Niche regulation of corneal epithelial stem cells at the limbus

Abstract

Among all adult somatic stem cells, those of the corneal epithelium are unique in their exclusive location in a defined limbal structure termed Palisades of Vogt. As a result, surgical engraftment of limbal epithelial stem cells with or without ex vivo expansion has long been practiced to restore sights in patients inflicted with limbal stem cell deficiency. Nevertheless, compared to other stem cell examples, relatively little is known about the limbal niche, which is believed to play a pivotal role in regulating self-renewal and fate decision of limbal epithelial stem cells. This review summarizes relevant literature and formulates several key questions to guide future research into better understanding of the pathogenesis of limbal stem cell deficiency and further improvement of the tissue engineering of the corneal epithelium by focusing on the limbal niche.

Figure 1

The limbal palisades of Vogt. Palisades of Vogt (arrow) are readily recognized in the human limbus (A). Such a unique pigmented structure can be identified on the flat mount preparation of Dispase-isolated human limbal epithelial sheets (B). In donors with a darker skin, these palisades of Vogt are pigmented (C, arrow). Under higher magnification, these limbal areas show undulated epithelial papillae (D, stars). Hematoxyline staining highlights higher stratification and more undulation of the limbal epithelium, and the underlying limbal stroma has high cellularity and vascularity (E, arrow shows blood vessel). (Bar represents 500 μm in A and B, 200 μm in C and E, and 50 μm in D) (A, B, [127])

Figure 2

Hypothetical Scheme of Limbal Stem Cell Niche. Limbal epithelial stem cells (SC) are located at the limbal basal layer. In this epithelial level, there are several other cell types in the vicinity such as the immediate progeny, i.e., early transient amplifying cells (eTAC), melanocytes (M), and Langerhan's cells (LC). It remains to be determined whether these cell types act as niche cells. It is believed that eTAC will be destined for progeny production by differentiating into late TACs (lTAC) located at the corneal basal layer, then into suprabasal post-mitotic cells (PMC), and finally into superficial terminally differentiated cells (TDC). The limbal basement membrane (BM) separating the epithelium from the underlying stroma has several unique components. The subjacent limbal stroma contains mesenchymal cells (MC), which may also serve as niche cells. Because the limbal stroma is highly innervated and vascularized, the respective role of nerves (N) and blood vessels (BV) in the niche remains to be defined.