Influenza-A virus (IAV) is a major cause of severe pneumonia, respiratory distress and hypoxia. In recent years, multiple studies have investigated how the alveolar epithelium regenerates upon IAV infection, providing insights into how epithelial stem and progenitor cells mediate lung repair after injury. At the same time, fibrosis is a feature of non-resolving pneumonia and little is known about the role of mesenchymal niche cells in this process. We have previously shown that metformin accelerates the resolution of lung fibrosis by targeting myofibroblasts, the effector cells in fibrotic disease. Therefore, we hypothesized that mesenchymal cells play an important role in guiding epithelial regeneration following infection and metformin boosts the regenerative capacity of the lung following IAV-induced acute respiratory distress syndrome.

Genetic lineage tracing combined with spatial and transcriptomic approaches was used to study the contribution of mesenchymal cells to the repair process after IAV infection. The therapeutic impact of metformin treatment on lung regeneration was also assessed.

Our data reveal dynamic changes in the mesenchymal niche in the peribronchial and alveolar compartments of the lung, and reveal the loss of the lipofibroblast after infection. We also demonstrate that metformin leads to enhanced reversal of lung damage inflicted by IAV, by boosting the mesenchymal niche, replenishing the lipofibroblast population, leading to the clearance of inflammatory cells and restoring alveolar architecture. Future experiments will further validate the downstream targets of metformin in the lung and test therapeutic candidates using in vivo, ex vivo and in vitro approaches.