title: Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice.
abstract: 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 C57Bl/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.
  
  
  CONCLUSIONS
  There is a growing experience demonstrating benefit of mesenchymal stromal cell (MSC)-based cell therapies in preclinical models of asthma. In the current study, conditioned media (CM) and, in particular, the extracellular vesicle fraction obtained from the CM were as potent as the MSCs themselves in mitigating Th2/Th17-mediated allergic airway inflammation in a mouse model of severe refractory clinical asthma. Moreover, human MSC CM and extracellular vesicles were effective in this immunocompetent mouse model. These data add to a growing scientific basis for initiating clinical trials of MSCs or extracellular vesicles derived from MSCs in severe refractory asthma and provide further insight into the mechanisms by which the MSCs may ameliorate the asthma.
authors.affiliation: Department of Medicine, Pulmonary, University of Vermont, Burlington, Vermont, USA Laboratory of Pulmonary Investigation, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
authors.forename: Fernanda F
authors.initials: FF
authors.lastname: Cruz
authors.affiliation: Department of Medicine, Pulmonary, University of Vermont, Burlington, Vermont, USA.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Borg
authors.affiliation: Department of Medicine, Pulmonary, University of Vermont, Burlington, Vermont, USA.
authors.forename: Meagan
authors.initials: M
authors.lastname: Goodwin
authors.affiliation: Department of Medicine, Pulmonary, University of Vermont, Burlington, Vermont, USA.
authors.forename: Dino
authors.initials: D
authors.lastname: Sokocevic
authors.affiliation: Department of Medicine, Pulmonary, University of Vermont, Burlington, Vermont, USA.
authors.forename: Darcy E
authors.initials: DE
authors.lastname: Wagner
authors.affiliation: Department of Medicine, Pulmonary, University of Vermont, Burlington, Vermont, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Coffey
authors.affiliation: Department of Medicine, Pulmonary, University of Vermont, Burlington, Vermont, USA Laboratory of Pulmonary Investigation, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Antunes
authors.affiliation: Department of Medicine, Pulmonary, University of Vermont, Burlington, Vermont, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Robinson
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: S Alex
authors.initials: SA
authors.lastname: Mitsialis
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Kourembanas
authors.affiliation: Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, Grafton, Massachusetts, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Thane
authors.affiliation: Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, Grafton, Massachusetts, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hoffman
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: McKenna
authors.affiliation: Laboratory of Pulmonary Investigation, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
authors.forename: Patricia R M
authors.initials: PR
authors.lastname: Rocco
authors.affiliation: Department of Medicine, Pulmonary, University of Vermont, Burlington, Vermont, USA dweiss@uvm.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001230:Aspergillus / Q000737:chemistry*; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001854:Bone Marrow Cells / Q000276:immunology*; D055252:Cell-Derived Microparticles / Q000276:immunology*; D045424:Complex Mixtures / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D025301:Hyphae / Q000737:chemistry*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice
chemical_list: D045424:Complex Mixtures
keywords: Asthma; Conditioned media; EDCI; Extracellular vesicles; Mesenchymal stromal cells; Mouse