Direct epithelial–stromal interaction in corneal wound healing: Role of EMMPRIN/CD147 in MMPs induction and beyond Eric E. Gabison a, b, c, * , Eric Huet a , Christophe Baudouin c , Suzanne Menashi a a CNRS UMR 7149, Universite´ Paris 12, Cre ´teil, France b Department of Ophthalmology, AP-HP, Ho ˆpital Bichat, APHP, Paris, France c UMRS968, INSERM UPMC, Vision Institute, Paris, France abstract In the cornea, the epithelium and the underlying stroma are separated by the basement membrane and Bowman’s layer. The disruption of these anatomical barriers during wound healing represents a key step which initiates tissue remodeling through the modification of the epithelial–stromal interactions (ESI). Diffusible cytokines are generally viewed as central modulators in the bidirectional communi- cation between these epithelial and stromal compartments and their implication in all stages of the wound healing process has been an active area of research for many years. Our studies which aimed to explore mechanisms of matrix degradation in pathological corneal wound healing have shown that EMMPRIN, a glycoprotein expressed on corneal epithelial cell surface, can induce matrix metal- loproteinase (MMP) production and myofibroblasts differentiation after direct interaction with corneal fibroblasts. EMMPRIN appears therefore as a potential mediator of ESI by direct cell–cell contact which represents a new mechanism for dysregulated MMPs’ induction observed in corneal ulcerations. These direct epithelial–stromal interactions (direct-ESI) can occur when delayed epithelial healing prevents regeneration of the basement membrane and allows the two cell types to come into close proximity. We propose that prevention of these interactions through inhibition of EMMPRIN may represent a promising therapeutic strategy in the inhibition of MMP induction in ulceration. Ó 2008 Elsevier Ltd. All rights reserved. Contents 1. Introduction ....................................................................................................................... 20 2. Background: cytokine mediated epithelial–stromal interactions (ESI) in the cornea ........................................................ 20 2.1. ESI in physiology: questioning basement membrane permeability ................................................................... 20 2.2. ESI in fibrosis ................................................................................................................ 21 2.3. ESI in ulcerations ............................................................................................................ 21 3. EMMPRIN as a mediator of direct epithelial–stromal interactions ........................................................................ 22 3.1. EMMPRIN in pathology ........................................................................................................ 22 3.2. Role of EMMPRIN in the induction of MMPs through direct-ESI in corneal ulcerations ................................................ 23 3.3. EMMPRIN and myofibroblast differentiation ..................................................................................... 24 4. Interplay between EMMPRIN, IL1 and TGFb in corneal stromal remodeling: melts versus fibrosis ............................................ 25 5. Protection against direct-ESI mediated corneal melts: hypothesis ........................................................................ 28 5.1. Corneal basement membrane and the Bowman layer as barriers against direct-ESI ................................................... 28 5.2. Additional role for stromal cells’ apoptosis as a dynamic barrier to the healing epithelium? ....................... .................... 30 6. Conclusions and future directions ..................................................................................................... 31 Acknowledgments .................................................................................................................. 31 References ......................................................................................................................... 31 * Corresponding author. UMRS968, INSERM UPMC, Vision Institute, Paris, France. E-mail address: egabison@free.fr (E.E. Gabison). Contents lists available at ScienceDirect Progress in Retinal and Eye Research journal homepage: www.elsevier.com/locate/prer 1350-9462/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.preteyeres.2008.11.001 Progress in Retinal and Eye Research 28 (2009) 19–33