Strategies for reconstructing the limbal stem cell niche

Abstract

The epithelial cell layer that covers the surface of the cornea provides a protective barrier while maintaining corneal transparency. The rapid and effective turnover of these epithelial cells depends, in part, on the limbal epithelial stem cells (LESCs) located in a specialized microenvironment known as the limbal niche. Many disorders affecting the regeneration of the corneal epithelium are related to deficiency and/or dysfunction of LESCs and the limbal niche. Current approaches for regenerating the corneal epithelium following significant injuries such as burns and inflammatory attacks are primarily aimed at repopulating the LESCs. This review summarizes and assesses the clinical feasibility and efficacy of current and emerging approaches for reconstruction of the limbal niche. In particular, the application of mesenchymal stem cells along with appropriate biological scaffolds appear to be promising strategies for long-term revitalization of the limbal niche.

Keywords: Corneal limbus; Epithelial cell; Extracellular matrix; Limbal epithelial stem cell deficiency; Mesenchymal stem cell; Regenerative medicine; Stem cell niche.

Figure 1:

Schematic of the limbal niche. The corneoscleral limbus contains the Palisades of Vogt (PV) and limbal epithelial crypts (LECs). The limbal epithelial stem cells (LESCs) are in close contact with niche cells including melanocytes and mesenchymal stem cells (MSCs) in the LECs. The basement membrane of the cornea, limbus, and conjunctiva have different constructs which are in turn necessary for maintaining proper homeostasis. In the basal epithelial layer of LEC, the LESCs are divided symmetrically into two identical cells (in the horizontal plane) or asymmetrically to give rise to another LESC and a transient amplifying cell (TAC, in both vertical and horizontal planes). Then, the TACs are divided into postmitotic cells (PMCs) as they migrate centripetally, Y. The PMCs are then differentiated into terminally differentiated cells (TDCs) and shed from the corneal surface, Z. In physiological situations, the sum of X and Y is equal to Z. Abbreviations: LESC, Limbal epithelial stem cell, TAC, Transient amplifying cell, PMC, Post-mitotic cell, TDC, terminal differentiated cell, MSC, mesenchymal stem cell.

Figure 2:

Schematic illustration of the interaction between limbal MSCs with LESCs in the limbal niche. In situ microscopic evaluations and specific staining have shown the existence of a physical cross-talk between limbal MSCs and LESCs. The limbal MSCs attach to the basement membrane by integrin α8 and dystroglycan. Moreover, MSCs projections pass through the basement membrane and have direct contact with LESCs [11, 12].

Figure 3:

Diagram summarizing current strategies and materials for restoring the function of the limbal stem cells in limbal stem cell deficiency/dysfunction. The current stage of clinical development is also included. Abbreviations: CLAU, Conjunctival limbal autograft, KLAL, Kerato-limbal allograft, Ir-CLAL, Living related conjunctival limbal allograft, SLET, Simple limbal epithelial transplantation, COMET, Cultivated oral mucosal epithelial transplantation, AET, Amniotic epithelial transplantation, CjET, Conjunctival epithelial transplantation, HAM, Human amniotic membrane.