Human Exosomes Accelerate Cutaneous Wound Healing by Promoting Collagen Synthesis in a Diabetic Mouse Model

Chronic wounds including diabetic foot ulcers are clinical emergencies that need careful management. Exosomes from human adipose-derived mesenchymal stem cells (hADSCs-Ex) are a new promising cell-free therapy for the regeneration of dermal wounds. We established a delayed wound healing model using diabetic female mice. A 1.5 cm2 full-thickness cutaneous wound was made ventrally in 6-week-old db/db mice. After treatment with phosphate-buffered saline, recombinant human epidermal growth factor, hADSCs-CM, or hADSCs-Ex three times a day for 2 weeks, we measured wound healing closure rates and performed histological analysis. Human dermal fibroblasts (WS1) were evaluated by PKH26-Exo co-localization test, CCK-8 test, cell scratch test, and the transwell test, while the expression of matrix metalloproteinase-1 (MMP1), MMP3, Collagen I, and Collagen III were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Wound closure and re-epithelialization were accelerated by hADSCs-Ex. Besides, hADSCs-Ex enhanced skin collagen production, angiogenesis, cell proliferation, inhibited apoptosis, promoted skin barrier function repair, and reduced inflammation in skin lesions. Furthermore, negative regulation of MMP1 and MMP3 enhanced collagen synthesis wound healing-promoting effects of hADSCs-Ex. hADSCs-Ex treatment for diabetic wounds provided a novel cell-free therapeutic strategy.