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

Juan Tong; Xinyue Cai; Meiling Wu; Bingdong Sui; Chao Ma; Haoyu Zhang; Ji Chen; Haokun Xu; Yu Fu; Siyuan Fan; Chenxi Zheng

doi:10.1016/j.bbrc.2025.152327

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

Biochem Biophys Res Commun. 2025 Jul 9:777:152327. doi: 10.1016/j.bbrc.2025.152327. Online ahead of print.

Authors

Juan Tong¹, Xinyue Cai², Meiling Wu¹, Bingdong Sui³, Chao Ma³, Haoyu Zhang³, Ji Chen⁴, Haokun Xu³, Yu Fu³, Siyuan Fan⁵, Chenxi Zheng⁶

Affiliations

¹ State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Disease, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
² State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Disease, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
³ State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
⁴ Department of Oral Implantology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
⁵ State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Disease, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: fsweeney@yeah.net.
⁶ State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. Electronic address: chenxizheng@fmmu.edu.cn.

PMID: 40651366
DOI: 10.1016/j.bbrc.2025.152327

Abstract

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.

Keywords: Diabetic wound healing; Extracellular vesicles; Gli1; Hair follicle stem cells.