Introduction

During life we are persistently exposed to environmental hazards. A first protective barrier is provided by the skin, protecting us against water loss and external physical, chemical, and biological insults such as wounding, UVB radiation, and microorganisms. The skin consists of an outer squamous epithelium, the epidermis, and an inner connective tissue, the dermis. The barrier is mainly constituted by the epidermis, which is continuously rejuvenated as a result of mitotic activity of the stem cells in the basal layer that provide new keratinocytes. Upon withdrawal from the cell cycle, basal keratinocytes detach from the basement membrane and undergo a terminal differentiation program to become corneocytes in the outer layers of the epidermis (Figure 28-1). At the transition from the granular to cornified layer, an increase in intracellular Ca2+ activates transglutaminases, which cross-link different structural proteins beneath the plasma membrane to form the cornified envelope. At the final stage of differentiation, the keratinocytes lose their organelles, including the nucleus, and become the dead, flattened corneocytes. This cell death program, called cornification, has to be well orchestrated because the dead cells act as an essential barrier and fulfill a specific function. Finally, corneocytes are shed from the skin by a process called desquamation. Melanocytes, also residing in the epidermis, are neurectoderm-derived cells that produce melanin, which provides skin pigmentation. Imbalances in the delicate physiologic turnover of proliferating or differentiating keratinocytes can result in the disturbance of the skin barrier function and are reflected in many skin disorders. In addition, improper removal of damaged cells by the terminal differentiation program can result in cancerous lesions.