A CD31-derived cytoplasmic ITIM peptide enhances epidermal and dermal regeneration in cutaneous wound repair

Chronic wounds affect millions globally, yet current therapies lack the ability to coordinate epithelial, dermal, and immune repair processes. We investigated whether a 16-amino acid immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing peptide derived from the cytoplasmic domain of CD31 (ICP) could enhance cutaneous wound repair through coordinated effects on epidermal and dermal regeneration.

The effects of ICP on proliferation, migration, cell-cycle progression, intracellular localization, and ERK signaling were evaluated in HaCaT keratinocytes and Hs27 fibroblasts. In vivo efficacy was evaluated in murine full-thickness dorsal and ear wounds, with local or systemic ICP administration. Wound closure, histological architecture, and cellular markers were analyzed at days 8 and 14.

ICP significantly enhanced keratinocyte and fibroblast proliferation and migration, increased Ki-67 expression, promoted G2/M cell cycle progression, and induced ERK phosphorylation. ICP internalized efficiently into both cell types with diffuse cytoplasmic localization. In murine wounds, local or systemic ICP administration accelerated closure, reduced epithelial gaps and granulation tissue, and improved tissue organization. ICP-treated wounds exhibited increased keratinocyte proliferation without aberrant keratin10 expression, diminished CD11b⁺ myeloid infiltration, and elevated keratin15 and LGR5 expression, indicating activation of epithelial and follicular stem/progenitor populations.

These findings identify ICP as a multifunctional regenerative peptide that coordinates epithelial and dermal repair while modulating inflammatory responses. The ability of ICP to promote regeneration through both local and systemic administration supports its potential as a therapeutic candidate for cutaneous wound healing and regenerative medicine applications.