Corneal epithelial regenerative medicine: lessons from somatic stem cell therapy toward iPS cell-based regeneration

Limbal stem cell deficiency (LSCD) is a severe ocular surface disorder caused by the loss of corneal epithelial stem cell function, and is clinically characterized by corneal neovascularization, opacity, and visual impairment. Conventional corneal transplantation for LSCD is limited by a severe worldwide shortage of donor corneas; even when transplantation is feasible, long-term outcomes remain poor because of postoperative complications such as immunologic rejection and infectious keratitis. To overcome these challenges, corneal epithelial regenerative medicine using somatic stem cells has been developed and translated into clinical practice. Autologous cultivated limbal or oral mucosal epithelial cell sheets have enabled ocular surface reconstruction using patient-derived epithelial cells. Through clinical trials, we demonstrated the efficacy and safety of these approaches. Based on these findings, two pioneering regenerative medicine products were approved in Japan: Nepic, an autologous cultivated limbal epithelial cell sheet, and Ocural, an autologous cultivated oral mucosal epithelial cell sheet. We also contributed to their clinical implementation by establishing criteria for appropriate use, including facility and physician requirements. Following approval, we have been conducting post-marketing surveillance to clarify clinical outcomes and safety in real-world practice. Using these post-marketing and real-world data, we aim to identify prognostic factors and optimize postoperative management for better clinical outcomes. These lessons from somatic stem cell therapy provide an important foundation for the development of next-generation corneal epithelial regenerative medicine, including induced pluripotent stem cell-derived corneal epithelial cell sheets. This review summarizes the historical challenges, clinical translation, implementation, post-marketing evidence, and future perspectives of corneal epithelial regenerative medicine.