The hyper-inflammatory SARS-CoV-2-induced ARDS patient micro-environment licenses MSCs and enhances their therapeutic efficacy in a model of acute lung injury

<bold>Background:</bold> Clinical trials investigating the potential of mesenchymal stromal cells (MSCs) in acute respiratory distress syndrome (ARDS) have provided disappointing results. MSCs are known to require cytokine-mediated activation signals, or licensing, in order to mediate protective effects in vivo and therefore MSCs may be more efficacious in the hyper-inflammatory ARDS sub-phenotype. We investigated the therapeutic efficacy of MSCs licensed with differential ARDS patient micro-environments (hyper- vs hypo-inflammatory) in a model of acute lung injury (ALI). <bold>Methods:</bold> MSCs were exposed to 20% patient serum from SARS-CoV-2-induced ARDS patients for 24 hours. ARDS patient serum was segregated into hypo- or hyper-inflammatory phenotype based on IL-6 levels. The MSCs and their secretome were then screened both in vitro and in vivo. <bold>Results:</bold> The secretome of MSCs exposed to the hyper- but not hypo-inflammatory ARDS serum reduced LPS-induced lung permeability, significantly increasing expression of tight junction genes <italic>occludin,</italic> <italic>claudin-4</italic> and <italic>zo-1</italic> in the lung epithelium in a VEGF dependent manner. <bold>Conclusion:</bold> MSCs exposed to hyper, but not hypo, ARDS patient serum have the capacity to reduce lung permeability, due to enhanced tight junction formation, in a VEGF-dependent manner. <bold>Disclosures:</bold> <bold>Conflict of interest:</bold> The authors declare there is no conflict of interest. <bold>Funding:</bold> This project has been supported by the Science Foundation Ireland Award to Prof. Karen English under the grant number 20/FFP-A/8948 and the National Irish COVID Biobank.