Comparative analysis of dorsal and tail skin reveals region-dependent heterogeneity in axolotl skin regeneration.

The mechanisms underlying scarless versus fibrotic wound healing remain a critical challenge in regenerative medicine. To elucidate the mechanisms of scarless repair, the axolotl (Ambystoma mexicanum), a model organism with exceptional regenerative capacity, has gained increasing prominence. Although axolotls are capable of regenerating complex structures such as limbs and tails, whether their skin regeneration is uniformly scarless-especially across different anatomical sites-remains undefined. Here, we demonstrate that adult axolotl tail skin achieves scarless regeneration, while dorsal skin repair results in fibrotic scarring. Through comparative histological and transcriptomic analyses of full-thickness excisional wounds, we identify accelerated re-epithelialization and reduced collagen deposition in tail skin compared to dorsal wounds. Developmental trajectory studies reveal prolonged retention of a hypodifferentiated state in tail skin, contrasting with early stratification in dorsal tissue. Mechanistically, we find that the extracellular matrix (ECM) glycoprotein gene Tenascin-N (TnN) exhibits higher expression in tail skin versus dorsal skin. The reported TnN downstream PI3K-Akt signaling pathway, demonstrated by Western blotting of pAkt, is significantly activated in tail skin versus dorsal skin during homeostasis and regeneration. These findings establish the axolotl as a key model for dissecting how developmental priming and ECM dynamics orchestrate regenerative versus fibrotic repair, offering novel insights for therapeutic strategies targeting scarless healing.