An Tiantian, Xu Zhaoyu, Yang Yang, Li Xinhui, Chen Shuaidong, Yang Xingmei, Man Yi, Hu Chen, Qu Yili
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China; Frontier Innovation Center for Dental Medicine Plus, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China.
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China.
Biomaterials. 2026 Feb;325:123543. doi: 10.1016/j.biomaterials.2025.123543. Epub 2025 Jul 9.
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.
本研究调查了γδ T细胞在由具有排列形貌的表没食子儿茶素没食子酸酯（EGCG）释放纳米纤维支架（APEMS）促进伤口愈合中的作用。该生物相容性支架结合了核壳微胶囊以实现EGCG在11天内的持续释放，增强了γδ T细胞活性以促进伤口的深度修复。在6 - 8周龄雄性C57BL/6J小鼠的夹板伤口切除模型中，与对照支架（APS）相比，APEMS显著改善了再上皮化和伤口闭合。单细胞RNA测序显示，APEMS组中γδ T细胞显著增加，γδ T细胞占T细胞群体的66.2%，而APS组为33.8%。Cellchat分析确定AREG - EGFR信号轴是γδ T细胞介导的伤口修复的关键。APEMS诱导的γδ T细胞分泌双调蛋白（AREG），其作用于角质形成细胞和成纤维细胞，以增强角质形成细胞的增殖、迁移以及成纤维细胞驱动的细胞外基质重塑。在缺乏成熟γδ T细胞（TCRδ-/-）的免疫缺陷小鼠中，伤口愈合明显受损，表现为再上皮化延迟、新生真皮厚度减小和炎症增加。通过抗AREG单克隆抗体和EGFR拮抗剂吉非替尼抑制AREG和EGFR功能同样延迟了伤口愈合，APEMS相对于APS的治疗优势消失，强调了其在该过程中的关键作用。这些发现为开发先进的伤口管理材料提供了框架，并突出了靶向γδ T细胞和AREG - EGFR信号以增强组织再生的治疗潜力。
