Abstract
Although mesenchymal stromal cells (MSCs) have demonstrated beneficial effects on experimental acute respiratory distress syndrome (ARDS), preconditioning may be required to potentiate their therapeutic effects. Additionally, administration of cell-free products, such as extracellular vesicles (EVs) obtained from MSC-conditioned media, might be as effective as MSCs. In this study, we comparatively evaluated the effects of MSCs, preconditioned or not with serum collected from mice with pulmonary or extrapulmonary ARDS (ARDSp and ARDSexp, respectively), and the EVs derived from these cells on lung inflammation and remodeling in ARDSp and ARDSexp mice. Administration of MSCs (preconditioned or not), but not their EVs, reduced static lung elastance, interstitial edema, and collagen fiber content in both ARDSp and ARDSexp. Although MSCs and EVs reduced alveolar collapse and neutrophil cell counts in lung tissue, therapeutic responses were superior in mice receiving MSCs, regardless of preconditioning. Despite higher total cell, macrophage, and neutrophil counts in bronchoalveolar lavage fluid in ARDSp than ARDSexp, MSCs and EVs (preconditioned or not) led to a similar decrease. In ARDSp, both MSCs and EVs, regardless of preconditioning, reduced levels of tumor necrosis factor- (TNF-) α, interleukin-6, keratinocyte chemoattractant (KC), vascular endothelial growth factor (VEGF), and transforming growth factor- (TGF-) β in lung homogenates. In ARDSexp, TNF-α, interleukin-6, and KC levels were reduced by MSCs and EVs, preconditioned or not; only MSCs reduced VEGF levels, while TGF-β levels were similarly increased in ARDSexp treated either with saline, MSCs, or EVs, regardless of preconditioning. In conclusion, MSCs yielded greater overall improvement in ARDS in comparison to EVs derived from the same number of cells and regardless of the preconditioning status. However, the effects of MSCs and EVs differed according to ARDS etiology.
Highlights
Despite recent advances in supportive care for acute respiratory distress syndrome (ARDS) patients, mortality remains high [1, 2] and those who survive usually face long-term morbidity [3]
mesenchymal stromal cells (MSCs) preconditioned with serum from either ARDSp or ARDSexp animals demonstrated formation of exosomes and microvesicles on MSC surfaces (Supplementary Fig. 1D-I)
No significant difference was observed in protein concentration as evaluated by the Bradford assay among groups (Supplementary Fig. 2)
Summary
Despite recent advances in supportive care for acute respiratory distress syndrome (ARDS) patients, mortality remains high [1, 2] and those who survive usually face long-term morbidity [3]. More effective therapeutic approaches for ARDS are required. Bone marrow-derived mesenchymal stromal cells (MSCs) have been shown to promote immunomodulatory effects by secreting trophic factors [5,6,7,8]. Both systemic administration and intratracheal administration of MSCs mitigated pulmonary and systemic inflammation as well as enhanced bacterial clearance, resulting in lower mortality in different models of ARDS [9,10,11,12]. The impact of EVs on lung fibrosis, which is an important determinant of ARDS patient outcome, has not yet been investigated and further studies are needed to closely compare the effects of MSCs and their EVs
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