Local transplantation of GMSC-derived exosomes to promote vascularized diabetic wound healing by regulating the Wnt/β-catenin pathways

With the increasing number of diabetic patients, chronic wound healing remains a great challenge in clinical medicine. As one of the main components secreted by stem cells, the exosome is considered to be a promising candidate for promoting chronic wound healing. Here, gingival mesenchymal stem cell (GMSC)-derived exosomes (GMSC-Exo) were isolated and demonstrated to promote the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) by regulating the Wnt/beta-catenin signaling pathway in a diabetic-mimicking high glucose environment. In order to deliver GMSCs-Exo to the target site and prolong their local retention, porous microspheres consisting of poly-lactic-co-glycolic acid (PLGA), amphiphilic block copolymer (PLLA-PEG-PLLA), nano-hydroxyapatite (nHAP), and poly-epsilon-l-lysine (EPL) coating were fabricated through a double emulsion method and following surface treatment, hereafter referred to as PHE microspheres. PHE microspheres loaded with GMSCs-Exo were implanted into the full-thickness skin wound of a diabetic mouse model, resulting in significant vascularized wound healing when compared to a control group only injected with GMSCs-Exo suspension or filled with PHE microspheres. These findings indicated that the GMSCs-Exo-loaded porous microspheres could efficiently treat diabetic wounds and have promising potential for future clinical translations.