Melanocytes as key cells of the limbal stem cell niche: Roles in ocular surface homeostasis, disease, and regenerative therapy.

Limbal melanocytes (LMs) are neural crest-derived cells that have emerged as multifunctional regulators of ocular surface homeostasis beyond their traditional role in pigmentation and photoprotection. Residing within the basal limbal epithelium, LMs form functional units with limbal epithelial stem/progenitor cells (LESCs/LEPCs) through cadherin-mediated adhesion and paracrine signaling through soluble factors and extracellular vesicles. LMs contribute to photoprotection by transferring melanosomes to LEPCs, which subsequently organize these organelles into supranuclear melanin caps that may shield LEPC DNA from ultraviolet-induced damage. In parallel, LMs regulate LEPCs stemness, proliferation, and differentiation through direct cell-cell interactions and paracrine signaling mechanisms. LMs exhibit pronounced immunomodulatory properties, including a hypoimmunogenic phenotype, T-cell suppressive capacity, and anti-inflammatory, anti-angiogenic potential. Recent technical advances-such as CD117+CD90- flow cytometric isolation and laminin-based culture systems-have enabled long-term LM expansion. Dysregulation of LMs has been reported in association with several pathological conditions, including corneal inflammation, aniridia-associated keratopathy, pterygium, and rare limbal melanomas. This review integrates current knowledge on LMs embryological origin, anatomical localization, molecular and cellular characteristics, interactions with LEPCs, and functional contributions to ocular surface homeostasis. We discuss the pathological implications of LMs dysfunction and critically evaluate emerging therapeutic strategies, including LMs-enriched tissue-engineered constructs for limbal stem cell deficiency and other ocular surface disorders. By synthesizing the current knowledge and identifying key gaps in understanding, this review aims to guide further research and accelerate the clinical translation of LMs-based regenerative therapies.