Influenza virus (IV) infects the upper respiratory tract and occasionally spreads to the alveolar compartment causing primary IV pneumonia. This frequently progresses to acute respiratory distress syndrome (ARDS) with severe alveolar damage, lung edema and hypoxemia, requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO) procedures. Antiviral therapies are only effective in the very beginning of infection and specific treatment strategies for IV-induced ARDS are still lacking. Mesenchymal stem cells (MSC) are multi-potent stromal cells with anti-inflammatory and regenerative potential: recently they were attributed a beneficial role in acute and chronic lung injury. This study investigated MSC delivery into the lung as a promising treatment strategy in IV-induced ARDS.In this study MSC were isolated from bone marrow (mBM-MSC) of C57Bl6. These MSC had fibroblast-like shape and expressed stem cell-specific markers and demonstrated de-differentiation potential upon defined culture conditions. No phenotypic changes were observed until passage 18. Genome array analysis revealed a strong up-regulation of the genes involved in cell proliferation (cell division, cyclins), in interferon signaling (ISGs) and virus resistance (Mx2, Bst2/Tetherin) in infected alveolar epithelial cells (iAECs) co-cultured with BM-MSC compared to iAECs in monoculture. In ex vivo infection experiments, BM-MSC as well as their conditioned medium (CM) strongly diminished IV replication, increased AEC regeneration and consequently decreased IV-induced AEC apoptosis. In vivo, intra-tracheal instillation of BM-MSC into C57BL/6 mice after 3 days post IV challenge strongly increased IV clearance, decreased alveolar injury and was associated with better outcome. Of note, BM-MSCs also increased the regenerative response of the epithelial stem/progenitor cell pool of the distal lung in vivo. Interferon alpha and beta receptor knockout (ifnar-/-) mice after IV infection could not clear the virus even under BM-MSCs treatment, demonstrating that the type I IFN pathway is responsible for the BM-MSC anti-viral (and concomitantly, anti-apoptotic) potential in vivo. In conclusion, our ex vivo as well as in vivo experiments show a beneficial role of BM-MSCs in IV pneumonia and demonstrate the therapeutic potential of these cells in IV-induced lung injury. Furthermore, the upregulation of type I IFN signaling-related pathways suggests that these cells are activated in a pathogen-specific way in presence of virus, which enhances their beneficial properties.
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