Systemic administration of human bone marrow-derived mesenchymal stromal cell extracellular vesicles ameliorates Aspergillus hyphal extract-induced allergic airway inflammation in immunocompetent mice

An increasing number of studies demonstrate that administration of either conditioned media (CM) or extracellular vesicles (EVs) released by mesenchymal stromal cells (MSCs) derived from bone marrow and other sources are as effective as the MSCs themselves in mitigating inflammation and injury. The goal of the current study was to determine whether xenogeneic administration of CM or EVs from human bone marrow-derived MSCs would be effective in a model of mixed Th2/Th17, neutrophilicmediated allergic airway inflammation, reflective of severe refractory asthma, induced by repeated mucosal exposure toAspergillus hyphal extract (AHE) in immunocompetent C57Bl/6mice. Systemic administrationofbothCMandEVs isolatedfromhumanandmurineMSCs,butnothumanlungfibroblasts, at the onset of antigen challenge in previously sensitized mice significantly ameliorated the AHEprovoked increases in airway hyperreactivity (AHR), lung inflammation, and the antigen-specific CD4 T-cell Th2 and Th17 phenotype. Notably, both CMand EVs from human MSCs (hMSCs) were generally more potent than those frommouseMSCs (mMSCs) inmost of the outcomemeasures. Theweak crosslinking agent 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride was found to inhibit release of both soluble mediators and EVs, fully negating effects of systemically administered hMSCs but only partly inhibited the ameliorating effects of mMSCs. These results demonstrate potent xenogeneic effects of CMand EVs from hMSCs in an immunocompetentmouse model of allergic airway inflammation and they alsoshowdifferences inmechanisms of action ofhMSCs versusmMSCs tomitigate AHR and lung inflammation in this model.