ABSTRACT

The epidermis is a stratified epithelium. The bulk of epidermal cells consists of keratinocytes, which undergo a complex process of differentiation as they transit outwards from the basal, proliferative compartment. This sequence culminates in terminal cellular cornification and in the deposition of an extracellular lipid-enriched lamellar matrix to form the ‘‘two-compartment’’ stratum corneum (SC) (Fig. 1) (1-3). Terminal cornification involves: (i) extrusion of lamellar bodies (LBs) to deliver lipid precursors and their hydrolytic enzymes to the extracellular domain to form lamellar bilayers unit structures; (ii) dissolution of the nucleus and other organelles; (iii) hydrolysis of profilaggrin to filaggrin; (iv) aggregation of keratin filaments to form macrofibrils; (v) breakdown of filaggrin and other intracellular proteins to yield amino acids and other small molecules; and (vi) extensive cross-linking of loricrin, involucrin, and other structural proteins by transglutaminases to form the cornified envelope (CE), at the inner surface of the keratinocyte plasma membrane (4-10). As a result of these events (i) highly organized hydrophobic lamellar membranes in the extracellular domain form a barrier to the movement of water, electrolytes, and other molecules from the organism’s interior to the skin surface and vice versa; (ii) intracellular keratin fibers and CEs, a rigid chemically resistant layer, provide a mechanical barrier to injury; and (iii) proteolysis of filaggrin generates a pool of osmotically active small molecules within the corneocyte to trap and hold water (corneocyte hydration) (11-16,19). Thus, the SC can be viewed as the end product of epidermal differentiation and as consisting of two interdependent compartments,

the corneocytes (i.e., the ‘‘bricks’’) and the extracellular lipid membranes (i.e., the ‘‘mortar’’). While the corneocytes are essential for the mechanical strength of the epidermis, the lipid-enriched matrix is primarily responsible for the permeability barrier to water and electrolyte transit (1).