Induced Pluripotent Stem Cells in Corneal Regeneration: Biological Progress, Translational Barriers and Clinical Outlook

Corneal blindness remains a major cause of visual impairment worldwide and may result from trauma, infectious keratitis, degenerative disorders, endothelial dysfunction, and limbal stem cell deficiency (LSCD). Although corneal transplantation remains the standard treatment for advanced disease, its effectiveness is limited by donor tissue shortage, immune-mediated rejection, postoperative complications, and progressive graft failure. These limitations have accelerated interest in regenerative approaches aimed at restoring native corneal structure and function. Induced pluripotent stem cells (iPSCs) have emerged as a promising platform for corneal regeneration because of their pluripotency, self-renewal capacity, and potential for autologous or immune-compatible therapy. Recent advances in differentiation protocols have enabled the generation of corneal epithelial-like cells, stromal keratocyte-like cells, and corneal endothelial-like cells from iPSCs. Preclinical studies have demonstrated encouraging improvements in corneal transparency, epithelial restoration, fibrosis reduction, and endothelial function, while early clinical investigations, particularly in LSCD, have reported favorable short-term safety and functional outcomes. However, major translational barriers remain, including tumorigenicity, immunogenicity, genomic instability, manufacturing complexity, scalability, and long-term safety concerns. Stromal regeneration also remains comparatively underdeveloped relative to epithelial and endothelial applications. This review summarizes current differentiation strategies, biological mechanisms, preclinical and early clinical evidence, and the principal translational challenges associated with iPSC-based corneal regeneration. Overall, iPSC-derived corneal therapies demonstrate considerable regenerative potential, although further standardization, long-term safety evaluation, and multicenter clinical validation remain necessary before widespread clinical adoption.