Keratinocyte - Cell Differentiation

Cell Differentiation

Keratinocytes are formed first by differentiation from epidermal stem cells (transit amplifying cells), residing in the lower part of the stratum basale of the epidermis, attached to the basement membrane through hemidesmosomes. Those stem cells and their differentiated progeny are organized into columns named epidermal proliferation units. Keratinocytes in the stratum basale layer of the epidermis are attached together through desmosomes and will proliferate through a few rounds of cell divisions within the stratum basale before moving up through the epidermis as they differentiate.

During this differentiation process, keratinocytes permanently withdraw from the cell cycle, initiate expression of epidermal differentiation markers, and move suprabasally as they become part of the stratum spinosum, stratum granulosum and eventually become corneocytes in the stratum corneum.

Corneocytes are keratinocytes that have completed their differentiation program and have lost their nucleus and cytoplasmic organelles. Corneocytes will eventually be shed off through desquamation as new one come in.

At each stage of differentiation, keratinocytes express specific keratins, such as keratin 1, keratin 5, keratin 10 and keratin 14, but also other markers such as involucrin, loricrin, transglutaminase, filaggrin and caspase 14.

In humans, it is estimated that keratinocytes turnover from stem cells to desquamation every 40–56 days whereas in mice the estimated turnover time is 8–10 days.

Factors promoting keratinocyte differentiation:

• A calcium gradient, with the lowest concentration in the stratum basale and increasing concentrations until the outer stratum granulosum, where it reaches its maximum. Calcium concentration in the stratum corneum is very low in part because those relatively dry cells are not able to dissolve the ions. Those elevations of extracellular calcium concentrations induces an increase in intracellular free calcium concentrations in keratinocyte. Part of that intracellular calcium increase comes from calcium released from intracellular stores and another part comes from transmembrane calcium influx, through both calcium-sensitive chloride channels and voltage-independent cation channels permeable to calcium. Moreover, it has been suggested that an extracellular calcium-sensing receptor (CaSR) also contributes to the rise in intracellular calcium concentration.
• Vitamin D3 (cholecalciferol) regulates keratinocyte proliferation and differentiation mostly by modulating calcium concentrations and regulating the expression of genes involved in keratinocytes differentiation. Keratinocytes are the only cells in the body with the entire vitamin D metabolic pathway from vitamin D production to catabolism and Vitamin D receptor expression.
• Cathepsin E.
• TALE homeodomain transcription factors.
• Hydrocortisone.

Since keratinocyte differentiation stops keratinocyte proliferation, factors that promote keratinocyte proliferation should be considered as preventing differentiation, such as:

• The transcription factor p63, by preventing epidermal stem cells to differentiate into keratinocytes.
• Vitamin A and its analogues.
• Epidermal growth factor.
• Tumor growth factor alpha.
• Cholera toxin