Overview of the Cornea

Structure, Function, and Development

Allen O. Eghrari; S. Amer Riazuddin; John D. Gottsch1    Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
1 Corresponding author: email address: jgottsch@jhmi.edu

Abstract

The cornea is a transparent tissue with significant refractive and barrier functions. The epithelium serves as the principal barrier to fluid and pathogens, a function performed through production of tight junctions, and constant repopulation through differentiation and maturation of dividing cells in its basal cell layer. It is supported posteriorly by basement membrane and Bowman's layer and assists in maintenance of stromal dehydration. The stroma composes the majority of corneal volume, provides support and clarity, and assists in ocular immunity. The posterior cornea, composed of Descemet membrane and endothelium, is essential for stromal dehydration, maintained through tight junctions and endothelial pumps. Corneal development begins with primitive formation of epithelium and lens, followed by waves of migration from cells of neural crest origin between these two structures to produce the stroma and endothelium. Descemet membrane is secreted by the latter and gradually thickens.

Keywords

Cornea

Corneal development

Corneal structure

Epithelium

Stroma

Descemet membrane

Endothelium

1 Structure

The human cornea is an avascular tissue that measures approximately 11.5 mm horizontally and 10.5 mm vertically. Its relative transparency, with average refractive index of 1.3375, and anterior radius of curvature centrally of 7.8 mm makes this tissue responsible for three-fourths of the total refractive power of the human eye.

1.1 Epithelium

The corneal epithelium is composed of four to six layers of nonkeratinized, stratified squamous epithelial cells, and in humans, it measures approximately 50 µm in thickness.

The most superficial two to three layers are flat and polygonal in shape1 with apical microvilli and microplicae, and covered by a charged glycocalyx,2 which maximizes surface area with the mucinous layer of the tear film. At the cell periphery, tight junctions provide a watertight seal and assist in the prevention of pathogenic organisms from entering the cornea.

Directly posterior, the wing or suprabasal cells contribute a two- to three-cell thick layer and also demonstrate tight junction complexes between cells.

Basal epithelial cells represent the posterior-most layer of the corneal epithelium. Perilimbal basal epithelial cells differentiate and migrate anteriorly to repopulate the cornea; microvilli appear on the surface gradually during this process of maturation. Basal epithelial cells utilize hemidesmosomes to adhere to the underlying basement membrane and underlying stroma. The hemidesmosome, anchoring fibril, and anchoring filament complex produce an anchoring complex, which represents a common link between the intracellular cytoskeleton of the basal epithelial cell and the stroma posteriorly.3

1.2 Epithelial Basement Membrane

The epithelial basement membrane lies posterior to the epithelium and anterior to the corneal stroma and is laid down by basal epithelial cells. Transmission electron microscopy reveals an anterior lamina lucida and posterior lamina densa, visible through transmission electron microscopy.4

While the lamina lucida is structured with laminins, the lamina densa is largely composed of collagens, laminin, heparan sulfate proteoglycans, and nidogens.5 Immunohistochemical studies reveal a heterogeneously distributed regional variation of collagen IV subtypes dependent on its location in the central or peripheral cornea; these subtypes are composed of heterotrimers from six alpha chains.5,6

Laminin is the most frequent protein besides collagen and is also composed of heterotrimers, with one alpha, one beta, and one gamma chain. Structurally, it self-assembles into sheets and contributes to the embryological development of the epithelial basement membrane. Expression of laminin subunits varies over time during development,7 and knockouts demonstrate severe dysfunction.8

The major heparan sulfate proteoglycan is perlacan, a protein distributed in basement membranes throughout the body which mediates migration, proliferation, and differentiation of other cells.4 Keratinocyte survival and differentiation are regulated by perlacan, which has been shown to be critical for the formation of epidermis,9 and upregulated after corneal stromal injury.10

Nidogens are sulfated glycoproteins with three globular domains connected with rodlike or thin segments11 and are distributed throughout the basement membrane with strong affinity to laminin and collagen IV.4 Nidogen-1 and Nidogen-2 each demonstrate distinct binding sites to collagen IV and laminin, respectively, reflected in inhibition assays and studies of recombinant fragment binding.11

1.3 Bowman's Layer

Bowman's layer is an acellular, nonregenerating layer posterior to the epithelial basement membrane, approximately 8-12 µm in depth and decreases in thickness over time.

Its collagen fibrils are distributed such that their posterior surfaces merge with the anterior stroma, leaving a smooth anterior surface. These fibers are only half to two-thirds the thickness of collagen fibrils in the stroma.12

1.4 Stroma

The stroma contributes the majority of the cornea's structural framework, measuring approximately 500 µm in humans and representing approximately 90% of the corneal anterior-posterior axis, as seen in Fig. 1. This layer is organized with a network of collagen fibers and ground substance, with an extracellular matrix composed of water, inorganic salts, proteoglycans, and glycoproteins.13

Stromal collagen is composed of a heterodimeric complex of Type I and Type V collagen with a narrow diameter.13 Lumican and keratocan are the major keratan sulfate proteoglycans in the stroma, which also include mimecan. These demonstrate a bifunctional role to contribute structural support; protein moieties bind to collagen fibrils to modulate their diameters, while glycosaminoglycan chains are highly charged and promote interfibrillar spacing.14 Loss of lumican in a mouse model results in corneal opacity,15 and in addition to its structural role, lumican regulates neutrophil migration during bacterial infections of the stroma.16 Decorin is a major proteoglycan associated with dermatan sulfate and similarly surrounds collagen fibrils. The concentration of proteoglycans varies with depth in the anterior-posterior axis, such that there is greater hydration in the posterior stroma.

Patterns of collagen lamellae also vary with depth. Anteriorly, the stroma is marked by short, narrow sheets with extensive interweaving, while collagen posteriorly demonstrates long, wide, thick lamellae extending from limbus to limbus, and without significant interlamellar connections.

Keratocytes, the major cells of the stroma, maintain the integrity of this layer, producing collagen, glycosaminoglycans, and matrix metalloproteinases.1

The corneal stroma represents one of the most highly innervated tissues in the human body. Sensory nerves from the nasociliary branch of the ophthalmic division of the trigeminal nerve course radially toward the central cornea through the anterior stroma. Between Bowman's layer and the anterior stroma, these nerves form the subepithelial nerve plexus, and then perforate through Bowman's layer to become the subbasal epithelial nerve plexus, innervating the basal epithelial layer.17

1.5 Descemet Membrane

Descemet membrane is the basement membrane of the corneal endothelium and measures approximately 3 µm in thickness in children, gradually thickening to 10 µm in adults. This membrane is composed of two layers: an anterior banded layer which is developed by collagen lamellae and proteoglycans and detected in fetal corneas as early as 12 weeks of gestation,18 and a posterior nonbanded layer which is laid down by endothelial cells and thickens over decades.

Structurally, Descemet membrane contains collagen type IV and VIII fibrils. In contrast to other basement membranes throughout the body in which the type IV subtype is common, collagen type VIII is relatively specific to Descemet membrane and forms ladder-like structures visible under electron microscopy. In the anterior banded layer, collagen fibrils demonstrate a lattice-like configuration with periodic banding at 110 nm intervals; an additional 0.3-0.4 µm extension of this layer borders the stroma and is electron dense and homogenous.18,19

Posteriorly, the nonbanded layer is relatively homogenous with a fine granular appearance and increases in...