Late Breaking Abstract - Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through systemic modulation of monocyte phenotypes

Abstract

Rationale: Mesenchymal stromal/stem cell (MSC) therapy has shown promise in experimental models of idiopathic pulmonary fibrosis (IPF), a chronic progressive lung disease characterized by interstitial fibrosis with decreasing lung volumes and hypoxemic respiratory failure. Recently, we reported that the therapeutic capacity of MSCs predominantly resides in the secretome, and that the chief therapeutic vector therein is represented by the exosomes. Objectives: To test the therapeutic effects of MSC-exosomes (MEx) in a bleomycin-induced pulmonary fibrosis model and investigate putative mechanisms of action. Methods: Exosomes were isolated from media conditioned by human bone marrow MSCs (MEx). Adult mice (C57BL/6 strain) were challenged with endotracheal instillation of bleomycin and treated with MEx concurrently or at day 7. Treated animals and appropriate control groups were assessed at day 7 and/or day 14. Results: Bleomycin-challenged mice presented with severe septal thickening and prominent fibrosis, and this was effectively prevented (day 0 treatment) or reversed (day 7 treatment) by a single dose of MEx. Furthermore, MEx therapy modulated whole lung macrophage phenotype, and shifted the proportion of lung ‘proinflammatory’ classical monocytes, ‘regulatory’ monocytes and alveolar macrophages to favor the monocyte/macrophage profiles of untreated-control mice, and, importantly a parallel immunomodulatory effect was demonstrated in the bone marrow. Notably, transplantation of MEx-preconditioned bone marrow-derived monocytes alleviated core features of pulmonary fibrosis. Conclusion: A bolus dose of MEx prevents and reverts core features of bleomycin-induced pulmonary fibrosis. The beneficial actions of MEx are mediated via the systemic modulation of monocyte phenotypes.