Deconstructing fibrosis research: do pro-fibrotic signals point the way for chronic dermal wound regeneration?

Abstract

Chronic wounds are characterized by inadequate matrix synthesis, no re-epithelialization, infection and ultimately no wound resolution. In contrast, fibrosis is characterized by overproduction of matrix and excess matrix contraction. As research in the fields of chronic wounds and fibrosis surges forward, important parallels can now be drawn between the dysfunctions in fibrotic diseases and the needs of chronic wounds. These parallels exist at both the macroscopic level and at the molecular level. Thus in finding the individual factors responsible for the progression of fibrotic diseases, we may identify new therapeutic targets for the resolution of chronic wounds. The aim of this review is to discuss how recent advances in fibrosis research have found a home in the treatment of chronic wounds and to highlight the benefits that can be obtained for chronic wound treatments by employing a translational approach to molecules identified in fibrosis research.

Fig. 1

Acute wound repair consists of three overlapping phases: inflammation, proliferative and remodeling. The inflammation phase is dominated by neutrophils and macrophages, which serve to remove foreign debris, bacteria and damaged tissue. The proliferative phase includes the formation of granulation tissue and reduced inflammatory signals. The dominant cell types are fibroblasts and myofibroblasts. Matrix turnover and contraction are key features of this phase. The remodeling phase serves to rearrange and strengthen the newly formed tissue, producing a matrix-dense, relatively acellular, scar. Development of chronic wounds and fibrotic lesions are both driven by increased inflammation. However, in chronic wounds sustained inflammation and failed progression to proliferative and remodeling phases results (A). Fibrosis results from failure of the remodeling process to terminate at an appropriate point. Instead, continued matrix secretion and contraction by myofibroblasts results in excessive scarring (B)

Fig. 2

Cannonical pro-fibrotic TGFβ signaling is initiated by the binding of active TGFβ to TGFβ receptors. Type I receptors phosphorylate receptor-Smads 2 and 3, which associate with Smad4 and translocate to the nucleus. In the nucleus the Smad complex interacts with Smad binding elements, promoting gene expression. Among the many genes influenced by TGFβ signaling are collagens I and III, α-SMA, fibronectin, TIMPs and periostin. Additionally, increased Smad7 expression creates a negative feedback loop, limiting pathway activation. The pro-fibrotic roles of periostin are summarized here. Via interactions with the ECM and BMP-1, periostin facilitates collagen crosslinking through activation of lysyl oxidase. Periostin’s influences on cell behaviours include altered proliferation, migration and adhesion. Recent evidence suggests that periostin plays a role in liberation of TGFβ from the latency-associated proteins in an MMP-2/9 dependent manner

Fig. 3

Domain structures of human periostin. Human full length periostin (isoform 1) consists of a typical signal peptide (SP) sequence, an EMI domain responsible for binding to fibronectin, four tandem fasciclin-like domains that are responsible for integrin binding and a C-terminal region (CTR) where multiple splice variants originate. Tryptophan 65 within the EMI domain is required for fibronectin binding. The CTR has been shown to inhibit binding of periostin to several binding partners. Numbers represent amino acid residues flanking each domain