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.

TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles

“…Similar results have been obtained with EV-mix released by murine BM-MSCs exposed to IL-6, TNF-α, and IL-1β, its administration in a murine model of colitis reduces the clinical-pathological signs of the disease. Reduction in the M1 marker iNOS and increase in the M2 marker CD163 is observed in the colon tissue, while in the intestinal lymph node the Treg/Teffectors ratio increases [117]. Moreover, the MVs obtained from 3D cultures of BM-MSCs exposed to ischemic brain extracts are enriched in immunoregulatory and angiogenic cytokines [111].…”

“…Stimulation of MSCs with proinflammatory cytokines increases the amount of EVs released by these cells [117][118][119][120], and changes its content which influences their immunoregulatory capacity. In addition, EVs released by resting or activated BM-MSCs do not express MHC-I or MHC-II [98].…”

Cow Milk Extracellular Vesicle Effects on an In Vitro Model of Intestinal Inflammation

“…Many studies highlighted the ability of EVs to regulate immune cells and cytokines within the inflammatory microen-vironment, dampening inflammation and restoring the intestinal barrier integrity and gut microbiome composition and diversity [19]. Evidence of these EVs improving effects on IBD emerged from in vivo studies on a dextran sodium sulfate-induced IBD animal model, where MSC-derived EV administration decreased the disease severity, reducing inflammation and improving epithelial functions [32,33]. Some studies on EVs derived from food showed ameliorating properties on intestinal inflammation for those isolated from edible plants such as Curcuma longa, grapes, and broccoli [34].…”

Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine

“…Furthermore, bone marrow mesenchymal stem cells (MSC) reduced severity of colitis through secretion of TSG6, facilitating the accumulation of IL‐10‐producing macrophages 260 . In another work, the anticolitic role of MSCs was attributed to extracellular vesicles 261 . Similarly, exosomes from umbilical cord mesenchymal stem cells (UCMSCs) were able to suppress the infiltration of inflammatory macrophages and reduce their production of colitogenic cytokines, thus alleviating DSS colitis in mice 262 The exact component(s) responsible for the anticolitic effect of UCMSC‐derived exosomes still need to be further elucidated.…”