EGCG-releasing nanofibrous scaffold enhances wound healing via γδ T cells modulation

This study investigates the role of γδ T cells in wound healing facilitated by an EGCG (Epigallocatechin gallate)-releasing nanofibrous scaffold with aligned topography (APEMS). Incorporating core-shell microcapsules for sustained EGCG release over 11 days, the biocompatible scaffold enhances γδ T cell activity to promote advanced wound repair. In a splinted wound excisional model in 6-8 weeks-old male C57BL/6J mice, APEMS significantly improved re-epithelialization and wound closure compared to a control scaffold (APS). Single-cell RNA sequencing revealed a marked increase in γδ T cell in the APEMS group, where γδ T cells accounted for 66.2 % of the T cell population, compared to 33.8 % in the APS group. Cellchat analysis identified the AREG-EGFR signaling axis as pivotal to γδ T cell-mediated wound repair. APEMS-induced γδ T cells secreted amphiregulin (AREG), which acted on keratinocytes and fibroblasts to enhance keratinocyte proliferation, migration, and fibroblast-driven extracellular matrix remodeling. In immunodeficient mice lacking mature γδ T cells (TCRδ-/-), wound healing was significantly impaired, characterized by delayed re-epithelialization, reduced neo-dermal thickness, and increased inflammation. Inhibition of AREG and EGFR function via monoclonal antibodies against AREG and EGFR antagonist Gefitinib similarly delayed wound healing, the therapeutic advantage of APEMS over APS was abolished, emphasizing its critical role in the process. These findings provide a framework for developing advanced wound management materials and highlight the therapeutic potential of targeting γδ T cells and AREG-EGFR signaling to enhance tissue regeneration.