The cornea is the window of the visual system. As the outermost layer of the eye, the cornea both serves as a barrier and provides the essential optical function of transmitting light to the retina. In addition to the transmission of light, the cornea provides 70-75% of the refractive power required to focus the light into an image [Zieske, 2004]. The cornea is made up of three unique differentiated cell types separated by basal laminae (Fig. 11.1). The outermost layer consists of a stratified squamous, nonkeratinized epithelium. This tissue is supported by a basement membrane overlying an acellular zone of connective tissue known as the Bowman layer. The stroma, a collagenous connective tissue, makes up 90% of the cornea. It is populated with keratocytes, neural crest-derived mesenchymal cells that secrete the unique transparent tissue of the corneal stroma. The most posterior boundary of the cornea is the endothelium, comprised of a single layer of flattened cuboidal cells that maintain corneal transparency by regulating corneal hydration. Separating the corneal endothelium and the stroma is a basal lamina known as the Descemet membrane.
Formation of the human cornea begins at approximately 5 to 6 weeks of gestation [Zinn and Mockel-Pohl, 1975]. After the lens vesicle separates from the surface ectoderm, the latter forms a layer of cuboidal epithelial cells, which develop into the corneal epithelium. Neural crest cells migrate between this epithelium and the lens, forming the corneal endothelium. A second wave of migration of cells from neural crest subsequently forms the stroma [Johnston et al., 1979; Wulle, 1972].
The three cellular layers of the cornea differ markedly in mitotic and self-renewal abilities. In the corneal epithelium, mitotically active basal cells continuously renew the nonmitotic population of suprabasal cells, which subsequently flatten as they migrate to the surface, where they are lost by desquamation. The stromal keratocytes, on the other hand, show little cell division in the normal adult. They undergo rapid cell division after localization in the cornea in late embryogenesis, but after birth the keratocyte cell number stabilizes and little or no mitosis can be detected throughout the lifetime. In the case of inflammation or wounding, however, the stromal keratocytes become activated and mitotic. The phenotype of the activated keratocytes changes to resemble that of fibroblasts and myofibroblasts, and connective tissue matrix secreted by these cells during wound-healing becomes opaque scars. After healing the cells become quiescent, but human corneal scars are very slow to resolve and it is not clear whether the resident cells return to a fully keratocytic phenotype. These properties suggest only a limited means of tissue renewal in the corneal stroma.
Renewal of corneal endothelial cells is even more limited than that of the keratocytes. After childhood, human corneal endothelial cells do not divide. Compensation for endothelial damage is accomplished by flattening of the remaining cells to cover the posterior surface of the cornea. In vitro, human corneal endothelial cells show only limited ability to divide after infancy [Engelmann et al., 1988, 2004; Ide et al., 2006; Joyce, 2003; Joyce and Zhu, 2004; Konomi et al., 2005; Sumide et al., 2006; Wilson et al., 1995; Yokoo et al., 2005; Zhu and Joyce, 2004].
These characteristics have led to the conventional view that the corneal epithelium is maintained by a stem cell population, but that the stroma and the endothelium, with limited ability for self renewal, are not products of tissue-resident stem cells.
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