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Vivien J Coulson-Thomas, Shao-Hsuan Chang, Lung-Kun Yeh, Yvette May Coulson- Thomas, Yu Yamaguchi, Jeffrey Esko, Chia-yang Liu, Winston Kao; Loss of corneal epithelial Heparan sulfate leads to corneal degeneration and impaired wound healing. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5616.
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© ARVO (1962-2015); The Authors (2016-present)
Heparan sulfate (HS) is a highly modified glycosaminoglycan (GAG) bound to a core protein to form heparan sulfate proteoglycans (HSPGs) that are vital in many cellular processes ranging from development to adult physiology, as well as, in disease through interactions with various protein ligands. This study aimed to elucidate the role of HS on cornea epithelial homeostasis and wound healing.
An inducible quadruple transgenic mouse model was generated to excise Ext1 and Ndst1, which encode the critical HS chain elongation enzyme and N-deacetylase/N-sulfotransferase, respectively, in keratin 14 positive cells upon doxycycline induction. Animal care and use conformed to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. All animal protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Cincinnati.
Ext1∆/∆CEpi (deletion of Ext1 in cornea epithelium) mice induced at P20 presented progressive thinning of the corneal epithelium with a significant loss in the number of epithelial layers by P55. Ext1∆/∆CEpi mice present a disruption in tight junctions, loss of cell-basement membrane adhesion complexes and impaired wound healing. Interestingly, Ext1∆/∆CEpi and Ndst1∆/∆CEpi mice presented an increase in cell proliferation which was assayed by both Ki67 staining and EdU incorporation. Moreover, Ext1∆/∆CEpi mice presented compromised epithelial stratification 7 days after a debridement wound. The conditional knock-out of HS from keratocytes using the keratocan promoter lead to no corneal abnormalities or any disruption in wound healing.
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.<br /> Grant support: NIH grants EY011845, Research to Prevent Blindness, Ohio Lions' eye Research foundation.
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