Cytokines and growth factors are key elements in scarless wound healing

Recently, many experimental and clinical studies have demonstrated that wound healing is regulated by a panoply of cytokines, growth factors and their receptors. They influence cell migration, growth and proliferation in a complex, orchestrated manner and are involved in neutrophil and macrophage infiltration, angiogenesis, fibroplasia, matrix deposition, scarring and re-epithelialization. Besides platelets and macrophages, fibroblasts are the major cellular source of cytokines or growth factors during wound healing.

Recent data strongly suggests that scarless wound healing in fetal skin at early gestation is a result of the unique cytokine or growth factor profile. Of these, transforming growth factor-beta (TGF-ß) has been most widely studied as it is implicated in the transition between scarless healing and repair with scar formation.

Called growth factors for historical reasons, their main function is to control cell proliferation and differentiation and to stimulate the synthesis of extracellular matrix such as collagen.

Three highly homologue TGF-ß isoforms are known in humans: ß1, ß2 and ß3. Each form has been found by immunohistochemistry in unwounded fetal skin. However, low levels of TGF-ß1 and high levels of TGF-ß3 are expressed at gestational ages associated with scarless repair. In addition, it appears that the relative proportion of TGF-ß isoforms, and not the absolute concentration of any one isoform determines the wound repair outcome.

Exogenous application of TGF-ß1 to normally scarless fetal wounds resulted in scar formation [12, 13]. Moreover, an adult-like inflammatory response was observed. The profibrotic nature of TGF-ß1, and possibly TGF-ß2, was confirmed in wounds of adult rats as neutralizing TGF-ß1 and ß2 with antibodies partially reduced the amount of scarring. TGF-ß1 stimulates collagen I production, which is the predominant collagen type in adult skin. On the other hand, supplementation with TGF-ß3 reduced scarring and inflammation in adult wounds confirming its potential antifibrotic properties. The fact that scarless fetal wounds heal with little inflammation and the onset of scarring during fetal repair correlates with the presence of an acute inflammatory infiltrate [14] may be related to the pronounced anti-inflammatory properties of TGF-ß3.

On the other hand, TGF-ß1 and ß2 neutralizing antibodies do not entirely prevent scarring in the adult, and recent studies question the efficacy of TGF-ß3 in wound healing [15, 16]. This suggests that factors other than TGF-ß may also be important in scarless repair. For instance, extracellular matrix constituents fibromodulin or decorin, which are expressed as a function of gestation age in fetal skin, are known to modulate TGF-ß activity. This supports the hypothesis that differential expression of TGF-ß isoforms and TGF-ß activity modulators, rather than the mere presence or absence of TGF-ß has a role in the regulation of scarless repair.

Other growth factors differently expressed during the transition from scarless to scar-forming repair include epidermal (EGF) and platelet derived growth factor (PDGF) [17], as well as fibroblast growth factors (FGFs) [18]. High EGF levels were found in early-gestational age skin, which may help to rapidly reepithelialize after skin injury. In addition, rapid healing of fetal wounds may be also related to a higher level of vascular endothelial growth factor (VEGF) in scarless fetal wounds than in scarring fetal and adult wounds [19]. This high VEGF level may increase angiogenesis and vascular permeability early during healing.

Although known for its profibrotic role in wound healing inducing scar formation [20, 21], PDGF mRNA levels were higher in scarless wound healing. This suggests that its function may be isoform dependent and may relate in a more complex manner to the extracellular environment.

Fibroblast growth factors have a broad range of function. For example, FGF-2 (basic FGF) is a potent stimulator of angiogenesis, while FGF-5 regulates the hair cycle. FGF-7 (also known as keratinocyte growth factor 1, KGF-1) and FGF-10 (KGF-2) are produced by fibroblasts but act on keratinocytes to stimulate migration and proliferation. FGF isoforms are regulated in a complex manner during fetal skin development. Whereas some FGF isoforms did not change, FGF-7 and FGF-10 were found to be down-regulated in scarless wounds.

Summarizing, unique properties of fetal skin appear to contribute to perfect wound healing: (i) differential expression of TGF-ß isoforms together with other cytokines decreases scar formation and enhances re-epithelialization, (ii) fetal fibroblasts with high synthetic capabilities deposit collagen rapidly and scarlessly, and (iii) lack of pro-inflammatory signals may limit the inflammatory infiltrate early during healing.

Despite the great increase in knowledge gained over the past decade, the precise mechanisms of scarless healing remain unknown. Additional cytokines, growth factors or modulators, which may further participate in the complex orchestration of coordinated cellular responses leading to perfect skin repair, are currently being researched.

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