The corneal fibrosis response to epithelial–stromal injury

Abstract

The corneal wound healing response, including the development of stromal opacity in some eyes, is a process that often leads to scarring that occurs after injury, surgery or infection to the cornea. Immediately after epithelial and stromal injury, a complex sequence of processes contributes to wound repair and regeneration of normal corneal structure and function. In some corneas, however, often depending on the type and extent of injury, the response may also lead to the development of mature vimentin+ α-smooth muscle actin+ desmin+ myofibroblasts. Myofibroblasts are specialized fibroblastic cells generated in the cornea from keratocyte-derived or bone marrow-derived precursor cells. The disorganized extracellular matrix components secreted by myofibroblasts, in addition to decreased expression of corneal crystallins in these cells, are central biological processes that result in corneal stromal fibrosis associated with opacity or “haze”. Several factors are associated with myofibroblast generation and haze development after PRK surgery in rabbits, a reproducible model of scarring, including the amount of tissue ablated, which may relate to the extent of keratocyte apoptosis in the early response to injury, irregularity of stromal surface after surgery, and changes on corneal stromal proteoglycans, but normal regeneration of the epithelial basement membrane (EBM) appears to be a critical factor determining whether a cornea heals with relative transparency or vision-limiting stromal opacity. Structural and functional abnormalities of the regenerated EBM facilitate prolonged entry of epithelium-derived growth factors such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) into the stroma that both drive development of mature myofibroblasts from precursor cells and lead to persistence of the cells in the anterior stroma. A major discovery that has contributed to our understanding of haze development is that keratocytes and corneal fibroblasts, but not myofibroblasts, produce large amounts of critical EBM components, such as nidogen-1, nidogen-2 and perlecan, that are essential for complete regeneration of a normal EBM once laminin secreted by epithelial cells self-polymerizes into a nascent EBM. Mature myofibroblasts that become established in the anterior stroma are a barrier to keratocyte contributions to the nascent EBM. These myofibroblasts, and the opacity they produce, often persist for months or years after the injury. Transparency is subsequently restored when the EBM is completely regenerated, myofibroblasts are deprived of TGFβ and undergo apoptosis, and the keratocytes re-occupy the anterior stroma and reabsorb disordered extracellular matrix. The aim of this review is to highlight factors involved in the generation of stromal haze and its subsequent removal.

Functional and Morphologic Alterations in Mechanical, Polymodal, and Cold Sensory Nerve Fibers of the Cornea Following Photorefractive Keratectomy

“…12 Release of cytokines, chemokines, and growth factors by injured epithelial cells and keratocytes of the anterior stroma, and by resident and migrating inflammatory cells, rapidly activates repair processes including migration and mitosis of healthy epithelial cells, nerve regrowth, and stromal healing. 13,14 Regeneration of corneal nerves after PRK occurs as a biphasic process. First, branches of the subepithelial nerve plexus at the margin of the injury site reconstruct a transient subbasal plexus composed by fine neurites that run centrally with migrating cells.…”

Long-Term Biomechanical and Histologic Results of WST-D/NIR Corneal Stiffening in Rabbits, Up to 8 Months Follow-up

“…The ability of activated keratocytes to migrate within the corneal stroma and repopulate after damage is well known. 26 Comparable keratocyte counts in the unaffected middle and posterior stroma of control and treated eyes, 1 week and 8 months after treatment, indicate that repopulation of the anterior stroma with keratocytes is independent of keratocyte counts in the middle and posterior stroma. Keratocyte repopulation may therefore begin from the periphery and follow the direction of the lamellae, rather than in posterioranterior direction.…”

Effect of Photobiomodulation on Wound Healing of the Corneal Epithelium through Rho-GTPase

“…4 Additionally, intercellular adherens and gap junctions are also lost, desmosomes are remodeled, and structural proteins and actin filaments are assembled in preparation for cellular migration. 1 The epithelial healing process is referred to as the migration phase, in which cells begin to move and cover the epithelial defect. This begins with the flattening of cells at the wound edge into a monolayer, and the formation of lamellipodia and filopodia that aid in cellular movement.…”

“…A repair system of injured corneal epithelium is delicate cross-talk of various signaling pathways for wound healing events such as proliferation, migration, adhesion, and differentiation of corneal epithelial cells. 1,2 Rapid healing of the corneal epithelium and the return of an intact basement membrane can restore the eye's normal mechanical barriers and prevent various epithelium-derived growth factors from leaking into the stroma. 3,4 Meanwhile, the use of low levels of visible or nearinfrared (NIR) light for reducing pain, inflammation, and edema, promoting healing of wounds, deeper tissues and nerves, and preventing tissue damage has been known.…”