Corneal macrophages and limbal stem cells: emerging roles in ocular surface regeneration

Corneal integrity and visual acuity rely on limbal stem cells (LSCs) and immune homeostasis. Macrophages, as critical immune regulators, are increasingly recognized for their roles in stem cell niche maintenance and tissue regeneration. Recent advances in human single-cell and spatial transcriptomic profiling have further revealed previously underappreciated macrophage heterogeneity, context-dependent activation states, and neuroimmune interactions within the limbal niche.

To review current evidence on the localization, plasticity, and immuno-modulatory functions of corneal macrophages-with emphasis on human-derived insights, emerging neuroimmune mechanisms, and their interactions with LSCs during homeostasis and injury.

This narrative review integrates findings from the immunology, stem cell biology, and ophthalmology literature. It focuses on macrophage-derived cytokines, metabolic mediators, and microenvironmental cues that influence LSC behavior, and incorporates recent human single-cell, spatial transcriptomic, and regenerative immunology studies as well as therapeutic strategies modulating macrophage phenotype.

Macrophages exhibit dynamic and spectrum-like polarization during corneal inflammation and repair, extending beyond the traditional M1/M2 dichotomy. Their secreted factors-including TNF-α, IL-6, TGF-β, IL-10, and NO, and Arg1-derived metabolites-affect LSC proliferation, migration, and differentiation in a dose-, time-, and context-dependent manner. Therapeutic reprogramming of macrophages via pharmacological agents, stem cell-derived exosomes, α-MSH-based neuroimmune modulation, and bioactive compounds enhances corneal regeneration.

Macrophages serve as pivotal modulators of the limbal niche. Targeting macrophage-stem cell crosstalk represents a promising avenue for restoring niche stability and preventing limbal stem cell deficiency. Future progress will rely on human single-cell atlases, immune microenvironment profiling, and macrophage-targeted immunoregenerative strategies.