Stem Cell Reviews

, 4:149

Tiers of Clonal Organization in the Epidermis: The Epidermal Proliferation Unit Revisited



As one of the most proliferative tissues in adult mammals, the epidermis is a good example of the precise regulation necessary between stem cell self-renewal and differentiation. The epidermis is derived from ectodermal progenitor cells and contains three distinct classes of cells: epidermal stem cells which are capable of infinite rounds of cell division; their immediate descendants, transient amplifying cells, which are capable of numerous but finite rounds of cell division; and finally, non-dividing, differentiating cells (Aberdam in Cell and Tissue Research 331:103–107, 2008). This proliferative hierarchy must be tightly regulated both temporally and spatially during epidermal development and homeostasis in order to prevent uncontrolled growth leading to hyperproliferative states and/or tumorigenesis. Historically, the most basic unit of epidermal proliferation has been described as the epidermal proliferation unit (EPU). The EPU, as originally characterized by Christophers, Potten and Mackenzie, is a proliferation unit consisting of approximately 10 basal cells with a clonogenic cell in the center and overlaid by the suprabasal and corneocyte progeny (reviewed in Potten, C. S. (1974). The epidermal proliferative unit: the possible role of the central basal cell. Cell and Tissue Kinetics, 7(1), 77–88). Numerous researchers have identified this classical EPU structure, consisting of approximately 20 cells, in a variety of mammalian skin sources. Recently however, lineage analyses have provided evidence for much larger clonal epidermal units consisting of hundreds to thousands of cells. Furthermore, cutaneous mosaicism as well as a variety of cutaneous pathologies indicate that clonal areas extend to whole patches of mammalian skin many centimeters across. In this review we revisit four decades of experimental evidence and put forward a model of clonal units derived from multiple classes of epidermal progenitors ranging from the largest and most primitive units, clonal ectodermal units, to epidermal stem cell units, and finally, to the most basic structural unit, the EPU.


Epidermis Stem cell Epidermal proliferation unit (EPU) Clonal analysis Progenitor Ectoderm Hierarchy Skin Mouse Human 


  1. 1.
    Aberdam, D. (2008). Epidermal stem cell fate: what can we learn from embryonic stem cells? Cell and Tissue Research, 331(1), 103–107.PubMedCrossRefGoogle Scholar
  2. 2.
    Elias, P. M. (2005). Stratum corneum defensive functions: an integrated view. Journal of Investigative Dermatolog, 125(2), 183–200.Google Scholar
  3. 3.
    Fuchs, E. (2008). Skin stem cells: rising to the surface. Journal of Cell Biology, 180(2), 273–284.PubMedCrossRefGoogle Scholar
  4. 4.
    Liang, L., & Bickenbach, J. R. (2002). Somatic epidermal stem cells can produce multiple cell lineages during development. Stem Cells, 20(1), 21–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Kameda, T., Nakata, A., Mizutani, T., Terada, K., Iba, H., & Sugiyama, T. (2003). Analysis of the cellular heterogeneity in the basal layer of mouse ear epidermis: an approach from partial decomposition in vitro and retroviral cell marking in vivo. Experimental Cell Research, 283(2), 167–183.PubMedCrossRefGoogle Scholar
  6. 6.
    Widelitz, R. B., Baker, R. E., Plikus, M., et al. (2006). Distinct mechanisms underlie pattern formation in the skin and skin appendages. Birth Defects Res C Embryo Today, 78(3), 280–291.PubMedCrossRefGoogle Scholar
  7. 7.
    Happle, R. (2002). Transposable elements and the lines of Blaschko: A new perspective. Dermatology, 204(1), 4–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Keegan, B. R., Kamino, H., Fangman, W., Shin, H. T., Orlow, S. J., & Schaffer, J. V. (2007). “Pediatric blaschkitis”: Expanding the spectrum of childhood acquired Blaschko-linear dermatoses. Pediatric Dermatology, 24(6), 621–627.PubMedCrossRefGoogle Scholar
  9. 9.
    Schmidt, G. H., Blount, M. A., & Ponder, B. A. (1987). Immunochemical demonstration of the clonal organization of chimaeric mouse epidermis. Development, 100(3), 535–541.PubMedGoogle Scholar
  10. 10.
    Chuong, C. M., Jung, H. S., Noden, D., & Widelitz, R. B. (1998). Lineage and pluripotentiality of epithelial precursor cells in developing chicken skin. Biochemistry and Cell Biology, 76(6), 1069–1077.PubMedCrossRefGoogle Scholar
  11. 11.
    Asplund, A., Guo, Z., Hu, X., Wassberg, C., & Ponten, F. (2001). Mosaic pattern of maternal and paternal keratinocyte clones in normal human epidermis revealed by analysis of X-chromosome inactivation. Journal of Investigative Dermatology, 117(1), 128–131.PubMedCrossRefGoogle Scholar
  12. 12.
    Chaturvedi, V., Chu, M. S., Carrol, B. M., Brenner, B. J., & Nickoloff, B. J. (2002). Estimation of size of clonal unit for keratinocytes in normal human skin. Archives of Pathology and Laboratory Medicine, 126(4), 420–424.PubMedGoogle Scholar
  13. 13.
    Jonason, A. S., Kunala, S., Price, G. J., et al. (1996). Frequent clones of p53-mutated keratinocytes in normal human skin. Proceedings of the National Academy of Sciences of the United States of America, 93(24), 14025–14029.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang, W., Remenyik, E., Zelterman, D., Brash, D. E., & Wikonkal, N. M. (2001). Escaping the stem cell compartment: sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations. Proceedings of the National Academy of Sciences of the United States of America, 98(24), 13948–13953.PubMedCrossRefGoogle Scholar
  15. 15.
    Levy, V., Lindon, C., Zheng, Y., Harfe, B. D., & Morgan, B. A. (2007). Epidermal stem cells arise from the hair follicle after wounding. Faseb Journal, 21(7), 1358–1366.PubMedCrossRefGoogle Scholar
  16. 16.
    Ro, S., & Rannala, B. (2004). A stop-EGFP transgenic mouse to detect clonal cell lineages generated by mutation. EMBO Reports, 5(9), 914–920.PubMedCrossRefGoogle Scholar
  17. 17.
    Ro, S., & Rannala, B. (2005). Evidence from the stop-EGFP mouse supports a niche-sharing model of epidermal proliferative units. Experimental Dermatology, 14(11), 838–843.PubMedCrossRefGoogle Scholar
  18. 18.
    Mackenzie, I. C. (1997). Retroviral transduction of murine epidermal stem cells demonstrates clonal units of epidermal structure. Journal of Investigative Dermatology, 109(3), 377–383.PubMedCrossRefGoogle Scholar
  19. 19.
    Ghazizadeh, S., & Taichman, L. B. (2001). Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. Embo Journal, 20(6), 1215–1222.PubMedCrossRefGoogle Scholar
  20. 20.
    Ghazizadeh, S., & Taichman, L. B. (2005). Organization of stem cells and their progeny in human epidermis. Journal of Investigative Dermatology, 124(2), 367–372.PubMedCrossRefGoogle Scholar
  21. 21.
    Kolodka, T. M., Garlick, J. A., & Taichman, L. B. (1998). Evidence for keratinocyte stem cells in vitro: long term engraftment and persistence of transgene expression from retrovirus-transduced keratinocytes. Proceedings of the National Academy of Sciences of the United States of America, 95(8), 4356–4361.PubMedCrossRefGoogle Scholar
  22. 22.
    Schneider, T. E., Barland, C., Alex, A. M., et al. (2003). Measuring stem cell frequency in epidermis: a quantitative in vivo functional assay for long-term repopulating cells. Proceedings of the National Academy of Sciences of the United States of America, 100(20), 11412–11417.PubMedCrossRefGoogle Scholar
  23. 23.
    Smith, L. G., Weissman, I. L., & Heimfeld, S. (1991). Clonal analysis of hematopoietic stem-cell differentiation in vivo. Proceedings of the National Academy of Sciences of the United States of America, 88(7), 2788–2792.PubMedCrossRefGoogle Scholar
  24. 24.
    Shackleton, M., Vaillant, F., Simpson, K. J., et al. (2006). Generation of a functional mammary gland from a single stem cell. Nature, 439(7072), 84–88.PubMedCrossRefGoogle Scholar
  25. 25.
    Potten, C. S., & Hendry, J. H. (1973). Letter: Clonogenic cells and stem cells in epidermis. International Journal of Radiation Biology & Related Studies in Physics, Chemistry & Medicine, 24(5), 537–540.Google Scholar
  26. 26.
    Potten, C. S. (1974). The epidermal proliferative unit: the possible role of the central basal cell. Cell and Tissue Kinetics, 7(1), 77–88.PubMedGoogle Scholar
  27. 27.
    Potten, C. S., & Bullock, J. C. (1983). Cell kinetic studies in the epidermis of the mouse. I. Changes in labeling index with time after tritiated thymidine administration. Experientia, 39(10), 1125–1129.PubMedCrossRefGoogle Scholar
  28. 28.
    Morris, R. J., Fischer, S. M., & Slaga, T. J. (1985). Evidence that the centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations. Journal of Investigative Dermatology, 84(4), 277–281.PubMedCrossRefGoogle Scholar
  29. 29.
    Rheinwald, J. G., & Green, H. (1975). Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell, 6(3), 331–643.CrossRefGoogle Scholar
  30. 30.
    Bickenbach, J. R., & Chism, E. (1998). Selection and extended growth of murine epidermal stem cells in culture. Experimental Cell Research, 244(1), 184–195.PubMedCrossRefGoogle Scholar
  31. 31.
    Morris, R. J., Tacker, K. C., Fischer, S. M., & Slaga, T. J. (1988). Quantitation of primary in vitro clonogenic keratinocytes from normal adult murine epidermis, following initiation, and during promotion of epidermal tumors. Cancer Research, 48(22), 6285–6290.PubMedGoogle Scholar
  32. 32.
    Popova, N. V., & Morris, R. J. (2004). Genetic regulation of mouse stem cells: identification of two keratinocyte stem cell regulatory loci. Current Topics in Microbiology and Immunology, 280, 111–137.PubMedGoogle Scholar
  33. 33.
    Jones, P. H., Harper, S., & Watt, F. M. (1995). Stem cell patterning and fate in human epidermis. Cell, 80(1), 83–93.PubMedCrossRefGoogle Scholar
  34. 34.
    Jones, P. H., & Watt, F. M. (1993). Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell, 73(4), 713–724.PubMedCrossRefGoogle Scholar
  35. 35.
    Strachan, L. R., Scalapino, K. J., Lawrence, H. J., & Ghadially, R. (2008). Rapid adhesion to collagen isolates murine keratinocytes with limited long-term repopulating ability in vivo despite high clonogenicity in vitro. Stem Cells, 26(1), 235–243.PubMedCrossRefGoogle Scholar
  36. 36.
    Potten, C. S., & Booth, C. (2002). Keratinocyte stem cells: A commentary. Journal of Investigative Dermatology, 119(4), 888–899.PubMedCrossRefGoogle Scholar
  37. 37.
    Ito, M., Yang, Z., Andl, T., et al. (2007). Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature, 447(7142), 316–320.PubMedCrossRefGoogle Scholar
  38. 38.
    Wang, C. K., Nelson, C. F., Brinkman, A. M., Miller, A. C., & Hoeffler, W. K. (2000). Spontaneous cell sorting of fibroblasts and keratinocytes creates an organotypic human skin equivalent. Journal of Investigative Dermatology, 114(4), 674–680.PubMedCrossRefGoogle Scholar
  39. 39.
    Lewis, J. (1998). Notch signalling and the control of cell fate choices in vertebrates. Seminars in Cell & Developmental Biology, 9(6), 583–589.Google Scholar
  40. 40.
    Bryder, D., Rossi, D. J., & Weissman, I. L. (2006). Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. American Journal of Pathology, 169(2), 338–346.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2008

Authors and Affiliations

  1. 1.Department of DermatologyUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Dermatology ResearchVeteran’s Affairs Medical CenterSan FranciscoUSA
  3. 3.Department of DermatologyUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Dermatology ResearchVeteran’s Affairs Medical CenterSan FranciscoUSA

Personalised recommendations