The Corneal Basement Membranes and Stromal Fibrosis

Abstract

PurposeThe purpose of this review was to provide detailed insights into the pathophysiology of myofibroblast-mediated fibrosis (scarring or late haze) after corneal injury, surgery, or infection.MethodLiterature review.ResultsThe epithelium and epithelial basement membrane (EBM) and/or endothelium and Descemet's basement membrane (BM) are commonly disrupted after corneal injuries, surgeries, and infections. Regeneration of these critical regulatory structures relies on the coordinated production of BM components, including laminins, nidogens, perlecan, and collagen type IV by epithelial, endothelial, and keratocyte cells. Whether a cornea, or an area in the cornea, heals with transparency or fibrosis may be determined by whether there is injury to one or both corneal basement membranes (EBM and/or Descemet's BM) and delayed or defective regeneration or replacement of the BM. These opaque myofibroblasts, and the disordered extracellular matrix these cells produce, persist in the stroma until the EBM and/or Descemet's BM is regenerated or replaced.ConclusionsCorneal stromal fibrosis (also termed “stromal scarring” or “late haze”) occurs as a consequence of BM injury and defective regeneration in both the anterior (EBM) and posterior (Descemet's BM) cornea. The resolution of fibrosis and return of stromal transparency depends on reestablished BM structure and function. It is hypothesized that defective regeneration of the EBM or Descemet's BM allows key profibrotic growth factors, including transforming growth factor beta-1 (TGF-β1) and TGF-β2, to penetrate the stroma at sustained levels necessary to drive the development and maintenance of mature opacity-producing myofibroblasts from myofibroblast precursors cells, and studies suggest that perlecan and collagen type IV are the critical components in EBM and Descemet's BM that bind TGF-β1, TGF-β2, platelet-derived growth factor, and possibly other growth factors, and regulate their bioavailability and function during homeostasis and corneal wound healing.

Extracellular Vesicles and Cell–Cell Communication in the Cornea

“…B), thus indicating that EVs travel further than just to adjacent cells within the cornea; however, it is unknown whether the EVs are moving to a site or simply moving at random. Finally, EVs are unable to penetrate the corneal basement membrane, which agrees with multiple publications that once the basement membrane is reformed and barrier function restored, topical applications of therapeutics are unable to affect the stroma (Medeiros et al, ); however, in this study, EVs appear to penetrate Descemet's membrane (Fig. C,D).…”

Induction of Fibroblast Senescence During Mouse Corneal Wound Healing

“…However, when EBM regeneration is impaired (such as in corneal scarring, alkali burn, and PKP), TGF-b and PDGF penetrate the stroma at high levels, leading to myofibroblast development and maturation, finally causing corneal scarring or fibrosis. 53,55,56 In this study, we found that activated corneal resident fibroblasts and invading fibrocytes, both having been reported to develop into myofibroblasts, 44 underwent senescence after epithelial debridement. These senescent cells expressed vimentin and a-SMA, but a few cells expressed desmin, characteristic of a fully developed myofibroblast.…”

Fibrocytes, Wound Healing, and Corneal Fibrosis

“…78,84 Normal versus defective BM regeneration likely relates to the type and severity of the stromal injury and results from inadequate production or incorrect localization of BM components-including laminins, nidogens, perlecan, and collagen type IV. 82,91 Corneal epithelial injury triggers release of IL-1 and apoptosis of the underlying keratocytes mediated by Fas-Fas ligand system in a manner that is proportional to the size of the original injury. 92 Extensive loss of keratocytes delays BM regeneration because of a deficiency or inadequate localization of some BM components contributed by keratocytes to the EBM.…”