The Role of Fibroblasts In Skin Aging

Fibroblasts are the most common cells of connective tissue that synthesizes the extracellular matrix and play a critical role in wound healing. Fibroblasts make and secrete collagens, elastin, ground substances such as glycosaminoglycans, glycoproteins found in the extracellular matrix and cytokine TSLP. Fibroblasts and fibrocytes are two states of the same cells, the former being the activated state, the latter the less active state, concerned with maintenance and tissue metabolism. Fibroblasts are morphologically heterogeneous with diverse appearances depending on their location and activity. Unlike the epithelial cells lining the body structures, fibroblasts do not form flat monolayers and are not restricted by a polarizing attachment to a basal lamina on one side. Fibroblasts have a branched cytoplasm surrounding an elliptical, speckled nucleus having one or two nucleoli. Active fibroblasts can be recognized by their abundant rough endoplasmic reticulum. Inactive fibroblasts (fibrocytes) are smaller and spindle shaped. They have a reduced rough endoplasmic reticulum. Although disjointed and scattered when they have to cover a large space, fibroblasts when crowded often locally align in parallel clusters. Tissue damage stimulates fibrocytes and induces the mitosis of fibroblasts. Fibrocytes are the “repair team” -once the need is detected, (e.g. repair of damaged skin), the fibrocyte team changes to fibroblasts and contributes to the repair process. The main function of fibroblasts is to maintain the structural integrity of connective tissues by continuously secreting precursors of the extracellular matrix. Fibroblasts secrete the precursors of all the components of the extracellular matrix, primarily the ground substance and a variety of fibers. The composition of the extracellular matrix determines the physical properties of connective tissues.

Maintaining the healthy and long term functioning of fibroblasts is critical to slowing skin aging. The multi-tasking Fibroblasts in the skin dermis produce the major components of the extra­cellular matrix – collagen, elastin, GAGs – and participates in skin regeneration, healing and immune defense. There are three principal types of fibroblasts in the skin dermis -papillary fibroblasts (in the superficial dermis), reticular fibroblasts (in the deep dermis), and follicle fibroblasts (associated with hair follicles). Papillary fibroblasts are most important in sustaining keratinopoiesis (skin regeneration) and in promoting epidermal morphogenesis (skin regeneration) in comparison to reticular fibroblasts. Papillary and reticular fibroblasts nourish the micro-vessels in the epidermis and contribute to the organization and maintenance of this microvasculature. Follicle fibroblasts are essential for hair development, eccrine functions, and skin repair. Follicle dermal cells may be important in wound healing. The complexity of its functions and its strategic position in the dermis make the fibroblast particularly vulnerable to damage and impairment by UV rays, pollutants and chemicals, and metabolically generated free radicals.

Fibroblast (Fibrocyte) are mitotic cells that do not divide indefinitely. The process that limits the cell division number is termed cellular or replicative senescence which inherently protective tumor suppressive mechanism. Cellular senescence contribute to biological aging. Senescent cells undergo three phenotypic changes: they irreversibly arrest growth, they acquire resistance to apoptotic death, and they acquire altered differentiated functions. The growth arrest is very likely critical for the role of replicative senescence in tumor suppression, but may be less important for the aging of skin. On the other hand, the altered differentiation may be critical for compromising the function and integrity of skin during aging. Senescent fibroblasts were observed to accumulate with age in human skin and trigger the differential expression of genes involved in skin aging – increased level of matrix degradation enzymes (matrix metalloproteinases – MMP), growth factors and inflammatory cytokines or proinflammatory mediators.

Aging fibroblast has reduced capacity of proliferation and reduced capacity in cellular repair and synthesis of matrix structural molecules. Senescent fibroblasts secrete more matrix destructive enzymes, i.e., metalloproteinases (MMP’s), keratinocyte growth factor (KGF) and vascular endothelial growth factor (VEGF) and less tissue inhibitors of metalloproteinase (TIMP). Papillary dermis and reticular dermis fibroblast age in distinct ways. The papillary fibroblast col­lagen lattice contraction capacity increases with age (collagen lattice contraction is important in tissue remodeling and wound healing). aging of reticular fibroblast reduced the secretion of the monocyte chemoatractant protein 1 (MCP-1) secretion (factor in tissue remodeling), but the collagen lattice contraction capacity is not changed. Fibroblasts that produce and organize the collagen matrix cannot attach to fragmented collagen. Loss of attachment prevents fibroblasts from receiving mechanical information from their support, and they collapse. Stretch of fibroblast morphologically is critical for normal balanced production of collagen and collagen-degrading enzymes. Attachment of fibroblasts to new collagen and undamaged nonfragmented collagen fiber allows maintenance the functioning stretch of fibroblast. In aged skin, fibroblasts were found morphologically altered and they produce low levels of collagen and high levels of collagen-degrading enzymes. This imbalance advances the skin aging process in a cycle. , which in turn balances collagen production and degradation and thereby slows the aging process. Collagen fragmentation is responsible for loss of structural integrity and impairment of fibroblast function in aged human skin. Treatments that stimulate production of new, nonfragmented collagen should provide substantial improvement to the appearance and health of aged skin.

Researches has found that some natural ingredients can positively affect fibroblast functionality in aged skin. L-carnosine, a well known anti-inflammatory agent, has been found to have beneficial effects on cultured fibroblasts in vitro. Physiological concentrations in standard media prolong fibroblast’s lifespan and strongly reduce the normal features of senescence. Late passage cells in normal medium are rejuvenated when transferred to medium containing l-carnosine, and become senescent when carnosine is removed. None of these effects are seen with its optical isomer, D-carnosine. L-Carnosine sustains the retention of cell morphology in fibroblast culture subjected to continuous nutritional depletion.


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