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Title: Human mesenchymal stromal cell regulation of pulmonary macrophage populations in the acute respiratory distress syndrome
Author: Morrison, Thomas
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical disorder with a high mortality rate and no pharmacologically effective treatment available. The alveolar macrophage (AM) is key to orchestrating the inflammatory responses in ARDS and so presents an ideal target for therapy. Mesenchymal stromal cells (MSCs) are a promising candidate therapy for ARDS proving therapeutic in pre-clinical models of lung injury through reducing inflammation and reducing bacterial burden, however their mechanisms of effect have not been entirely elucidated. Moreover, MSC efficacy varies considerably between donors. In this piece of work the hypothesis was tested that human MSCs would promote an anti-inflammatory M2-,ike human macrophage phenotype which may explain another mechanism of their beneficial effects. The mechanisms by which MSCs exert these effects were also studied. hMSCs were found to induce an M2-like human macrophage phenotype characterised by a dampened inflammatory cytokine secretory profile, enhanced expression of the M2 surface marker CD206 and increased phagocytic capacity. These effects were seen with either bacterial lipopolysaccharide or bronchoalveolar lavage fluid from ARDS patients as inflammatory stimuli. Mechanistic studies demonstrate that it is mitochondrial transfer via MSC extracellular vesicles (EVs) exerting these effects on human macrophages and that this was dependent on the enhancement of macrophage mitochondrial oxidative phosphorylation. In a murine endotoxin-induced lung injury model, the treatment of mice with MSC EV-treated AMs was protective. This suggests that the AM is a key cellular target of MSC-EVs in vivo and that they are cellular mediators of MSCs therapeutic effects in lung injury. These findings expand on our understanding of MSC mechanisms of effect in lung injury and have highlighted the potential for induction of CD206 expression in human macrophages by MSCs as a potency assay for donor selection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available