- The Ordered Architecture of Murine Ear Epidermis Is Maintained by Progenitor Cells with Random Fate
Developmental Cell, Volume 18, Issue 2, 16 February 2010, Pages 317-323
David P. Doupé, Allon M. Klein, Benjamin D. Simons and Philip H. Jones
SummaryTypical murine epidermis has a patterned structure, seen clearly in ear skin, with regular columns of differentiated cells overlying the proliferative basal layer. It has been proposed that each column is a clonal epidermal proliferative unit maintained by a central stem cell and its transit amplifying cell progeny. An alternative hypothesis is that proliferating basal cells have random fate, the probability of generating cycling or differentiated cells being balanced so homeostasis is achieved. The stochastic model seems irreconcilable with an ordered tissue. Here we use lineage tracing to reveal that basal cells generate clones with highly irregular shapes that contribute progeny to multiple columns. Basal cell fate and cell cycle time is random. Cell columns form due to the properties of postmitotic cells. We conclude that the ordered architecture of the epidermis is maintained by a stochastic progenitor cell population, providing a simple and robust mechanism of homeostasis.
- Genetic pathways in disorders of epidermal differentiation
Trends in Genetics, Volume 29, Issue 1, 1 January 2013, Pages 31-40
Vanessa Lopez-Pajares, Karen Yan, Brian J. Zarnegar, Katherine L. Jameson and Paul A. Khavari
AbstractMore than 100 human genetic skin diseases, impacting over 20% of the population, are characterized by disrupted epidermal differentiation. A significant proportion of the 90 genes identified in these disorders to date are concentrated within several functional pathways, suggesting the emergence of organizing themes in epidermal differentiation. Among these are the Notch, transforming growth factor β (TGFβ), IκB kinase (IKK), Ras/mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), p63, and Wnt signaling pathways, as well as core biological processes mediating calcium homeostasis, tissue integrity, cornification, and lipid biogenesis. Here, we review recent results supporting the central role of these pathways in epidermal differentiation, highlighting the integration of genetic information with functional studies to illuminate the biological actions of these pathways in humans as well as to guide development of future therapeutics to correct their dysfunction.
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- Differentiation of the epidermal keratinocyte in cell culture: Formation of the cornified envelope
Cell, Volume 9, Issue 4, 1 December 1976, Pages 511-521
Tung-Tien Sun and Howard Green
SummaryHuman epidermal keratinocytes grow from single cells into stratified colonies. Cells in the upper layers of the colonies lose their ability to divide and begin terminal differentiation. In this process, there develops a cornified cell envelope that remains insoluble after heating in solutions of sodium dodecylsulfate and β-mercaptoethanol. The insolubility of the cornified envelope depends upon proteins, since after treatment with proteolytic enzymes, the envelope becomes soluble in the detergent. Cells with cornified envelopes can be identified under the light microscope either in living colonies or following fixation and silver nitrate staining. Keratinocytes of the basal layer move in a characteristic way, but cornified cells do not move at all and form an immobile upper layer in the colonies.Keratinocytes disaggregated from growing colonies are of differing size and density, and can be separated on isopycnic gradients of Ficoll. The DNA-synthesizing cells are small (mean diameter 14 μm). The nonmultiplying cells are large and have a protein content proportionate to their size. Their final diameter may exceed 30 microns (volume increase >10 fold). Cornified envelopes are found in some of the large cells but in none of the small.In growing colonies, usually 5–10% of the cells have cornified envelopes. The fraction is reduced in colonies growing in the presence of epidermal growth factor. Strain XB, an established keratinocyte line of mouse teratomal origin, also forms cornified envelopes, but the kinetics of the process are different, indicating that the program of terminal differentiation is not initiated at corresponding times in the two cell types.
- Culture conditions can be manipulated to vary the rate at which keratinocytes (stratified squamous epithelial cells) become committed to differentiate terminally. When deprived of anchorage in semi-solid medium, normal human keratinocytes irreversibly lose the ability to reinitiate growth in surface culture with a t12 of 3 hr and then proceed to form cornified envelopes. We examined six established lines from human squamous cell carcinomas (SCCs) for defects in this function. One SCC line which grew progressively in semi-solid medium could not be induced to form cornified envelopes. The other five lines, which grew abortively, at best, in semi-solid medium, formed envelopes under this condition but at subnormal rates. During anchorage deprivation the SCC lines became committed to differentiate much more slowly than normal, with t12's of 24–144 hr. SCC cells therefore possess at least a partial defect in the triggering of terminal differentiation. In vivo, such an alteration may permit malignant behavior by evading an important tissue-specific mechanism for limiting growth. In culture, the phenotype of increased survival in semi-solid medium may be used to detect and select malignantly transformed keratinocytes.