Loss of Corneal Epithelial Heparan Sulfate Leads to Corneal Degeneration and Impaired Wound Healing

Coulson‐Thomas, Vivien Jane; Chang, Shao-Hsuan; Lung-Kun, Yeh; Coulson-Thomas, Yvette M.; Yamaguchi, Yu; Liu, Chia-Yang; Kao, Winston Whei‐Yang

doi:10.1167/iovs.14-15341

Cited by 39 publications

(37 citation statements)

References 42 publications

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“…Similar findings were observed in the absence and presence of HSV-1, with infection causing a further delay in wound healing. Additional support comes from recent work showing that genetic depletion of heparan sulfate caused impaired corneal wound healing in mice (Coulson-Thomas et al, 2015). As such, our observations indicate that HPSE has a previously unknown role in epithelial cell migration and corneal pathology.…”

Section: Resultsmentioning

confidence: 93%

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

et al. 2017

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Summary Herpes simplex virus type-1 (HSV-1) causes lifelong recurrent pathologies without a cure. How infection by HSV-1 triggers disease processes, especially in the immune-privileged avascular human cornea, remains a major unresolved puzzle. It has been speculated that a cornea-resident molecule must tip the balance in favor of pro-inflammatory and pro-angiogenic conditions observed with herpetic as well as non-herpetic ailments of the cornea. Here, we demonstrate that heparanase (HPSE), a host enzyme, is the molecular trigger for multiple pathologies associated with HSV-1 infection. In human corneal epithelial cells, HSV-1 infection upregulates HPSE in a manner dependent on HSV-1 infected cell protein 34.5. HPSE then relocates to the nucleus to regulate cytokine production, inhibits wound closure, enhances viral spread, and thus generates a toxic local environment. Overall, our findings implicate activated HPSE as a driver of viral pathogenesis, and call for further attention to this host protein in infection and other inflammatory disorders.

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Section: Resultsmentioning

confidence: 93%

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

et al. 2017

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“…However, these mice presented no stromal phenotype (Coulson‐Thomas et al . ). Keratocan expression during mouse corneal development starts around embryonic day 12, and Ext1 expression would therefore only be ablated from the keratocytes of these mice approximately around embryonic day 13.…”

Section: The Role Of Heparan Sulphate In the Development Of Ectodermamentioning

confidence: 97%

“…However, the important role HS plays in corneal epithelial development was clearly demonstrated using K14rtTA;TetOcre removing Ext1 from keratin 14 + cells (corneal epithelial cells) (Coulson‐Thomas et al . ). We have recently demonstrated that HS is essential for corneal epithelial stratification (Coulson‐Thomas et al .…”

Section: The Role Of Heparan Sulphate In the Development Of Ectodermamentioning

confidence: 97%

“…We have recently demonstrated that HS is essential for corneal epithelial stratification (Coulson‐Thomas et al . ). The loss of epithelial HS in the cornea leads to a loss of tight junctions, culminating in corneal dysgenesis (Coulson‐Thomas et al .…”

Section: The Role Of Heparan Sulphate In the Development Of Ectodermamentioning

confidence: 97%

“…The loss of epithelial HS in the cornea leads to a loss of tight junctions, culminating in corneal dysgenesis (Coulson‐Thomas et al . ).…”

Section: The Role Of Heparan Sulphate In the Development Of Ectodermamentioning

confidence: 97%

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The role of heparan sulphate in development: the ectodermal story

Coulson‐Thomas

2016

Int J Experimental Path

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SUMMARYHeparan sulphate (HS) is ubiquitously expressed and is formed of repeating glucosamine and glucuronic/iduronic acid units which are generally highly sulphated. HS is found in tissues bound to proteins forming HS proteoglycans (HSPGs) which are present on the cell membrane or in the extracellular matrix. HSPGs influence a variety of biological processes by interacting with physiologically important proteins, such as morphogens, creating storage pools, generating morphogen gradients and directly mediating signalling pathways, thereby playing vital roles during development. This review discusses the vital role HS plays in the development of tissues from the ectodermal lineage. The ectodermal layer differentiates to form the nervous system (including the spine, peripheral nerves and brain), eye, epidermis, skin appendages and tooth enamel.

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Effect of a Matrix Therapy Agent on Corneal Epithelial Healing After Standard Collagen Cross-linking in Patients With Keratoconus

et al. 2016

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IMPORTANCE Corneal abrasions are frequent after standard (epithelium-off [epi-off]) corneal collagen cross-linking (CXL) in patients with progressive keratoconus. A new matrix therapy agent (ReGeneraTing Agent [RGTA]) has been developed to promote corneal wound healing. OBJECTIVE To assess the effect of the new type of matrix therapy agent on corneal wound healing after epi-off CXL in patients with keratoconus. DESIGN, SETTING, AND PARTICIPANTS This double-masked randomized clinical trial enrolled 40 patients with keratoconus undergoing epi-off CXL from July 18, 2014, to October 21, 2015, when the last follow-up was completed. The analysis of the intention-to-treat population was performed at the Department of Clinical Pharmacology in cooperation with the Center for Medical Physics and Biomedical Engineering and the Department of Ophthalmology and Optometry of the Medical University of Vienna. INTERVENTIONS Patients were randomized to receive the matrix therapy agent or hyaluronic acid-containing eyedrops, 0.1%, every other day starting immediately after surgery. The size of the corneal defect was measured using ultrahigh-resolution optical coherence tomography (OCT) and slitlamp photography (SLP) with fluorescein staining. MAIN OUTCOMES AND MEASURES Corneal wound healing rate, defined as the size of the defect over time. RESULTS Among the 40 patients undergoing epi-off CXL (31 men; 9 women; mean [SD] age, 31 [10] years), wound healing was significantly faster in the matrix therapy agent group compared with the hyaluronic acid group (4.4 vs 6.1 days; mean difference, 1.7 days; 95% CI, 0.25-3.15 days; P = .008). The defect size was smaller in the matrix therapy agent group than in the hyaluronic acid group as measured with OCT (12.4 vs 23.9 mm 2 ; mean difference, 11.6 mm 2 ; 95% CI, 0.8-23.5 mm 2 ; P = .045) and SLP (11.9 vs 23.5 mm 2 ; mean difference, 11. 6 mm 2 ; 95% CI, 1.3-22.9 mm 2 ; P = .03). A correlation between the defect size measured with OCT and SLP was found (r = 0.89; P < .001). No ocular or serious adverse events occurred. CONCLUSIONS AND RELEVANCE Use of a new matrix therapy agent appears to improve corneal wound healing after CXL in patients with keratoconus. Monitoring of corneal wound healing using ultrahigh-resolution OCT might be an attractive alternative to SLP because OCT provides an objective and 3-dimensional evaluation of the corneal defect. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02119039

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Loss of Corneal Epithelial Heparan Sulfate Leads to Corneal Degeneration and Impaired Wound Healing

Abstract: Corneal epithelial cells require HS for maintaining corneal homeostasis, and the loss of epithelial HS leads to both impaired wound healing and impaired corneal stratification.

Cited by 39 publications

References 42 publications

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

The role of heparan sulphate in development: the ectodermal story

Effect of a Matrix Therapy Agent on Corneal Epithelial Healing After Standard Collagen Cross-linking in Patients With Keratoconus

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