Therapeutic role of extracellular vesicles derived from stem cells in cutaneous wound models: A systematic review

A growing body of evidence has shown that extracellular vesicles can be efficient as experimental therapeutics in pre-clinical models of skin wounds, but there is a significant unmet need to translate this to clinical utilization. The objectives of the current systematic review were to identify the strength of the therapeutic effects of EVs derived from stem cells in cutaneous wounds and to assess which EV-mediated mechanisms could be involved in the therapeutic response. PubMed, ISI Web of Science, and Scopus databases were systematically searched. We retrieved English-language articles published through June 2020. In vivo studies which applied stem cell-derived EVs were included for further analysis. The Risk of bias was assessed by the SYRCLE tool. We identified thirtynine pre-clinical studies that evaluated the effects of EVs on the wound healing process. The included studies varied greatly in EVs isolation techniques, route of administration, EVs producing cells, and follow-up time. In vivo application revealed beneficial effects of EVs on accelerating wound closure and re-epithelialization in a dose-dependent manner. Elevated angiogenesis was reported in twelve eligible studies through multiple signaling pathways such as PI3K/Akt, MAPK/ERK, and JAK/STAT. The well-known signaling pathway to inhibit scar formation was TGF-beta 2/SMAD2. However, all included studies were not blinded enough which may have introduced bias. Therefore, the transition of EV's efficacy into the clinics is deeply rooted in the following important factors: 1) pre-clinical studies with a lower risk of bias and longer follow-up time, and 2) consistent, reproducible, and feasible manufacturing of EVs production in a large-scale commercial program.