Lung mesenchymal stem cells-derived extracellular vesicles attenuate the inflammatory profile of Cystic Fibrosis epithelial cells

Background: Mesenchymal stromal/stem cells (MSCs) are multi-potent non-hematopoietic stem cells, residing in most tissues including the lung. MSCs have been used in therapy of chronic inflammatory lung diseases such as Cystic Fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD) but the main beneficial effects reside in the anti-inflammatory potential of the released extracellular vesicles (EVs). Recent reports demonstrate that EVs are effective in animal model of asthma, E.coli pneumonia, lung ischemia-reperfusion, and virus airway infection among others. Despite this growing literature, the EVs effects on CF are largely unexplored. Methods: We treated IB3-1 cells, an in vitro human model of CF, with EVs derived from human lung MSCs under basal and inflammatory conditions (TNF alpha stimulation). Results: We demonstrated here that treatment of IB3-1 CF cell line with EVs, down-regulates transcription and protein expression of pro-inflammatory cytokines such as IL-1 beta, IL-8, IL-6 under TNF alpha - stimulated conditions. EVs treatment upregulates the mRNA expression of PPAR gamma, a transcription factor controlling anti-inflammatory and antioxidant mechanisms via NF-kappa B and HO-1. Accordingly, NF-kappa B nuclear translocation is reduced resulting in impairment of the downstream inflammation cascade. In addition, the mRNA of HO-1 is enhanced together with the antioxidant defensive response of the cells. Conclusions: We conclude that the anti-inflammatory and anti-oxidant efficacy of EVs derived from lung MSCs could be mediated by up-regulation of the PPAR gamma axis, whose down-stream effectors (NF-kappa B and HO-1) are well-known modulators of these pathways. General significance: EVs could be a novel strategy to control the hyper-inflamed condition in Cystic Fibrosis.