title: Hevin plays a pivotal role in corneal wound healing.
abstract: BACKGROUND
  Hevin is a matricellular protein involved in tissue repair and remodeling via interaction with the surrounding extracellular matrix (ECM) proteins. In this study, we examined the functional role of hevin using a corneal stromal wound healing model achieved by an excimer laser-induced irregular phototherapeutic keratectomy (IrrPTK) in hevin-null (hevin(-/-)) mice. We also investigated the effects of exogenous supplementation of recombinant human hevin (rhHevin) to rescue the stromal cellular components damaged by the excimer laser.
  
  
  RESULTS
  Wild type (WT) and hevin (-/-) mice were divided into three groups at 4 time points- 1, 2, 3 and 4 weeks. Group I served as naïve without any treatment. Group II received epithelial debridement and underwent IrrPTK using excimer laser. Group III received topical application of rhHevin after IrrPTK surgery for 3 days. Eyes were analyzed for corneal haze and matrix remodeling components using slit lamp biomicroscopy, in vivo confocal microscopy, light microscopy (LM), transmission electron microscopy (TEM), immunohistochemistry (IHC) and western blotting (WB). IHC showed upregulation of hevin in IrrPTK-injured WT mice. Hevin (-/-) mice developed corneal haze as early as 1-2 weeks post IrrPTK-treatment compared to the WT group, which peaked at 3-4 weeks. They also exhibited accumulation of inflammatory cells, fibrotic components of ECM proteins and vascularized corneas as seen by IHC and WB. LM and TEM showed activated keratocytes (myofibroblasts), inflammatory debris and vascular tissues in the stroma. Exogenous application of rhHevin for 3 days reinstated inflammatory index of the corneal stroma similar to WT mice.
  
  
  CONCLUSIONS
  Hevin is transiently expressed in the IrrPTK-injured corneas and loss of hevin predisposes them to aberrant wound healing. Hevin (-/-) mice develop early corneal haze characterized by severe chronic inflammation and stromal fibrosis that can be rescued with exogenous administration of rhHevin. Thus, hevin plays a pivotal role in the corneal wound healing.
authors.affiliation: Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, Singapore, Singapore ; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore ; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Chaurasia
authors.forename: Promoda R
authors.initials: PR
authors.lastname: Perera
authors.forename: Rebekah
authors.initials: R
authors.lastname: Poh
authors.forename: Rayne R
authors.initials: RR
authors.lastname: Lim
authors.forename: Tina T
authors.initials: TT
authors.lastname: Wong
authors.forename: Jodhbir S
authors.initials: JS
authors.lastname: Mehta
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D003315:Cornea / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D065306:Corneal Injuries; D003319:Corneal Stroma / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D014945:Wound Healing / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C503127:Sparcl1 protein, mouse