Mesoglycan induces the secretion of microvesicles by keratinocytes able to activate human fibroblasts and endothelial cells: A novel mechanism in skin wound healing

Mesoglycan is a fibrinolytic compound but recently promising pro-healing effects in skin wound repair have been reported. Previously, we have showed that mesoglycan activates human keratinocytes, fibroblasts and endothelial cells and induces the secretion of microvesicles (EVs), particularly exosomes, from keratinocytes. These EVs may contribute to wound healing since they further activate cells generating an autocrine loop with a positive feedback. In this work, EVs isolated from keratinocytes, treated with mesoglycan, have been tested on human fibroblasts and endothelial cells. The in vitro investigation has been carried out through Wound-Healing/invasion assays to analyze cell motility and assess the differentiation process. Then, the formation of capillary-like structures by human endothelial cells has been performed to evaluate in vitro angiogenesis. We found that EVs secreted from keratinocytes treated with mesoglycan promote fibroblasts and endothelial cells migration and invasion. Furthermore, these receiving cells acquire a mesenchymal phenotype. Additionally, the angiogenesis appears strongly enhanced in presence of this kind of EVs. In conclusion, we show that EVs deriving from keratinocytes trigger a paracrine positive feedback able to further amplify the effects of mesoglycan. This mechanism adds up to the autocrine loop previously reported and culminates with the activation of fibroblasts and endothelial cells. Particularly, this activation is amplified by the action of growth factors as FGF-2 (Fibroblast Growth Factor-2) for the fibroblasts and by VEGF (Vascular Endothelial Growth Factor) for the endothelial cells.