Irwin Freeberg, MD

Keratinocytes are stratified, squamous, epithelial cells that comprise skin and mucosa, including oral, esophageal, corneal, conjunctival, and genital epithelia. Keratinocytes provide a barrier between the host and the environment. They prevent the entry of toxic substances from the environment and the loss of important constituents from the host. Keratinocytes differentiate as they progress from the basal layer to the skin surface. The normal turnover time for keratinocytes is around 30 days, but epidermal turnover might be accelerated in some skin diseases such as psoriasis.

Keratinocyte stem cells reside in the basal layer. These cells have a low rate of mitosis and give rise to a population of transient amplifying cells (Figure 1). Transient amplifying cells go through a limited number of divisions, differentiate, and move up in the epidermis. The cells above the basal layer are known as the spinous layer. Under routine microscopy small bridges, resembling spines, can be seen between the keratinocytes that represent intercellular adhesion complexes known as desmosomes.

Figure 1. A diagram of the cell cycle. The cycling component consists of cells in the G1 phase, the most variable part of the cycle. Cells then move into the S phase, during which the DNA content of the cell is doubled. Subsequently, cells enter the second gap phase (G2), which leads to mitosis and the production of two daughter cells. The daughter cells might proceed through another replicative cycle, enter the differentiation pathway or, according to some investigators, enter a resting phase (G0).

As the cells further differentiate, they synthesize keratohyaline granules, a prominent feature of cells in the granular layer. Proteins synthesized in the granular layer are important in the final stages of epidermal differentiation and include profilagrin, loricrin, involucrin, and cornifin. These molecules are important in the formation of the stratum corneum, the outer most layer of the epidermis (Figure 2).

Figure 2. Schematic representation of the heterogeneity in basal keratinocytes. The nonserrated (NS) cells at the tips of the deep rete ridges are believed to be the slowly cycling stem cells. These give rise to suprabasally located transient amplifying cells (TA) cells, which actively incorporate [3H] thymidine. The TA cells give rise to the more superficial nonlabelled post mitotic (PM) cells. The serrated (S) cells located in the more shallow rete ridges are believed to play a role in anchoring of epidermis to dermis. B=basal; S=spinous; G=granular; SC=statum corneum. From Lavker and Sun (reference 7). Fifth edition. Freedberg IM, Eisen AZ, Wolff K, Goldsmith LA, Katz SI and Fitzpatrick TB (eds), New York: McGraw-Hill, 1999, pp. 133-143.

The major proteins formed within keratinocytes are keratins (Table 1). Keratins are intermediate filament proteins that form the cytoskeleton of keratinocytes. Keratins are alpha-helical molecules and belong to two families: Type I (acidic keratins) and Type II (basic keratins). During keratin assembly, an acidic and basic keratin pair up to form obligate heteropolymers, which are then assembled into filaments. During epithelial differentiation the expression of keratins changes.

Table 1.  Keratin Location 

Basal cells express keratins 5 and 14. As keratinocytes leave the basal layer, they become larger and synthesize keratins 1 and 10 ((Figure 3). Different keratins are associated with hair and nail formation. In hyperprolific epidermis, such as psoriasis and atopic dermatitis, keratin 6 and 16 predominate. A congenital blistering disease, epidermolysis bullosa simplex, is due to defects in keratins 5 and 14, resulting in blistering at the basal layer. Other keratin pairs are involved in a variety of diseases of epidermis, hair, and nails.

Figure 3 The epidermis and keratin expression. On the left is a histologic cross section of human skin and on the right is a cartoon representing the process of epidermal differentiation. The four major steps in epidermal differentiation are 1) an innermost basal layer of mitotically active cells; 2) three to six layers of spinous cells that are still transcriptionally active but are no longer dividing; these cells can devote most of their translational machinery to expressing keratins; 3) one to three layers of granular cells that are transcriptionally active and deposit a cornified envelope of cross-linked proteins beneath the plasma membrane; and 4) 5-20 layers of stratum corneum, which consist of metabolically inert, enucleated squames that are sloughed from the skin surface. Basal epidermal cells express keratins 5 and 14. As basal cells commit to terminally differentiate, they switch off the expression of K5 and K14 and induce the expression of K1 and K10. As epidermal cells move up through the spinous, they express K2e, which can pair with K10. Squames sloughed from the skin surface are merely dead sacs, chock full of keratin macrofibrils.

References

1. Latkowski, JA & Freedberg, IM. Epidermal Cell Kinetics, Epidermal Differentiation and Keratinization. In: Fitzpatrick's Dermatology in General Medicine. Fifth edition. Freedberg IM, Eisen AZ, Wolff K, Goldsmith LA, Katz SI and Fitzpatrick TB (eds), New York: McGraw-Hill, 1999, pp. 133-143.

2. Moll R, et al. The catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982; 31:11.

3. Fuchs E. Of mice and men: Genetic disorders of the cytoskeleton. Mol Biol Cell 1997; 8:189.
   Sun TT, et al. Classification, expression, and possible mechanisms of evolution of mammalian epithelial keratins: A unifying model. Cancer Cell 1984; 1:169.

4. Steinert PM. The two-chain coiled-coil molecule of native epidermal keratin intermediate filaments is a type I-type II heterodimer. J. Biol Chem 1990; 265:8766.

5. Goldman RD, et al. The function of intermediate filaments in cell shape and cytoskeletal integrity. J Cell Biol 1996;134:971

6. Lavker RM, and Sun T-T. Epidermal stem cells. J Invest Dermatol 1983;81:121s-127s.

Questions: Keratinocytes

1. Stem cells in the epidermis are found in the:

A) stratum corneum
B) granular layer
C) spinous layer
D) basal layer
E) spinous and basallayers

2. The keratin pair in the basal layer keratinocytes consists of keratins

A) 1 and 2
B) 1 and 10
C) 5 and 14
D) 8 and 18
E) 6 and 16

3. Which of the following epidermal layers is transcriptionally inert?

A) basal layer
B) spinous layer
C) granular layer
D) stratum corneum

Answers: Keratinocytes