Exosomes derived from dental pulp stem cells accelerate cutaneous wound healing by enhancing angiogenesis via the Cdc42/p38 MAPK pathway

Skin wound healing is a common challenging clinical issue which requires advanced treatment strategies. The present study investigated the therapeutic effects of exosomes derived from dental pulp stem cells (DPSC-Exos) on cutaneous wound healing and the underlying mechanisms. The effects of DPSC-Exos on cutaneous wound healing in mice were examined by measuring wound closure rates, and using histological and immunohistochemical analysis. A series of functional assays were performed to evaluate the effects of DPSC-Exos on the angiogenic activities of human umbilical vein endothelial cells (HUVECs) in vitro. Tandem mass tag-based quantitative proteomics analysis of DPSCs and DPSC-Exos was performed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were used to evaluate the biological functions and pathways for the differentially expressed proteins in DPSC-Exos. Western blot analysis was used to assess the protein levels of cell division control protein 42 (Cdc42) and p38 in DPSC-Exos and in HUVECs subjected to DPSC-Exos-induced angiogenesis. SB203580, a p38 mitogen-activated protein kinase (MAPK) signaling pathway inhibitor, was employed to verify the role of the p38 MAPK pathway in vitro and in vivo. Histological and immunohistochemical staining revealed that the DPSC-Exos accelerated wound healing by promoting neovascularization. The DPSC-Exos promoted the migration, proliferation and capillary formation capacity of HUVECs. Proteomics data demonstrated that proteins contained in DPSC-Exos regulated vasculature development and angiogenesis. Pathway analysis revealed that proteins expressed in DPSC-Exos were involved in several pathways, including MAPK pathway. Western blot analysis demonstrated that the DPSC-Exos increased the protein levels of Cdc42 and phosphorylation of p38 in HUVECs. SB203580 suppressed the angiogenesis induced by DPSC-Exos. On the whole, the present study demonstrates that DPSC-Exos accelerate cutaneous wound healing by enhancing the angiogenic properties of HUVECs via the Cdc42/p38 MAPK signaling pathway.