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.