Excisional wounds of skin exhibit both regenerative and fibrotic responses to injury. The dermis repairs by scar formation, but within this context the epidermis and vasculature regenerate, although the epidermis may lack structures such as hair follicles and sebaceous and sweat glands. Repair of an excisional wound can be divided into three tightly integrated and overlapping phases: hemostasis, inflammation, and structural repair. During hemostasis, one set of serum factors causes adhesion of platelets to injured blood vessel walls, sealing them off, while another set induces formation of a fibrin clot that forms a provisional matrix for the migration of immune cells, epidermal cells, and fibro-blasts into the wound. The phase of inflammation is initiated by factors in the fibrin clot, as well as PDGF and TGF-P from degranulating platelets, that attract neutrophils, monocytes and T-cells. The neutrophils and macrophages kill bacteria, degrade collagen, and debride the wound. Neutrophils die by apoptosis within a few hours after entering the wound and are removed by macrophage phagocytosis. The macrophages stay longer and initiate the phase of structural repair. Re-epithelialization begins and PDGF and TGF-P secreted by the macrophages promotes fibroblast proliferation and migration into the fibrin matrix to form granulation tissue. In mammals with loose skins, myofibroblasts appear at the edges of the wound in the early phase of structural repair and contract the skin. Granulation tissue is at first hypervascularized and hyperinnervated by the regeneration of capillaries and nerves, but these later regress. The fibroblasts of the granulation tissue are stimulated to secrete ECM by PDGF and TGF-P that replaces the fibrin clot, which is degraded. In the final stages of structural repair, the number of fibro-blasts is reduced by apoptosis and the organization of the ECM is modified. The number of elastin fibers is reduced and collagen I fibers are broken down by MMPs and cross-linked into thick bundles parallel to the skin surface by lysyl oxidase. These dense, relatively acellular bundles of collagen fibers constitute the visible scar.
Fetal mammalian skin does not scar after wounding and regenerates perfectly until late in gestation, when the response shifts to the adult scarring pattern. The fibroblasts of the fetal wound synthesize the same collagens as fibroblasts in adult wounds, but lay down the normal architecture of the ECM. This regenerative response is associated with several differences between fetal and adult skin. Fetal skin has a higher ratio of type III to type I collagen than does adult skin, sulfated PG synthesis does not accompany collagen synthesis in fetal wounds, and fetal wound fibroblasts synthesize higher levels of HA and its receptor. This in turn is associated with a minimal inflammatory response in fetal wounds. Platelets, neutrophils, and macrophages are present in very low numbers if at all, and the adult levels of the growth factors and cytokines produced by these cells are correspondingly lower, with the exception of TGF-P3, which is higher in fetal wounds. Adding adult levels of growth factors (TGF-P1 and 2) and cytokines to fetal wounds induces their scarring, whereas reducing the levels of these molecules in, or adding TGF-P3 to, adult wounds reduces scarring. These data suggest that it is possible, by manipulating the wound environment, to confer regenerative capacity on the adult dermis after excisional wounding. This notion is backed up by studies on tattooing, which injures a large area of tissue with thousands of small wounds that do not evoke an inflammatory response, and on neonatal PU.1 null mice, which lack macrophages and neutrophils. These mice repair skin wounds by regeneration, not scarring, suggesting that they fail to undergo the transition from the fetal to the adult wound healing response.
Microarray analysis of wounded versus unwounded skin is now being used in an attempt to identify all the molecular elements that are upregulated and downreg-ulated during wound repair by fibrosis. These analyses have shown that genes that are up-regulated early in wound repair are primarily genes involved in signal transduction pathways. Such comparisons could also be made between the wounded skin of wild-type and PU.1 neonatal mice, or the wounded skins of fetal and adult wild-type mice to identify what differences in gene activity characterize regenerating vs scarring skin. Coupled with bioinformatics and systems biology approaches, these data will be invaluable in providing a complete molecular description of scarring vs regenerative pathways in wounded skin.
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