Therapeutic reprogramming of bone marrow derived mesenchymal stem cells during influenza infection is mediated by type I interferon signaling and interleukin 11

Abstract

Mesenchymal stem cells (MSC) show promising therapeutic potential in different forms of acute lung injury. However, it is not clear how MSC sense injury during viral lung infections. The aim of this study was to understand how the anti-viral and tissue-protective effects of bone marrow derived-MSC (BM-MSC) are mediated and can be applied in the context of influenza-virus (IV) infection. Using IV-infected alveolar epithelial cells (iAEC)/MSC coculture systems together with the bronchioalveolar lung organoid (BALO) model, it was possible to compare the extent of epithelial cell survival, proliferation and differentiation supported by either lung resident MSC (lung-MSC) or BM-MSC. Strikingly, pre-conditioning with soluble factors derived from iAEC or from bronchioalveolar lavage fluid of infected animals significantly enhanced the capacity of BM-MSC to drive alveolarization in BALO. Despite lower cell differentiation capacity within BALO when BM-MSC were used, compared to lung-MSC, both cell types displayed similar anti-viral, pro-proliferative and antiapoptotic effects when in co-culture with iAEC. BM-MSC protective properties and transcriptional changes were also evaluated in vivo by intra-tracheal (IT) cell application after 3 days of IV-infection in wild-type (WT) mice. The presence of BM-MSC led to the reduction of viral load and infection-associated AEC apoptosis, while significantly improving mice survival. Bulk-RNA sequencing of IT-delivered-BM-MSC flow sorted back from infected or mock-infected lungs revealed that interferon-related genes and the cytokine interleukin (IL)-11 were upregulated in iAEC and BM-MSC, respectively. Notably, data acquired from IFNARko IV-infected mice revealed that the activation of type I interferon (IFN) signaling is essential for BM-MSC’s anti-viral and anti-apoptotic effects. As a response to this activation, IL-11 release by BM-MSC was proven to significantly enhance iAEC resilience. In conclusion, the type I IFN/IL-11 signaling axis could represent a promising target for the development of human MSC-based therapies.