Abstract
Corneal epithelial wound repair involves the migration of epithelial cells to cover the defect followed by the proliferation of the cells to restore thickness. Heparan sulfate proteoglycans (HSPGs) are ubiquitous extracellular molecules that bind to a plethora of growth factors, cytokines, and morphogens and thereby regulate their signaling functions. Ligand binding by HS chains depends on the pattern of four sulfation modifications, one of which is 6-O-sulfation of glucosamine (6OS). SULF1 and SULF2 are highly homologous, extracellular endosulfatases, which post-synthetically edit the sulfation status of HS by removing 6OS from intact chains. The SULFs thereby modulate multiple signaling pathways including the augmentation of Wnt/ß-catenin signaling. We found that wounding of mouse corneal epithelium stimulated SULF1 expression in superficial epithelial cells proximal to the wound edge. Sulf1−/−, but not Sulf2−/−, mice, exhibited a marked delay in healing. Furthermore, corneal epithelial cells derived from Sulf1−/− mice exhibited a reduced rate of migration in repair of a scratched monolayer compared to wild-type cells. In contrast, human primary corneal epithelial cells expressed SULF2, as did a human corneal epithelial cell line (THCE). Knockdown of SULF2 in THCE cells also slowed migration, which was restored by overexpression of either mouse SULF2 or human SULF1. The interchangeability of the two SULFs establishes their capacity for functional redundancy. Knockdown of SULF2 decreased Wnt/ß-catenin signaling in THCE cells. Extracellular antagonists of Wnt signaling reduced migration of THCE cells. However in SULF2- knockdown cells, these antagonists exerted no further effects on migration, consistent with the SULF functioning as an upstream regulator of Wnt signaling. Further understanding of the mechanistic action of the SULFs in promoting corneal repair may lead to new therapeutic approaches for the treatment of corneal injuries.
Highlights
The corneal epithelium, like other epithelial barriers, encounters physical, chemical, and pathogen insults, often resulting in a wound and a loss of barrier functions
Sulf1 expression increases in wounded mouse cornea Sulf12/2 and Sulf22/2 mice have been generated in a number of labs [22,28,29,30], but ocular phenotypes have not been reported
To first explore whether the SULFs might be involved in corneal wound repair, a pilot experiment was carried out to determine the expression of Sulf transcripts in needle-scratched mouse corneas
Summary
The corneal epithelium, like other epithelial barriers, encounters physical, chemical, and pathogen insults, often resulting in a wound and a loss of barrier functions. Healing of the corneal epithelium begins with superficial cells adjacent to the wound migrating as a sheet to resurface the defect [1,2,3]. Cytokines, morphogens, and ECM proteins, derived either from the epithelium or the underlying stromal layer, have been implicated in the regulation of migration and proliferation of the epithelial cells during corneal repair (reviewed in [2,7]). HSPGs are comprised of heparan sulfate chains, which are covalently linked to a restricted number of core proteins [13]. HSPGs bind to an enormous number of growth factors, morphogens, cytokines, matrix proteins, enzymes, and cell adhesion molecules. Ligand binding by HSPGs generally depends on the structure of the heparan sulfate chains, in particular the density and pattern of sulfation modifications
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