LSC Abstract – Murine bone marrow-derived mesenchymal stem cells exert anti-viral and barrier-protective properties in influenza virus infection

Abstract

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. Antiviral therapies are only effective in the very beginning of infection and specific treatment strategies for IV-induced ARDS are lacking. Mesenchymal stem cells (MSC) are multi-potent stromal cells with anti-inflammatory and regenerative potential; recently MSC were attributed a beneficial role in acute and chronic lung injury. In the current study we generated MSC from mouse bone marrow (mBM-MSC). We characterised their expression markers and demonstrated their stem cell properties. In ex vivo infection experiments using primary murine alveolar epithelial cells (AEC), mBM-MSC decreased IV-induced AEC apoptosis, increased AEC regeneration and strongly diminished IV replication in a paracrine manner. This was associated with expression of type I interferons, of the anti-apoptotic factor stanniocalcin 1(STC-1) and of growth factors FGF10 and VEGF in mBM-MSC after co-culture with infected AEC, suggesting a pathogen-/injury-specific priming of mBM-MSC. In vivo , intratracheal instillation of MSC after IV challenge strongly increased IV clearance and decreased IV-induced apoptotic injury of AEC. Of note, MSCs also increased the regenerative response of the epithelial stem/progenitor cell pool of the distal lung. Taken together, our experiments show a beneficial role of mBM-MSCs in IV pneumonia and suggest a therapeutic potential of these cells in IV-induced lung injury