Hyaluronic acid stimulation of induced MSCs produces extracellular vesicles with enhanced healing for skin burn wounds

Background Skin injuries occur for various reasons during whole life. Some chronic wounds could cause an impaired wound healing process characterized by wound hypoxia, high levels of oxygen radicals, elevated levels of matrix metalloproteases, delayed cellular infiltration and granulation tissue formation, reduced angiogenesis, decreased collagen synthesis and organization. In this study, we report the EVs from hyaluronic acid-primed iMSCs (HA-iMSC-EVs) accelerating wound healing and regenerating damaged tissues by inducing the various growth factors in the thermal injury of mice. Methods EVs were collected from iMSCs primed with HA (HA-iMSC-EVs) or without HA (iMSC-EVs) and were isolated using TFF systems. Both EVs analyzed the characteristics. We investigated the proteome of HA-iMSC-EVs using the protein set ontology analysis and protein-protein interaction network. To evaluate the effect of HA-iMSC-EVs on the oxidative stress-induced wound healing delayed model, we assessed the effect of EVs on cell viability, cell migration rate, and the mRNA expression of growth factors using a hydrogen peroxide-exposed HDF model. In addition, we observed elastin and collagen expressions using an ICC staining in the HDF model. In thermal burn wound mice (BALB/c), we compared the effect of EVs in wound closure rate and histological analysis, including expression of elastin, collagen, α-SMA, and CD31. Results HA-iMSC-EVs exhibited typical EV characteristics, including size distribution, markers, and surface protein expression. In GO term analysis, HA-iMSC-EVs increased the proteins associated with ECM, including collagen biosynthesis and elastin fiber formation. In hydrogen peroxide exposed HDF models, HA-iMSC-EVs notably increased cell viability and migration activity. Furthermore, HA-iMSC-EVs increased RNA expression of VEGF, IGF1 , and HGF and decreased IL-6 mRNA expression compared to the PBS group. Elastin and collagen expression in the HA-iMSC-EVs group were also significantly increased. In burn-injured mice, HA-iMSC-EVs accelerated wound closure and enhanced histological recovery. HA-iMSC-EVs increased collagen and elastin density on the upper dermis and decreased α-SMA expression. Additionally, HA-iMSC-EVs promoted the capillary density in the dermis. Conclusions Our results suggest that HA-iMSC-EVs accelerated the recovery from burn wound by providing ECM composition signal and regulating growth factors. Our strategy may contribute to the development of alternative treatment option for burn wounds. Trial registration : Not applicable.