Journal
STEM CELLS TRANSLATIONAL MEDICINE
Volume 4, Issue 11, Pages 1302-1316Publisher
WILEY
DOI: 10.5966/sctm.2014-0280
Keywords
Mesenchymal stromal cells; Extracellular vesicles; Conditioned media; EDCI; Asthma; Mouse
Categories
Funding
- NIH ARRA [RC4HL106625]
- National Heart, Lung, and Blood Institute (NHLBI) [R21HL108689]
- NHLBI [RO1 HL096702, R21HL110023-01, R21HL117090]
- National Institute of Environmental Health Sciences [T32ES007122]
- Vermont Lung Center CoBRE Grant [P20RR15557]
- Brazilian National Counsel of Technological and Scientific Development (CNPq)-Science Without Borders
- National Center for Research Resources of the NIH [P40RR017447]
- Shipley Foundation
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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, neutrophilic-mediated allergic airway inflammation, reflective of severe refractory asthma, induced by repeated mucosal exposure to Aspergillus hyphal extract (AHE) in immunocompetent C57BI/6 mice. Systemic administration of both CM and EVs isolated from human and murine MSCs, but not human lung fibroblasts, at the onset of antigen challenge in previously sensitized mice significantly ameliorated the AHE provoked increases in airway hyperreactivity (AHR), lung inflammation, and the antigen-specific CD4 T-cell Th2 and Th17 phenotype. Notably, both CM and EVs from human MSCs (hMSCs) were generally more potent than those from mouse MSCs (mMSCs) in most of the outcome measures. The weak cross-linking 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 CM and EVs from hMSCs in an immunocompetent mouse model of allergic airway inflammation and they also show differences in mechanisms of action of hMSCs versus mMSCs to mitigate AHR and lung inflammation in this model.
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