Keratinocyte terminal differentiation

Since caspase 14 plays an important role in epidermal keratinocyte terminal differentiation and denucleation, the effect of topical application of GTPs, with 40% EGCG, on the psoriasis symptoms in flaky skin mice was tested in this in vivo pilot study. The rationale for using GTPs instead of purified EGCG is that GTPs are naturally available without any chemical or compositional modification. 

Walsh, D. et al. Psoriasis is characterized by altered epidermal expression of caspase 14, a novel regulator of keratinocyte terminal differentiation and barrier formation. J Dermatol Sci. 37, 61, 2005. 

Martinez, L. A., Chen, Y., Fischer, S. M., and Conti, C. J. (1999). Coordinated changes in cell cycle machinery occur during keratinocyte terminal differentiation. Oncogene 18, 397 06. 

In the skin, ENaC is expressed in keratinocytes of the epidermis and in hair follicles. It could play a role in terminal differentiation by modulating keratinocyte calcium signaling. The skin expresses MR, GR, and 11 3HSD2, but the role of aldosterone and glucocorticoids on ENaC activity and keratinocyte differentiation is not yet understood. 

The most superficial layer of skin is the stratum comeum (SC), which consists of terminally differentiated keratinocytes (comeocytes) that originate from actively proliferating keratinocytes in lower epidermis (basale, spinosum, and granulosum cells), and contain a lamellar lipid layer secreted from lamellar bodies (Fig. 7a). Flydration of the SC is an important determinant of skin appearance and physical properties, and depends on a number of factors including the external humidity, and its structure, lipid/protein composition, barrier properties, and concentration of water-retaining osmolytes (natural moisturizing factors, NMFs) including free amino acids, ions, and other small solutes. 

FIGURE 2.2 A diagram of human skin. Epidermal thickness depends upon body site being thickest on the palms and soles (-1500 pm) and thinnest around the eyes (-10 pm). The stratum corneum is the only layer composed of anucleated, terminally differentiated kerati-nocyte cells called corneocytes. All other epidermal layers contain nucleated keratinocytes. The dermis is composed primarily of the structural proteins collagen and elastin. 

Steven, A.C., et al. 1990. Biosynthetic pathways of filaggrin and loricrin—two major proteins expressed by terminally differentiated epidermal keratinocytes. J Struct Biol 104 150. 

The stratum corneum consists of denucleated corneocytes filled with cross-linked proteins, while the intercellular space is occupied by lipids synthesized prior to and during cornification [24], Formation of this barrier relies on the cornification of epidermal keratinocytes, which undergo growth arrest, terminal differentiation, and an epidermal-specific cell death, referred to as planned cell death [25], Abnormalities in any of these programmed events may lead to epidermal disorders such as psoriasis, atopic dermatitis, and cancer. Flowever, biological events that enable basal cells (stem cells) to proliferate, differentiate, and commit planned cell death are still poorly understood [10]. The keratinocyte differentiation process can be stimulated by prodifferentiation agents such as extracellular calcium and 1,25-dihydroxy cholecalciferol (referred to as vitamin D3 hereafter) [23], Aberrant or absent differentiation can be found in other skin disorders such as atopic keratosis, seborrheic keratosis, and rosacea. 

Eckhart, L. et al. Terminal differentiation of human keratinocytes and stratum comeum formation is associated with caspase-14 activation. J Invest Dermatol. 115, 1148, 2000. 

Reichert, U., Michel, S., and Schmidt, R. The cornified envelope a key structure of terminally differentiating keratinocytes, in Molecular Biology of the Skin the Keratinocyte, Darmon, M. and Blumberg, M. Eds., Academic Press, New York, 1994, chap 2. 

Alternatively, the calcium stores may be concentrated by lamellar bodies from the intercellular fluids released during terminal differentiation. The lamellar bodies are thought to be modified lysosomes containing hydrolytic enzymes, and a potential source of the hyaluronidase activity. The lamellar bodies fuse with the plasma membranes of the terminally differentiating keratinocytes, increasing the plasma membrane surface area. Lamellar bodies are also associated with proton pumps that enhance acidity. The lamellar bodies also acidify, and their polar lipids become partially converted to neutral lipids, thereby participating in skin barrier function. 

Seishima, M., Takagi, H., Okano, Y., Mori, S., and Nozawa, Y., Ganglioside-induced terminal differentiation of human keratinocytes early biochemical events in signal transduction, Arch. Dermatol. Res., 285, 397, 1993. 

Calcitriol induces terminal differentiation of skin keratinocytes in culture, an action that has been exploited in the treatment of psoriasis (Section 3.6.2). In keratinocytes in culture, both calcium and calcitriol are required for differentiation. Cells lacking the calcium-sensing receptor or phospholipase C-y 1 fail to differentiate in response to calcium or calcitriol, suggesting that in... 

The remarkable barrier function of the skin is primarily located in the stratum corneum (SC), the thin, outermost layer of the epidermis. The SC consists of several layers of protein-filled corneocytes (i.e., terminally differentiated keratinocytes) embedded in an extracellular lipid matrix. Attached to the outer cor-neocyte envelope are long-chain covalently bound cer-amides that interact with the lipids of the extracellular space. These lipids are composed primarily of free fatty acids, ceramides, and cholesterol arranged in multiple lamellae.f Passive permeation across the SC is believed to occur primarily via the intercellular... 

Yuspa, S. H., Kilkenny, A. E., Stanley, J., and Lichti, U. (1985). Keratinocytes blocked in phorbol ester-responsive early stage of terminal differentiation by sarcoma viruses. Nature 314, 459-462. 

Rosenthal DS, Simbulan-Rosenthal CMG, Iyer S et al. (1998). Sulfur mustard induces markers of terminal differentiation and apoptosis in keratinocytes via a Ca2+-calmodulin and caspase-dependent pathway. J Invest Dermatol, 111, 64—71. 

Terminally differentiated keratinocytes of the stratum corneum are known as comeocytes and are largely devoid of normal cellular functions, being predominantly composed of protein (keratin). The ultrastructure of the stratum corneum is described by the brick and mortar model (Elias, 1983 Figure 3). The functional implication of this architecture is that some skin penetrants must diffuse via a long and tortuous route between adjacent comeocytes, thus reducing their rate of absorption. This is known as the intercellular route. In contrast, some chemicals may diffuse equally through both comeocytes and the lipid mortar, resulting in a transcellular route. 

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