Integrins are α β heterodimeric transmembrane receptors that mediate the attachment (adhesion) between a cell and the tissues that surround it, such as other cells or the extracellular matrix (ECM) in the skin epidermis and dermis. There are a number of different α and β subunits identified. Integrins isoforms are named as the combination of their α and β chain numbers. Which ligand in the ECM the integrin can bind to is defined by which α and β subunits the integrin is made of. ECM protein ligands that bind to integrins all contain a RGD (arginine-glycine-aspartic acid) domain which provide the specificity of binding/interaction between ligands and integrin receptors. Common integrin binding proteins in the ECM of the skin include fibronectin, vitronectin, collagen, and laminin.
Integrin signaling pass information about the chemical composition, organization and biomechanical forces of the ECM into the cell and the skin cell responds via a cascade of signal transduction pathways. Therefore, integrins are involved in cell signaling and the regulation of cell cycle, morphology, and motility. Not only do integrins perform this outside-in signaling, but they also operate an inside-out mode in that they reveal the status of the cell to the outside. Integrin not only is available on fibroblast but is also synthesized and located on epidermal keratinocyte. Integrins connect the ECM outside a cell to the cytoskeleton (in particular the microfilaments) inside the cell. Cell attachment to the ECM is a basic requirement to connect ECM and the intracellular actin filamentous system. Focal adhesions (also cell–matrix adhesions or FAs) are specific types of large macromolecular adhesion complexes/assemblies through which both mechanical force and regulatory function of integrin for initiating signaling. Integrin signaling begins with the attachment of ECM to the cell through formation of cell adhesion complexes, which consist of integrins and many cytoplasmic proteins such as talin, vinculin, paxillin, and alpha-actin in. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two networks across the plasma membrane: the extracellular signals are transmitted. Focal adhesions serve as the mechanical linkages to the ECM, and as a biochemical signaling hub to concentrate and direct numerous signaling proteins at sites of integrin binding and clustering. Next, adhesion complexes relay signal into the cells via their ability to regulate and activate cascades of protein kinases. Integrin signaling pathways can result in and regulate the cell growth, cell division, cell survival, cellular differentiation, and apoptosis.
Integrin-signaling activates pathways on cellular level that are essential in maintaining the functional and healthy skin physiology and homeostasis. An important and still unanswered question is how the surrounding microenvironment in the skin and, in particular, the ECM constituents influence basal keratinocyte and dermis fibroblast behavior during normal homeostasis. Three members of this family are known to be the major receptors for collagens, namely α1β1, α2β1, and α3β1 all of which are synthesized by fibroblasts. They seem to regulate different functions. Integrin α1β1, for example, appears to regulate collagen synthesis, whereas α2β1 mediates collagen gel contraction.
The epidermal cell integrins and their ECM ligands provide a diverse proliferative stimuli for skin basal cells and are key regulators of keratinocyte proliferation and differentiation. Members of basal keratinocytes integrins include: α3β1 (the laminin-5 receptor), α2β1 (the collagen receptor), α5β1 (fibronectin receptor), and αvβ3 and αvβ6 (vitronectin receptors), and α9β1. α9β1 bind to several ligands available beneath migrating keratinocytes only during wound healing. β1 Integrin-mediated adhesion signaling is essential for epidermal progenitor cell expansion. Integrin α6 β4 links to the keratin intermediate filament system in epidermal cells.
During aging, the ECM of the skin dermis (collagen fibers, elastic fibers, ground substance, and cells) and basement membrane (collagen IV, VII, laminin) are changed. Fibers are fragmented or damaged, the fiber organization and alignment are damaged. Adhesion of skin cells to modified ECM structures via specific receptors (integrins) is disturbed; there is no tight connection between cytoskeleton and ECM fibers. Deficiency in integrin-mediated transmembrane signaling and microfilament stress fiber formation by cultured aging dermal fibroblasts were observed. In vivo analysis of fibroblasts sample from different age groups revealed that aged fibroblasts α2β1 integrin (the collagen receptor) amount is not significantly decreased. However, the lines of aged fibroblasts that were poor migrators exhibited a significant reduction in alpha2beta1 activity. Moreover, the lines of aged fibroblasts showed a disordered actin cytoskeleton. Aged fibroblasts with deficient migration are characterized by disorganized cytoskeletal actin and reduced alpha2beta1 function. There is decreased expression of keratinocyte beta1 integrins by epidermal basal cells (basal keratinocyte) in chronically sun-exposed skin in vivo. .
Ingredients that stimulate the integrin signaling has been developed using biomimetic peptide that mimic the ligand conformation containing the integrin binding motif – RGD domain. Cyclopeptide-5 (CP-5) is a biomimetic cyclic oligopeptide that mimic the optimal conformation of the natural ligands of integrin for the stimulation of integrin signaling pathways in skin. The cyclic structure of the peptide provides a rigid, stable and optimal conformation for specificity in binding to integrin. In vitro efficacy studies and DNA microassay (gene chip technology) revealed pathways/process/genes that are activated in the presence of ingredient. Important basement membrane proteins, e.g. laminin IV, collagen IV are increased while ECM enzymatic degradation and MMP levels are decreased.