Chicago — Mimicking the wound healing environment in embryonic skin may allow adult skin to heal scar-free, according to Mark Ferguson, D.D.S., Ph.D., professor in the faculty of life sciences at the University of Manchester, England, and chief executive officer of Renovo Ltd. Dr. Ferguson summarized research in this field at the 15th Annual Meeting of the Wound Healing Society. Wounds in early mammalian embryos heal without scar formation. During development, the embryo gradually loses this ability and transitions to an adult wound healing response. "Mammalian embryos in approximately the first half of gestation heal their wounds with absent scarring, but in the later stages of gestation and neonatal life, scarring is present," Dr. Ferguson tells Cosmetic Surgery Times. "Scarring is often worse in children and teenagers, due to their enhanced inflammatory response, whilst the quality of scarring in people over 65 years is often improved as a result of an altered inflammatory and immune response at the wound site." To gain insights into the mechanisms underlying scar-free wound healing, researchers have analyzed the differences in cellular and molecular responses to wounding in embryonic and adult wound healing models.Scar formation To restore the barrier function of the skin as quickly as possible, closure of skin wounds and repair of missing skin tissue occur rapidly in adult skin by a mechanism that leads to scarring. In normal skin formation or in skin regeneration without scarring, extracellular matrix is formed with the collagen bundles deposited in a basketweave pattern. By contrast, when granulation tissue forms in wound healing, collagen bundles are laid down in parallel bundles between the margins of the wound. The abnormal architecture of the collagen bundle deposition creates tissue of weaker tensile strength and produces the characteristic scar. Scarless healing Two major differences between embryo and adult are critical in understanding the molecular and cellular environments of scar-free versus scarring mechanisms of wound healing. First, the immune system of an embryo is not fully developed. Consequently, the repertoire of inflammatory cells, the extent of inflammatory cell differentiation and the duration of the inflammatory response in embryonic skin are all considerably diminished compared to adult skin. Second, the embryo is undergoing rapid growth and differentiation, stimulated by exposure to growth factors and cytokines at levels and combinations not seen in adults. Embryonic and adult wounds differ significantly in the levels and isoforms of cytokines and growth factors detected in the wound environment, such as transforming growth factor beta (TGF-Beta), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF). In embryos, the cytokine and growth factor repertoire in the wound environment is derived from fibroblasts and keratinocytes, whereas in adults it is derived from platelets and inflammatory cells. Embryonic cells express high levels of the TGF-Beta3 isoform, derived from keratinocytes and fibroblasts, and low levels of the TGF-Beta1 and TGF-Beta2 isoforms, derived from degranulating platelets and inflammatory cells in adult wounds. FGF is expressed at high levels in embryos, but PDGF expression is not detected. By contrast, TGF-Beta1, TGF-Beta2 and PDGF expression is high in adult wounds, with little if any expression of TGF-Beta3 or FGF. Studies of wound healing in animal models suggest a possible therapeutic role for TGF-Beta isoforms. Wound healing studies in rodents have shown that neutralization of TGF-Beta1 and TGF-Beta2 by antibodies markedly improves scarring. Similarly, wounds heal with less scarring following topical application of mannose-6-phosphate, which inhibits activation of TGF-Beta1 and of TGF-Beta2. By contrast, addition of exogenous TGF-Beta3 improves scarring in rodent models, and TGF-Beta3 deficiency in heterozygous null knockout mice results in impaired healing with scar formation. Scar formation is the final event in the wound healing process, and scars are not considered stable and mature until several weeks post-wounding. Nevertheless, the first 48 hours appears to be critical in determining the scar outcome. Best results were obtained in animal models when interventions were made within this window. A possible explanation is that the small number of master signaling molecules in the initial cytokine cascade triggered by the wound healing process can profoundly affect the levels and ratios of inflammatory cells and growth factors recruited to the wound site. In addition, the recruited cells influence the receptor profiles on the target cells, further affecting the wound healing response and subsequent scar formation. |
