The Mammalian Limbal Stem Cell Niche: A Complex Interaction Between Cells, Growth Factors and Extracellular Matrix

Abstract

Stem cell niche may be described as an anatomically defined and protected location that provides housing, positioning information and signaling inputs necessary to support normal stem cell activity. Based on the distribution of the differentiation-linked keratins, proliferative potential and wound healing abilities in ocular surface, it was proposed that an anatomical structure, the limbus, was the presumptive site of residence of corneal stem cells. Further analysis determined that the limbus contains a specific anatomical structure that probably provides the microenvironmental characteristics that correspond to the stem cell niche. This structure was termed as the Limbal Epithelial Crypt (LEC). Accumulated evidences show that the LEC is the site where stem cells interact directly and/or indirectly with at least six different cell types: epithelial, stromal, Langerhans cells, melanocytes, and telocytes. In addition, a rich and distinctive vasculature as well as an extensive neural network exist at limbal niches. These cell types, together with growth factors, cytokines and specific components of the Extracellular Matrix establish the conditions for the regulated growth, migration and delayed differentiation of the corneal stem cells. In spite of the wide variety of molecular markers described for limbal epithelial cells, it has been extremely difficult to isolate stem cells. This is explained by the persistence of stem cell markers in the transient amplifying cell population and in the early differentiating cells. Consequently, the use of stem cells in ophthalmic therapy shows variable outcomes and research must be increased before a formal clinical use. Nevertheless, the analysis of the different cells and factors involved in stem cell regulation, may help the development of new therapies based on the interference or stimulation of the signaling pathways and microenvironmental components that control limbal stem cells.