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JCI Insight. 2019 Nov 1;4(21). pii: 128060. doi: 10.1172/jci.insight.128060.

Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes.

Author information

1
Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital (BCH), Boston, Massachusetts, USA.
2
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
3
Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
4
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5
Division of Pulmonary Medicine, Department of Medicine, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.
6
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.

Abstract

Mesenchymal stromal/stem cell (MSC) therapy has shown promise in experimental models of idiopathic pulmonary fibrosis (IPF). The aim of this study was to test the therapeutic effects of extracellular vesicles produced by human BM MSCs (MEx) in a bleomycin-induced pulmonary fibrosis model and investigate mechanisms of action. Adult C57BL/6 mice were challenged with endotracheal instillation of bleomycin and treated with MEx concurrently, or for reversal models, at day 7 or 21. Experimental groups were assessed at day 7, 14, or 28. Bleomycin-challenged mice presented with severe septal thickening and prominent fibrosis, and this was effectively prevented or reversed by MEx treatment. MEx modulated lung macrophage phenotypes, shifting the proportions of lung proinflammatory/classical and nonclassical monocytes and alveolar macrophages toward the monocyte/macrophage profiles of control mice. A parallel immunomodulatory effect was demonstrated in the BM. Notably, transplantation of MEx-preconditioned BM-derived monocytes alleviated core features of pulmonary fibrosis and lung inflammation. Proteomic analysis revealed that MEx therapy promotes an immunoregulatory, antiinflammatory monocyte phenotype. We conclude that MEx prevent and revert core features of bleomycin-induced pulmonary fibrosis and that the beneficial actions of MEx may be mediated via systemic modulation of monocyte phenotypes.

KEYWORDS:

Adult stem cells; Fibrosis; Monocytes; Pulmonology; Stem cells

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