FIG. 1. Schematic representation of different stages of wound repair. A: 12–24 h after injury the wounded area is filled with a blood clot. Neutrophils have invaded into the clot. B: at days 3–7 after injury, the majority of neutrophils have undergone apoptosis. Instead, macrophages are abundant in the wound tissue at this stage of repair. Endothelial cells migrate into the clot; they proliferate and form new blood vessels. Fibroblasts migrate into the wound tissue, where they proliferate and deposit extracellular matrix. The new tissue is called granulation tissue. Keratinocytes proliferate at the wound edge and migrate down the injured dermis and above the provisional matrix. C: 1–2 wk after injury the wound is completely filled with granulation tissue. Fibroblasts have transformed into myofibroblasts, leading to wound contraction and collagen deposition. The wound is completely covered with a neoepidermis.
FIG. 2. Epidermal growth factor (EGF; A) and vascular endothelial growth factor (VEGF; B) family members and their receptors. Upon ligand binding, receptors form homo- or heterodimers. Note the lack of a ligand for HER2 homodimers. However, this receptor binds the ligand of a partner upon heterodimerization.
FIG. 3. Activation of Smad proteins by transforming growth factor (TGF)- receptors. TGF- is first produced as an inactive precursor that binds to latency-associated protein (LAP). The latter is covalently bound to latent TGF- binding protein (LTBP). Upon activation, TGF- is either sequestered by extracellular binding proteins (decorin, fibromodulin) or it binds to a type III receptor that presents it to the signal-transducing receptors (type II and type I). Upon ligand binding, TGF- type II receptor recruits and phosphorylates the type I receptor. The latter subsequently binds and phosphorylates Smad2 and Smad3. Phosphorylated Smad2 and Smad3 bind to Smad4 and translocate to the nucleus where they bind to other transcription factors that confer specificity, leading to activation of target genes. Other signaling pathways that are also used by the TGF- receptor (282) are not included in the figure.
FIG. 4. Multiple functions of TGF- during wound healing. Upon local hemorrhage, TGF- is released in large amounts from platelets. In the healing wound, it is produced by leukocytes, macrophages, fibroblasts, and keratinocytes and acts on these cells to stimulate infiltration of inflammatory cells, fibroplasia, matrix deposition, and angiogenesis. In contrast, endogenous TGF- has been shown to inhibit reepithelialization.
FIG. 5. Growth factor interactions at the wound site. A: regulation of fibroblast growth factor (FGF) 7 at the wound site—hypothetical model. Local hemorrhage causes extravasation of platelets and their release of PDGF and EGF. These mitogens stimulate FGF7 expression in fibroblasts. In addition, invading neutrophils and macrophages secrete the proinflammatory cytokines IL-1 and TNF- which then cause a further induction of FGF7 expression in fibroblasts. Finally, IL-1 and TGF- derived from keratinocytes also stimulate FGF7 expression in fibroblasts. B: regulation of VEGF expression at the wound site—hypothetical model. Local hemorrhage causes extravasation of platelets and their release of TGF-. Invading macrophages also secrete this growth factor, together with the proinflammatory cytokines IL-1 and TNF-. These factors stimulate VEGF expression in keratinocytes and macrophages. In addition, FGF7 and hepatocyte growth factor (HGF) derived from fibroblasts as well as keratinocyte-derived TGF- stimulate VEGF expression in the epidermis.