The healing process after corneal injury is initiated through the release of a number of proteins that disassemble the epithelial junctions and contribute to the movement of the epithelial sheet to cover the wounded area. Matrix metalloproteinases (MMPs), a family of proteolytic enzymes that degrade components of the cell surface and extracellular matrix, are central to this process. Barely detected in unwounded cornea, their induction is thought to play a key role during wound healing and in the establishment of chronic wounds. The production and activation of MMPs are tightly regulated by complex mechanisms that include homo-oligomerization of CD147, a heavily N-glycosylated transmembrane protein highly expressed in tumor cells. We recently discovered that CD147 is a novel cell surface counter-receptor for galectin-3, a ?alactoside-binding lectin known to cluster cell surface receptors. More importantly, we found that clustering of CD147 by galectin-3 dramatically upregulates MMP9, the primary metalloproteinase synthesized and secreted by corneal epithelial cells migrating to resurface a wound. The long-term objective of this proposal is to determine whether induction of CD147 clustering by galectin-3 is a powerful regulatory mechanism of the physiological and pathological remodeling processes associated with wound repair in the cornea. The following specific aims will address this objective: (1) to investigate te role of CD147 clustering by galectin-3 as modulator of collective cell detachment and cell migration in corneal epithelial cells, and to determine whether degradation of the galectin-3 by MMP9 inhibits CD147 clustering, thereby constituting a negative feedback mechanism to prevent sustained corneal remodeling, (2) to investigate the role of CD147 N-glycosylation in modulating galectin-3 binding affinity, CD147 clustering, and MMP9 induction, and (3) to characterize the biological role of the CD147/galectin-3 complex in mouse models of wound healing and recurrent erosion, and determine whether inhibiting galectin-3 receptor clustering and CD147 function have a therapeutic potential during recurrent epithelial wound healing. This research will explore, for the first time, the molecular mechanism linking glycan dynamics to the biological process by which wounded tissue initiates epithelial cell detachment and migration, and will provide better insight into the pathogenesis of chronic wounds.

Public Health Relevance

Clinical management of impaired or delayed re-epithelialization and associated persistent epithelial defects during corneal wound healing is a vexing problem for the ophthalmologist, particularly because current wound healing therapies are limited in efficacy. Failure of the epithelia adjacent to the denuded area to migrate properly makes the underlying cornea more susceptible to inflammation and infection. We have discovered a likely mechanism responsible for modulating re-epithelization in cornea and are evaluating its role in the development of chronic wounds.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology of the Visual System Study Section (BVS)
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Mckie, George Ann
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Schepens Eye Research Institute
United States
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Rodriguez Benavente, Maria C; Argüeso, Pablo (2018) Glycosylation pathways at the ocular surface. Biochem Soc Trans 46:343-350
Cruzat, Andrea; Gonzalez-Andrades, Miguel; Mauris, Jérôme et al. (2018) Colocalization of Galectin-3 With CD147 Is Associated With Increased Gelatinolytic Activity in Ulcerating Human Corneas. Invest Ophthalmol Vis Sci 59:223-230
McDermott, Alison M; Baidouri, Hasna; Woodward, Ashley M et al. (2018) Short Tandem Repeat (STR) Profiles of Commonly Used Human Ocular Surface Cell Lines. Curr Eye Res 43:1097-1101
AbuSamra, Dina B; Argüeso, Pablo (2018) Lectin-Glycan Interactions in Corneal Infection and Inflammation. Front Immunol 9:2338
Argüeso, Pablo (2017) Proteolytic activity in the meibomian gland: Implications to health and disease. Exp Eye Res 163:53-57
Gonzalez-Andrades, Miguel; Alonso-Pastor, Luis; Mauris, Jérôme et al. (2016) Establishment of a novel in vitro model of stratified epithelial wound healing with barrier function. Sci Rep 6:19395
Bauskar, Aditi; Mack, Wendy J; Mauris, Jerome et al. (2015) Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye. PLoS One 10:e0138958
Argüeso, Pablo; Mauris, Jerome; Uchino, Yuichi (2015) Galectin-3 as a regulator of the epithelial junction: Implications to wound repair and cancer. Tissue Barriers 3:e1026505
Mauris, J; Dieckow, J; Schob, S et al. (2015) Loss of CD147 results in impaired epithelial cell differentiation and malformation of the meibomian gland. Cell Death Dis 6:e1726