Introduction-The acute respiratory distress syndrome (ARDS) is a devastating clinical condition common in patients with respiratory failure. Based largely on numerous preclinical studies and recent Phase I/II clinical trials, administration of stem cells, specifically mesenchymal stem or stromal cells (MSC), as a therapeutic for acute lung injury (ALI) holds great promise. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, remains unresolved. Accumulating evidence now suggest that stem cell-derived conditioned medium (CM) and/or extracellular vesicles (EV), might constitute compelling alternatives.Areas covered-The current review focuses on the preclinical studies testing MSC CM and/or EV as treatment for ALI and other inflammatory lung diseases.Expert opinion-Clinical application of MSC or their secreted CM may be limited by the cost of growing enough cells, the logistic of MSC storage, and the lack of standardization of what constitutes MSC CM. However, the clinical application of MSC EV remains promising, primarily due to the ability of EV to maintain the functional phenotype of the parent cell as a therapeutic. However, utilization of MSC EV will also require large-scale production, the cost of which may be prohibitive unless the potency of the EV can be increased.

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Background Although promising, clinical translation of human mesenchymal stem or stromal cell-derived extracellular vesicles (MSC EV) for acute lung injury is potentially limited by significant production costs. The current study was performed to determine whether pretreatment of MSC EV with high molecular weight hyaluronic acid (HMW HA) would increase the therapeutic potency of MSC EV in severe bacterial pneumonia. Methods In vitro experiments were performed to determine the binding affinity of HMW HA to MSC EV and its uptake by human monocytes, and whether HMW HA primed MSC EV would increase bacterial phagocytosis by the monocytes. In addition, the role of CD44 receptor on MSC EV in the therapeutic effects of HMW HA primed MSC EV were investigated. In Pseudomonas aeruginosa (PA) pneumonia in mice, MSC EV primed with or without HMW HA were instilled intravenously 4 h after injury. After 24 h, the bronchoalveolar lavage fluid, blood, and lungs were analyzed for levels of bacteria, inflammation, MSC EV trafficking, and lung pathology. Results MSC EV bound preferentially to HMW HA at a molecular weight of 1.0 MDa compared with HA with a molecular weight of 40 KDa or 1.5 MDa. HMW HA primed MSC EV further increased MSC EV uptake and bacterial phagocytosis by monocytes compared to treatment with MSC EV alone. In PA pneumonia in mice, instillation of HMW HA primed MSC EV further reduced inflammation and decreased the bacterial load by enhancing the trafficking of MSC EV to the injured alveolus. CD44 siRNA pretreatment of MSC EV prior to incubation with HMW HA eliminated its trafficking to the alveolus and therapeutic effects. Conclusions HMW HA primed MSC EV significantly increased the potency of MSC EV in PA pneumonia in part by enhancing the trafficking of MSC EV to the sites of inflammation via the CD44 receptor on MSC EV which was associated with increased antimicrobial activity.

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