Scarring Skin: Mechanisms and Therapies

Abstract

Skin injury always results in fibrotic, non-functional scars in adults. Although multiple factors are well-known contributors to scar formation, the precise underlying mechanisms remain elusive. This review aims to elucidate the intricacies of the wound healing process, summarize the known factors driving skin cells in wounds toward a scarring fate, and particularly to discuss the impact of fibroblast heterogeneity on scar formation. To the end, we explore potential therapeutic interventions used in the treatment of scarring wounds.

Keywords: fibroblast heterogeneity; scar formation; scar treatments.

Figure 1

Cross-talk between fibroblasts and immune cells. Upon injury, immune cells, such as macrophages, are activated to release cytokines, including PDGF, TGF-β, and IL-4/IL-13. IL-4/IL-13 acts on fibrocytes and induces fibrocytes differentiation into fibroblasts, such as Postn⁺ fibroblasts, via the activation of ROCK/Rho signaling. TGF-β acts on fibroblasts and promotes fibroblast differentiation into different lineages of myofibroblasts, such as En1⁺, Lrrc15⁺, or Adam12⁺ fibroblasts. The activated fibroblasts and myofibroblasts subsequently generate elevated levels of collagens and other ECM components that play a pivotal role in the process of scar formation. Arrows demonstrate the levels of En1⁺, Postn, Lrrc15⁺, or Adam12⁺ are increased.

Figure 2

Signaling pathways involved in the induction of profibrotic gene expression. TGF-β1 binds to TGFβRII and then recruits and activates TGFβRI. The resulting signal transduction induces the phosphorylation of Smad2 and Smad3. Phosphorylated Smam2 and Smad3 complex with Smad4 to enter the nuclei, and then positively regulate the expression of Postn, α-SMA, type I collagen, and a tissue inhibitor of metalloproteinase (TIMP) but inhibits the expression of metalloproteases in fibroblasts. IL-4 and IL-13 bind to their receptor IL-4R and then activate JAK and Erk, which results in the expression of periostin (Postn) in fibroblasts. Postn, in turn, acts on fibroblasts to induce TGF-β1 secretion via the activation of the Itgb3/Itgav-RhoA/ROCK pathway. Secreted TGF-β1 further stimulates the production and secretion of periostin and other profibrotic genes, thus exacerbating scar formation.