Role of Integrins in Cell Adhesion and Polarity in Normal Keratinocytes and Human Skin Pathologies

In vitro, normal human keratinocytes reconstitute a differentiated stratified epidermis, maintaining the same gene expression pattern as its in vivo counterpart and are suitable for permanent grafting onto patients. Keratinocyte adhesion to basal lamina and lateral interactions among basal epidermal cells are also mediated by integrin receptors that are sorted to defined plasma membrane domains. The hemidesmosome-associated integrin α₆β₄ is sharply localized at the basal surface of basal cells and codistributes with laminin and nicein/kalinin; the α₂β₁ and α₃β₁ integrins are enriched laterally and play crucial roles in cell-cell interaction and proper colony morphology. During wound healing, proliferating and migrating keratinocytes express on their plasma membrane α_vβ₅ and α₅β₁, which allow keratinocyte attachment and migration over the provisional matrix present in the wound. TGFβ, which is an autocrine and paracrine mediator in wound healing, specifically increases the synthesis and expression of α_vβ₅ and α₅β₁, induces the de novo expression of α_vβ₆, and determines the loss of integrin polarization. In hyperproliferative skin diseases, such as skin cancer or psoriasis vulgaris, and in normal keratinocytes forced into more frequent cell cycles, the polarized expression of integrins is lost, and α₅β₁ becomes costitutively expressed on the plasma membrane. In addition, the α₆β₄ integrin becomes associated with focal contacts. Nerve growth factor (NGF) is a potent autocrine stimulator of keratinocyte growth and induces melanocyte migration toward the leading edge of a healing wound. We are currently investigating the NGF-dependent modulation of integrin expression and function in keratinocytes and melanocytes in both normal epidermis and several hyperproliferative skin diseases.