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Extracellular Vesicles Secreted by Mesenchymal Stromal Cells Exert Opposite Effects to Their Cells of Origin in Murine Sodium Dextran Sulfate-Induced Colitis.

Abstract
Several reports have described a beneficial effect of Mesenchymal Stromal Cells (MSCs) and of their secreted extracellular vesicles (EVs) in mice with experimental colitis. However, the effects of the two treatments have not been thoroughly compared in this model. Here, we compared the effects of MSCs and of MSC-EV administration in mice with colitis induced by dextran sulfate sodium (DSS). Since cytokine conditioning was reported to enhance the immune modulatory activity of MSCs, the cells were kept either under standard culture conditions (naïve, nMSCs) or primed with a cocktail of pro-inflammatory cytokines, including IL1β, IL6 and TNFα (induced, iMSCs). In our experimental conditions, nMSCs and iMSCs administration resulted in both clinical and histological worsening and was associated with pro-inflammatory polarization of intestinal macrophages. However, mice treated with iEVs showed clinico-pathological improvement, decreased intestinal fibrosis and angiogenesis and a striking increase in intestinal expression of Mucin 5ac, suggesting improved epithelial function. Moreover, treatment with iEVs resulted in the polarization of intestinal macrophages towards and anti-inflammatory phenotype and in an increased Treg/Teff ratio at the level of the intestinal lymph node. Collectively, these data confirm that MSCs can behave either as anti- or as pro-inflammatory agents depending on the host environment. In contrast, EVs showed a beneficial effect, suggesting a more predictable behavior, a safer therapeutic profile and a higher therapeutic efficacy with respect to their cells of origin.
AuthorsAnna Maria Tolomeo, Ignazio Castagliuolo, Martina Piccoli, Michele Grassi, Fabio Magarotto, Giada De Lazzari, Ricardo Malvicini, Federico Caicci, Chiara Franzin, Melania Scarpa, Veronica Macchi, Raffaele De Caro, Imerio Angriman, Antonella Viola, Andrea Porzionato, Michela Pozzobon, Maurizio Muraca
JournalFrontiers in immunology (Front Immunol) Vol. 12 Pg. 627605 ( 2021) ISSN: 1664-3224 [Electronic] Switzerland
PMID33927713 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 Tolomeo, Castagliuolo, Piccoli, Grassi, Magarotto, De Lazzari, Malvicini, Caicci, Franzin, Scarpa, Macchi, De Caro, Angriman, Viola, Porzionato, Pozzobon and Muraca.
Chemical References
  • Cytokines
  • Muc5ac protein, mouse
  • Mucin 5AC
  • Dextran Sulfate
Topics
  • Animals
  • Cell Lineage
  • Colitis (chemically induced, immunology, metabolism, surgery)
  • Colon (immunology, metabolism, pathology)
  • Cytokines (pharmacology)
  • Dextran Sulfate
  • Disease Models, Animal
  • Extracellular Vesicles (immunology, metabolism, transplantation)
  • Fibrosis
  • Intestinal Mucosa (immunology, metabolism, pathology)
  • Mesenchymal Stem Cell Transplantation (adverse effects)
  • Mesenchymal Stem Cells (drug effects, immunology, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mucin 5AC (metabolism)
  • Neovascularization, Pathologic
  • Phenotype
  • RAW 264.7 Cells
  • Stem Cell Niche

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