Introduction & aims
Authors: Pr Éric Gabison, M. Caillé and C. Tolosa Leal — ophthalmology, cornea & ocular surface. Reference course, original synthesis (2026), grounded in the team's own work.
Corneal wound healing is a tightly regulated process whose goal is not merely to close a wound, but to do so without compromising transparency or the avascular state of the cornea — what sets it radically apart from skin repair [1,2].
An injury may involve the epithelium alone, the epithelium + stroma, and more rarely the endothelium (whose regenerative capacity in humans is very limited). The healing response must restore the epithelial barrier, rebuild the stroma and preserve optical clarity, while avoiding three pitfalls: fibrosis (opacity), delayed healing (ulceration, melting) and neovascularization.
The thread of this course is a permanent epithelial–stromal dialogue: it steers repair toward transparent regeneration or toward fibrosis. We follow the physiology (epithelial then stromal repair), the pathological situations (persistent epithelial defect, haze, ulceration and direct epithelial–stromal interactions), then the corneal angiogenic privilege and its breakdown.
Repairing the cornea means winning three bets at once: fast, transparent, vessel-free. The key to the outcome is when the epithelium and its basement membrane reform: while they remain open, stromal signals (TGF-β, PDGF, MMPs) sustain fibrosis and melting [2,3].
Epithelial healing & the barrier
The first step after an epithelial injury is the removal of necrotic cells, aided by the tear film and blinking. Within minutes, edge cells form a migration front and move centripetally at about 60–80 µm/h. The classic kinetics combine a sliding phase (migration, no mitosis) then a proliferation phase restoring epithelial thickness [2,10].
Mechanics of migration
To advance, cells disassemble their hemidesmosomes (integrin α6β4) via metalloproteinases, anchor to the stroma through focal adhesions mediated by integrins (α5β1 for fibronectin), while actin cables linked by adherens junctions drive collective migration. They rely on a provisional matrix rich in fibrin, fibronectin and hyaluronic acid, and on growth-factor flux (EGF, HGF, KGF) partly derived from the underlying stroma — the first illustration of epithelial–stromal coupling [2,4].
Basement membrane: the conductor
Once the basal layer is restored, a new epithelial basement membrane (EBM) is synthesized (laminins 511/521, then perlecan, nidogens, collagen IV) and matures over ~6 weeks. Its reformation is more than anchorage: it regulates cytokine passage to the stroma. In Wilson's model, EBM regeneration is the true switch that ends the TGF-β/PDGF inflow and hence fibrosis [3]. Note that Bowman's layer does not regenerate, with no notable functional consequence.
A healthy basement membrane, adequate vitamin A, good-quality tears and a cornea that keeps its sensation: if any one of these four supports is missing, epithelial closure lags.
Barrier function & tight junctions (occludin)
Beyond healing, the epithelium forms a barrier through its apical tight junctions, of which occludin is a key component. Our work showed that the metalloproteinase inducer EMMPRIN/CD147 regulates surface occludin by modulating MMP-9 expression: an inverse correlation between EMMPRIN and occludin already exists physiologically, along epithelial differentiation (Huet et al., Am J Pathol 2011). CD147 thus emerges as a regulator of epithelial organization, not only a disease player.
Epithelial renewal & limbal stem cells
The epithelium renews continuously from limbal stem cells, following Thoft's “XYZ” scheme: basal proliferation (X), centripetal migration (Y), surface desquamation (Z). The speed of this turnover governs surface homeostasis and the fate of the epithelium after transplantation.
Our work quantified this turnover. Combining corneal impression cytology with FISH on sex-mismatched grafts lets one trace the origin — donor or recipient — of each cell. Across 24 samples (21 grafted patients), mosaicism was found in 13 cases, showing donor-derived cells at the graft centre for at least 211 days; Kaplan–Meier analysis put their median survival at 385 days — over a year (Catanese et al., IOVS 2011).
Contrary to the idea that recipient epithelium quickly replaces the graft, these data show prolonged survival of donor cells — thus slow renewal at the corneal centre — with topical 2% cyclosporine tending to further delay their loss (non-significant trend). Immunomodulation therefore influences post-graft epithelial homeostasis.
Stromal healing: keratocytes, cytokines & myofibroblasts
The stroma makes up most of the corneal thickness; its transparency depends on an orderly collagen array and on the quiescent phenotype of keratocytes. Its healing may be regenerative (transparent) or fibrotic (opaque), and its direction depends directly on re-epithelialization and basement-membrane reformation [3,5].
Three phases of stromal repair
A destruction phase (neutrophils, macrophages, collagenases), a synthesis phase (collagen and proteoglycan deposition by fibroblasts), then a remodeling phase that reorganizes the matrix to recover transparency.
Keratocyte apoptosis & the acellular zone
When the epithelial barrier breaks, epithelial cells release IL-1α/β which, binding neighbouring keratocytes, trigger their apoptosis (relayed by TNF-α, PAF and soluble FasL). A transient acellular zone forms: this redundancy of pro-apoptotic signals is thought to limit stromal (notably viral) invasion and to reduce the pool of future myofibroblasts [6].
From keratocyte to myofibroblast
Surviving keratocytes become fibroblasts (migrating within 24 h), proliferate, then differentiate into myofibroblasts under TGF-β (Smad pathway) and PDGF — factors normally kept away from the stroma by the basement membranes. Some myofibroblasts also arise from circulating bone-marrow fibrocytes [14]. Identified by α-SMA stress fibres, the myofibroblast is strongly contractile, lays down abundant matrix… and scatters light. In humans, maturation takes 1–4 months [5,2].
Epithelium-derived extracellular vesicles (exosomes), when they cross a damaged basement membrane, also contribute to keratocyte-to-myofibroblast conversion [11].
In normal healing, the epithelium and its basement membrane reform before myofibroblast progenitors mature. The resulting TGF-β drop restores IL-1 sensitivity: they undergo apoptosis before producing disorganized matrix. This timing allows opacity-free repair, under an MMP / TIMP balance [5,6].