Bioactive derivatives of the antimicrobial peptide esculentin-1a promote human dermal fibroblast migration and activate genes involved in early wound healing

• Esculentin-1a derivatives stimulate fibroblast migration during wound healing. • Peptides-induced fibroblast migration involves the activation of MAPK/ERK pathway. • Esculentin-1a derivatives upregulate early wound healing gene expression. Antimicrobial peptides (AMPs) are essential components of the innate immune system and have emerged as promising candidates against antibiotic-resistant infections. Beyond their antimicrobial activity, AMPs also play a crucial role in regulating tissue regeneration processes, including wound healing. Previous studies have shown that the frog skin-derived AMP, esculentin-1a(1-21) [Esc(1-21)], promotes wound healing by accelerating keratinocyte migration. Its derivative, esculentin-1a(1-21)-1c [Esc(1-21)-1c] has proven even more effective in facilitating wound closure in alveolar and bronchial epithelial cell monolayers. Given the essential role of dermal fibroblasts in skin regeneration, this study aimed to investigate the effects of Esc(1-21) and its two derivatives, Esc(1-21)-1c and [Aib 8 ]-Esc(1-21) (containing the non-natural α-aminoisobutyric acid at position 8), on the activation of human primary dermal fibroblasts (hDFs) during the healing of a pseudo-wound. The results demonstrated that all three peptides significantly enhanced hDFs migration and stimulated wound closure by activating the MAPK/ERK signaling pathway, without affecting cell proliferation. Importantly, for Esc(1-21) and [Aib 8 ]-Esc(1-21), this activation was mediated by Epidermal Growth Factor Receptor (EGFR). Finally, the peptides upregulated the expression of early wound healing markers, such as Collagen I and Collagen III, but did not alter the expression of late-stage markers, including MMP9 and α-SMA. These findings highlight the regenerative potential of Esc(1-21) and its derivatives and suggest their relevance in therapeutic strategies for impaired wound healing.