Mesenchymal Stromal Cells Are More Effective Than Their Extracellular Vesicles at Reducing Lung Injury Regardless of Acute Respiratory Distress Syndrome Etiology

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.

Current understanding of the therapeutic benefits of mesenchymal stem cells in acute respiratory distress syndrome

“…Nevertheless, compared to MSCs, MSC-conditioned media (administered intravenously) was unable to improve lung edema and inflammation, arterial oxygenation, or static compliance in a subsequent study conducted by the same group (Hayes et al 2015). Similar findings were observed in models of endotoxin-induced lung injury (Silva et al 2019a).…”

Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients

“…MSCs were more effective than EVs in reducing lung injury. Specifically, MSCs demonstrated superior ability to reduce neutrophil cell count, alveolar collapse, lung elastance, interstitial edema and fibrosis [151]. The safety of intravenous infusion of high dose (10 × 10 6 cells/kg body weight) BM-MSCs was also demonstrated in an ovine model of bacterial pneumonia [152].…”

Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization

“…Conforti et al discovered that MSC-EVs had a lower ability to modulate T cell proliferation and antibody formation than MSCs [36]. In models of LPSinduced lung injury, Silva et al reported that MSCs BM bone marrow, MSC-EVs mesenchymal stem cells-derived extracellular vesicles, miR microRNA, TLR4 toll-like receptor 4, HMGA2 high-mobility group A2, LPS/GalN lipopolysaccharide and D-galactosamine, GVHD graft versus host disease, NLRP3 NOD-, LRR-and pyrin domain-containing protein 3, TSG-6 tumor necrosis factor-α-stimulated gene-6, CCR2 C-C motif chemokine receptor-2, TLR Toll-like receptor, IFN-γ interferon gamma produced greater protection compared with MSC-EVs prepared from the same number of cells [37]. Compared with MSCs, MSC-EVs may confer several advantages.…”