contre le Cancer, the ULB fondation, the fond Gaston Ithier, the European Research Council (ERC) and the EMBO Young Investigator Program.

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Authors and Affiliations

  1. Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium ,

    Guilhem Mascré, Sophie Dekoninck, Benjamin Drogat, Khalil Kass Youssef, Sylvain Brohée, Panagiota A. Sotiropoulou & Cédric Blanpain

  2. Université Libre de Bruxelles, Machine Learning Group, Brussels B-1050, Belgium ,

    Sylvain Brohée

  3. Department of Physics, Cavendish Laboratory, J. J. Thomson Avenue, Cambridge CB3 0HE, UK,

    Benjamin D. Simons

  4. The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK ,

    Benjamin D. Simons

  5. WELBIO, Université Libre de Bruxelles, Brussels B-1070, Belgium ,

    Cédric Blanpain

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  1. Guilhem Mascré
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Contributions

C.B., G.M., B.D., S.D., P.A.S. and B.D.S. designed the experiments and performed data analysis. G.M., S.D., B.D. and K.K.Y. performed all the experiments. S.B. performed bioinformatic analysis of the microarray. C.B. and B.D.S. wrote the manuscript.

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Correspondence to Benjamin D. Simons or Cédric Blanpain.

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The authors declare no competing financial interests.

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Mascré, G., Dekoninck, S., Drogat, B. et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 257–262 (2012). https://doi.org/10.1038/nature11393

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