RT Journal Article
A1 Coulson-Thomas, Vivien Jane
A1 Chang, Shao-Hsuan
A1 Yeh, Lung-Kun
A1 Coulson-Thomas, Yvette May
A1 Yamaguchi, Yu
A1 Esko, Jeffrey
A1 Liu, Chia-Yang
A1 Kao, Winston
T1 Loss of Corneal Epithelial Heparan Sulfate Leads to Corneal Degeneration and Impaired Wound Healing
JF Investigative Ophthalmology & Visual Science
JO Invest. Ophthalmol. Vis. Sci.
YR 2015
DO 10.1167/iovs.14-15341
VO 56
IS 5
SP 3004
OP 3014
SN 1552-5783
AB    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 in corneal 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.    EXTΔ/ΔCEpi mice (deletion of Ext1 in corneal epithelium) induced at P20 presented progressive thinning of the corneal epithelium with a significant loss in the number of epithelial layers by P55. EXTΔ/ΔCEpi mice presented tight junction disruption, loss of cell–basement membrane adhesion complexes, and impaired wound healing. Interestingly, EXTΔ/ΔCEpi and NDSTΔ/ΔCEpi mice presented an increase in cell proliferation, which was assayed by both Ki67 staining and 5-ethynyl-2′-deoxyuridine (EdU) incorporation. Moreover, EXTΔ/ΔCEpi mice presented compromised epithelial stratification 7 days after a debridement wound. The conditional knockout of HS from keratocytes using the keratocan promoter led 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.  
RD 4/19/2021
UL https://doi.org/10.1167/iovs.14-15341