## 2 Overview on the Cornea Anatomy  
The human cornea, together with the surrounding sclera, constitutes the protective outer barrier of the eye. In particular, it represents the outer covering of the anterior portion of the eyeball by exerting two essential functions: it protects from external physical trauma and provides about 70% refractive power of the eye. To perform these functions, the corneal tissue is both mechanically strong and transparent. The anterior surface of the cornea is convex and aspheric [41]. The cornea comprises five main layers: the epithelium, the Bowman's membrane, the stroma, the Descemet's membrane, and the endothelium [42; 43] (Figure 1). The epithelium represents the outermost layer of the cornea. It originates from the ectoderm overlying the developing lens. The corneal epithelium is approximately 50 um in thickness and is characterized by four to six layers of nonkeratinized stratified squamous epithelial cells. These cells can be morphologically distinguished into the basal columnar, wing, and superficial squamous cells. Basal cells form a monolayer anchored to the underlying basal lamina by hemidesmosomes and filaments. The adjacent cells are tightly joined together with desmosomes and tight junctions by forming a watertight barrier to pathogens entry. The wing cells, so named for their cross-sectional alar shape, originate from basal cells differentiation and are stratified into two or three layers. These cells  
Figure 1: Structural anatomy of the human cornea. From left to right: (1) A diagram of human cornea structure; (2) The XYZ hypothesis. The asymmetric division of LESCs generates a stem-like daughter cell, remaining within the limbus, and a TAC, migrating in a centripetal direction (Y). TACs undergo multiple replications. In this process, they lose stemness, migrate anteriorly and differentiate to post-mitotic suprabasal wing cells (X), and progress in superficial squamous cells, which are lost during normal corneal surface exfoliation (Z) of the epithelial corneal maintenance. possess tight lateral and intercellular junctions contributing to the structural integrity of the epithelium. Above the wing cell layer, there are two or three nonkeratinized stratified squamous epithelial cell layers. These cells are flat and polygonal in shape with extensive apical microvilli and micropliace covered by a fine glycocalyceal layer that allows the hydrophilic spreading of the tear film every eyelid blink. Laterally, the cells are joined by barrier tight-junctional complexes limiting the access of tears into the intercellular spaces [44]. The corneal epithelium is continuously subjected to a wide range of insults; therefore, its long-term maintenance is regulated by limbal epithelial stem cells (LESCs). The LESCs reside in an annular transition zone known as the limbus, laying at the junction area between the cornea and the sclera. They show typical characteristics of immature and undifferentiated cells [45; 46]. In particular, they do not express the cytokeratin 3 and 12, commonly detected in mature, differentiated corneal epithelial cells, whereas they express cytokeratin 14 or TP63, which are stem markers of the immature or progenitor cells in various stratified epithelia. The LESCs give rise to transit-amplifying cells (TACs), which migrate and divide into basal corneal epithelial cells in normal homeostasis conditions or to replace those cells desquamated or lost by lesions (Figure 1) [47; 48]. The basement membrane of basal epithelial cells (\(\sim\)40-60 nm thickness) is formed by Type IV collagen and laminin. It comprises a lamina lucida and lamina densa. Between the basement membrane and the stroma is located the Bowman's membrane (BM). The BM is composed of randomly oriented collagen fibrils, which help the cornea to maintain its shape [49]. It is approximately 8 to 12 um thickness in humans, but it decreases with age. The stroma represents the major part of the cornea, comprising approximately more than 80% of its thickness.