INTRODUCTION
Organization and Function of Epidermis Providing an Efficient Skin Barrier
The epidermis maintains its homeostasis and serves critical functions through a dynamic, self-renewing process in which the basal keratinocytes divide and migrate through the stratum spinosum and granulosum while progressively differentiating (Figure 1). When the keratinocytes reach the top of the granular layer, the process of terminal differentiation occurs in which the keratinocytes undergo programmed cell death and flatten out to form the stratum corneum (SC).1 During this process, the lamellar bodies of granular layer keratinocytes merge with the plasma membranes and release their predominantly lipid contents into the intercellular spaces of the nascent horny layer. An interplay of hydrolytic enzymes and their inhibitors, also excreted via the lamellar bodies, participate in elaboration of the intercellular layered lipid structure and, ultimately, are involved in cell desquamation at the top of the skin.2 Simultaneous to the extracellular lipid build-up, important changes occur within the keratinocytes upon the formation of SC. Transglutaminase-1 –mediated cross-linking of cytoplasmic proteins at the cell periphery results in the formation of highly insoluble cornified envelopes of the SC cells, thereafter called corneocytes.3 It is followed by a covalent binding to these structures of a monolayer of ceramides, replacing phospholipid plasma membranes of the living cells. These newly formed cornified lipid envelopes constitute the scaffold for further stacking and organization of the intercellular lipids. The composite structure of the SC, made of corneocytes intercalated by polar lipids, can be compared to a brick and mortar wall constituting SC permeability barrier.4
In order to perform its function as a permeability barrier, the epidermis must remain mechanically resistant while sufficiently flexible to accommodate skin movements and the treadmill-like flow of keratinocytes through the successive layers. Cell-cell and cell-substrate junctions play central roles in the maintenance of mechanical properties of the epidermis. Desmosomes, which interconnect individual cell cytoskeletons into a superstructure, evolve throughout the epithelial tissue, and change their location, protein composition, and glycan distribution according to the stage of the cell differentiation and the occurrence of mechanical constraints.5–7 In this process, actin cytoskeleton-bound adherens junctions participate in the dynamics of desmosome and tight junction expression. Upon the SC formation, these junctions become cross-linked to cornified envelopes and contribute to the enhanced physical resistance of the functional SC barrier.8 Mechanical properties of the SC show a significant increase in stiffness between the deep and superficial corneocytes.9 The mechanical integrity of the SC also depends on the direction of the applied shearing forces since lateral, side to side adhesion between the cells is stronger compared to that between the successive corneocyte layers.9–12
The epidermis maintains its homeostasis and serves critical functions through a dynamic, self-renewing process in which the basal keratinocytes divide and migrate through the stratum spinosum and granulosum while progressively differentiating (Figure 1). When the keratinocytes reach the top of the granular layer, the process of terminal differentiation occurs in which the keratinocytes undergo programmed cell death and flatten out to form the stratum corneum (SC).1 During this process, the lamellar bodies of granular layer keratinocytes merge with the plasma membranes and release their predominantly lipid contents into the intercellular spaces of the nascent horny layer. An interplay of hydrolytic enzymes and their inhibitors, also excreted via the lamellar bodies, participate in elaboration of the intercellular layered lipid structure and, ultimately, are involved in cell desquamation at the top of the skin.2 Simultaneous to the extracellular lipid build-up, important changes occur within the keratinocytes upon the formation of SC. Transglutaminase-1 –mediated cross-linking of cytoplasmic proteins at the cell periphery results in the formation of highly insoluble cornified envelopes of the SC cells, thereafter called corneocytes.3 It is followed by a covalent binding to these structures of a monolayer of ceramides, replacing phospholipid plasma membranes of the living cells. These newly formed cornified lipid envelopes constitute the scaffold for further stacking and organization of the intercellular lipids. The composite structure of the SC, made of corneocytes intercalated by polar lipids, can be compared to a brick and mortar wall constituting SC permeability barrier.4
In order to perform its function as a permeability barrier, the epidermis must remain mechanically resistant while sufficiently flexible to accommodate skin movements and the treadmill-like flow of keratinocytes through the successive layers. Cell-cell and cell-substrate junctions play central roles in the maintenance of mechanical properties of the epidermis. Desmosomes, which interconnect individual cell cytoskeletons into a superstructure, evolve throughout the epithelial tissue, and change their location, protein composition, and glycan distribution according to the stage of the cell differentiation and the occurrence of mechanical constraints.5–7 In this process, actin cytoskeleton-bound adherens junctions participate in the dynamics of desmosome and tight junction expression. Upon the SC formation, these junctions become cross-linked to cornified envelopes and contribute to the enhanced physical resistance of the functional SC barrier.8 Mechanical properties of the SC show a significant increase in stiffness between the deep and superficial corneocytes.9 The mechanical integrity of the SC also depends on the direction of the applied shearing forces since lateral, side to side adhesion between the cells is stronger compared to that between the successive corneocyte layers.9–12
