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Review
. 2018 Jan:166:49-55.
doi: 10.1016/j.exer.2017.10.006. Epub 2017 Oct 10.

The role of hepatocyte growth factor in corneal wound healing

Hidetaka Miyagi  1 , Sara M Thomasy  2 , Paul Russell  3 , Christopher J Murphy  4
Affiliations
Review

The role of hepatocyte growth factor in corneal wound healing

Hidetaka Miyagi et al. Exp Eye Res. 2018 Jan.

Abstract

Hepatocyte growth factor (HGF) is a glycoprotein produced by mesenchymal cells and operates as a key molecule for tissue generation and renewal. During corneal injury, HGF is primarily secreted by stromal fibroblasts and promotes epithelial wound healing in a paracrine manner. While this mesenchymal-epithelial interaction is well characterized in various organs and the cornea, the role of HGF in corneal stromal and endothelial wound healing is understudied. In addition, HGF has been shown to play an anti-fibrotic role by inhibiting myofibroblast generation and subsequent production of a disorganized extracellular matrix and tissue fibrosis. Therefore, HGF represents a potential therapeutic tool in numerous organs in which myofibroblasts are responsible for tissue scarring. Corneal fibrosis can be a devastating sequela of injury and can result in corneal opacification and retrocorneal membrane formation leading to severe vision loss. In this article, we concisely review the available literature regarding the role of HGF in corneal wound healing. We highlight the influence of HGF on cellular behaviors in each corneal layer. Additionally, we suggest the possibility that HGF may represent a therapeutic tool for interrupting dysregulated corneal repair processes to improve patient outcomes.

Keywords: Fibrosis; HGF; Myofibroblast; TGF-β; Wound healing.

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Figures

Fig. 1
Fig. 1. The Activating Process of HGF upon the Tissue Injury
Tissue injury activates the blood coagulation system leading to conversion of pro-thrombin to thrombin to form blood clots and prevent further hemorrhage. Concomitantly, thrombin activates HGFA by processing an enzymatically inactive pro-HGFA produced by hepatocytes in the liver into an active HGFA that possesses HGF-processing enzymatic activity. Therefore, HGFA represents the link between tissue injury and activation of HGF. This diagram was modified after Conway et al., 2006.
Fig. 2
Fig. 2. The Sources of HGF in the Cornea
Hepatocyte growth factor and c-Met are expressed in the corneal epithelium, stromal cells, endothelium, as well as in the lacrimal grand. The size of the HGF and c-Met icons and width of arrows represent relative contributions. In addition to its classical paracrine mechanism, this expression pattern shows that HGF has the potential to act in an autocrine manner.
Fig. 3
Fig. 3. The Role of HGF in Epithelial-Mesenchymal Crosstalk in Corneal Epithelial Wound Healing
Upon epithelial wounding, HGF mRNA is highly induced in stromal fibroblasts, while the expression of c-Met is upregulated in epithelial cells. The binding of HGF to c-Met activates the MAPK pathway via Grb2/Sos complex to the Ras or through PKC to promote epithelial wound healing. PI3K-S6K pathway mediated by PKC or Akt is another route influenced by HGF that promotes epithelial cell survival.
Fig. 4
Fig. 4. HGF represents a potential therapeutic tool to minimize corneal fibrosis
In the cornea, TGF-β induces a myofibroblast-phenotype following KFM transformation in the stroma and EMT in the endothelium, which can result in corneal fibrosis and retrocorneal membrane formation, respectively. Hepatocyte growth factor could play an antifibrotic role to counteract TGF-β promotion of myofibroblast generation by activating Smad7, an inhibitory Smad. Additionally, HGF promotes apoptosis of myofibroblasts by inducing MMPs which degrade the ECM including fibronectin, which is an essential anchor for myofibroblasts.
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