Axolotl-derived decellularized skin ECM as a pro-regenerative scaffold for attenuating fibrotic wound healing.

Conventional wound healing in mammals often results in fibrosis, leading to permanent scarring and compromised skin function. Inspired by the remarkable regenerative capacity of axolotls, we developed an axolotl skin decellularized extracellular matrix (A-dECM) as a pro-regenerative scaffold for mammalian wound healing. A-dECM retained its native ECM composition, including a glycosaminoglycan-rich and collagen-dense profile, while effectively eliminating cellular and immunogenic components, as confirmed by histological staining and DNA quantification. Whole scanning electron microscopy revealed a highly organized ultrastructure in intact A-dECM. To improve biocompatibility, potentially cytotoxic ∼40 kDa protein fractions were removed from A-dECM via size-exclusion chromatography, and the fractionated A-dECM promoted enhanced proliferation of HaCaT keratinocytes. In a murine burn model, A-dECM significantly enhanced re-epithelialization, dermal remodeling, and collagen organization compared to murine dECM and PBS controls. Moreover, A-dECM reduced expression of fibrotic markers (α-SMA, TXNDC5), suppressed inflammatory cytokines (IL-1β, TNF-α), and inhibited M1 macrophage polarization. These molecular changes correlated with improved restoration of key skin features, including epidermal rete ridge formation and partial hair follicle regeneration. This work demonstrates that decellularized axolotl ECM can guide mammalian tissue regeneration, highlighting its potential as an evolution-inspired biomaterial for clinical translation.