Plasminogen activator inhibitor-1 and tenascin-C secreted by equine mesenchymal stromal cells stimulate dermal fibroblast migration in vitro and contribute to wound healing in vivo

摘要

BackgroundImpaired cutaneous wound healing is common in humans, and treatments are often ineffective. Based on the significant emotional and economic burden of impaired wound healing, innovative therapies are needed. The potential of mesenchymal stromal cell (MSC)–secreted factors to treat cutaneous wounds is an active area of research that is in need of refinement before effective clinical trials can be initiated. The aims of the present study were to (i) study which MSC-secreted factors stimulate dermal fibroblast (DF) migrationin vitroand (ii) evaluate the potential of these factors to promote wound healingin vivo.MethodsTo this end, MSCs were isolated from the peripheral blood of healthy horses, a physiologically relevant large animal model appropriate for translational wound-healing studies. Conditioned medium (CM) from cultured equine MSCs was analyzed using liquid chromatography-mass spectrophotometry (LC-MS/MS) to identify secreted proteins of interest. Double-stranded RNA-mediated interference (RNAi) was used to silence the genes encoding selected proteins, and the effects of CM from these transfected MSCs on migration of cultured equine DF cellsin vitroand full-thickness wounds in mice were evaluated.ResultsWe found that MSC-derived plasminogen activator inhibitor-1 (PAI-1) and tenascin-C significantly increased DF migrationin vitroand improved wound healingin vivoby decreasing time to wound closure.DiscussionThese results suggest that in a complex wound environment, MSC-secreted factors PAI-1 and tenascin-C contribute to the positive effect of therapeutically applied MSC CM on wound healing.