Aged differentiated cells reverse into native stemness-like state by niche cytokines to sustain lifelong homeostasis and tissue repair

Abstract

Recent studies report that epithelial differentiated cells can undergo a reverse process called dedifferentiation in response to stem cell loss. However, the extent of this reversion and the plasticity of young versus aged-differentiated cells remain unclear. Here we show that dedifferentiated corneal epithelial cells acquire a transcriptomic state closely resembling native stem cells, sustain tissue homeostasis across lifespan and efficiently repair repeated tissue injury. Transplantation of stage-specific genetically traceable aged differentiated epithelial cells onto a denuded niche reveals reversion into a stemness-like state, restoring both quiescent and active stem cell compartments. This plasticity operates within the epithelial lineage, allowing transitions along the differentiation axis, but remains restricted across lineages, as transplanted conjunctival cells fail to regenerate the corneal stem cell pool. Mechanistically, we identify niche-derived cytokines that trigger reprogramming in vivo and enhance stemness in primary human corneal epithelial cells, revealing a conserved and therapeutically exploitable pathway for epithelial regeneration.