Current and Emerging Therapies for Limbal Stem Cell Deficiency

Abstract

The corneal epithelium serves to protect the underlying cornea from the external environment and is essential for corneal transparency and optimal visual function. Regeneration of this epithelium is dependent on a population of stem cells residing in the basal layer of the limbus, the junction between the cornea and the sclera. The limbus provides the limbal epithelial stem cells (LESCs) with an optimal microenvironment, the limbal niche, which strictly regulates their proliferation and differentiation. Disturbances to the LESCs and/or their niche can lead to the pathologic condition known as limbal stem cell deficiency (LSCD) whereby the corneal epithelium is not generated effectively. This has deleterious effects on the corneal and visual function, due to impaired healing and secondary corneal opacification. In this concise review, we summarize the characteristics of LESCs and their niche, and present the current and future perspectives in the management of LSCD with an emphasis on restoring the function of the limbal niche.

Surgical Management of Bilateral Limbal Stem Cell Deficiency

“…Allogenic limbal grafts are the mainstay for the treatment of bilateral total LSCD, such as kerato-limbal allograft (cadaveric donor) and living related conjunctival limbal allograft (with some risk of causing LSCD in the donor's eye). 5,6 Like ours, most ophthalmology centers do not have the technology to perform LSC culture and transplantation, which would have been a good option for our patient. 7 Nevertheless, there are limitations of LSC transplantation, particularly in bilateral LSCD cases, as both techniques require immunosuppression, and success rates vary between 33% to 77%.…”

“…7 Nevertheless, there are limitations of LSC transplantation, particularly in bilateral LSCD cases, as both techniques require immunosuppression, and success rates vary between 33% to 77%. 5,8 Holoclar ® , a stem-cell treatment, requires healthy cells from the patient's limbus. 6 Other non-limbal autologous sources of grafts include cultivated oral mucosal epithelial transplantation and autologous conjunctival epithelial transplantation, but both have been associated with corneal neovascularization.…”

“…More studies are necessary to ascertain the safety and efficacy of mesenchymal stem cells as an LSC niche. 5,6 Finally, keratoprostheses do not require immunosuppression and lead to a fast visual recovery, although more than half of patients suffer from complications, such as glaucoma. 6,9 In this clinical case, attempts to restore vision in the OD with PK and Boston-KPro were unsuccessful and of limited value.…”

Therapeutic Strategies for Restoring Perturbed Corneal Epithelial Homeostasis in Limbal Stem Cell Deficiency: Current Trends and Future Directions

“…Given the benefits of autologous LSC transplantation over allogeneic limbal transplantation, methodologies for autologous transplantation in patients who do not have a healthy reservoir of LSCs are urgently needed. Moreover, allogeneic limbal grafts are often scarce, further limiting this transplantation option [ 83 ]. Transdifferentiation of a different stem cell line is one therapeutic avenue that may allow clinicians to avoid allogeneic transplantation in bilateral complete LSCD ( Table 3 ).…”

“…Transdifferentiation of a different stem cell line is one therapeutic avenue that may allow clinicians to avoid allogeneic transplantation in bilateral complete LSCD ( Table 3 ). In the early 2000s, transplantation of cultivated oral mucosa epithelium was found to recapitulate corneal epithelium development in [ 58 ], but further research since then has demonstrated that persistent oral epithelium morphology hampers post-transplantation visual outcomes [ 83 , 84 , 85 ]. Stem cells derived from hair follicle, pluripotent, dental pulp, and umbilical cord sources have been shown to transdifferentiate into corneal epithelium-like cells when exposed to the limbal niche in vitro and in animal models, but related clinical trials have been limited [ 86 , 87 , 88 , 89 , 90 ].…”