SHED aggregation-released extracellular vesicles rejuvenate Gli1 cells and improve diabetic wound healing.

Hair follicle stem cells (HFSCs) play an important role in skin tissue repair, exhibiting remarkable heterogeneity. However, the roles of distinct subpopulations in wound healing remain unclear. Here, we employed transgenic mice to specifically label and ablate Gli1 cells subpopulation, unraveling their pivotal function in cutaneous wound repair. Our findings demonstrate that during wound healing, Gli1 cells migrate from hair follicles, differentiate into epithelial cells, and promote re-epithelialization. Notably, diabetic microenvironment significantly impairs the function of Gli1 cells and delayed skin wound healing. Based on mesenchymal condensation in developmental process, aggregates assembled by stem cells from human exfoliated deciduous teeth (SHED) were demonstrated to promote diabetic wound healing through extracellular vesicle (EV)-mediated recruitment of Gli1 cells to wound margins, followed by enhanced epithelial lineage differentiation and accelerated re-epithelialization. This study not only elucidates the role of Gli1 subpopulations in skin repair but also establishes a promising therapeutic strategy for diabetic skin wound healing.