Mesenchymal Stem Cell-Derived Microvesicles Modulate Lipopolysaccharides-Induced Inflammatory Responses to Microglia Cells

Abstract

Microglia cells are the central nervous system immune cells and have been pointed out as the main mediators of the inflammation leading to neurodegenerative disorders. Mesenchymal stromal cells (MSCs) are a heterogeneous population of cells with very high self-renewal properties and uncomplicated in vitro culture. Research has shown that MSCs have the capacity to induce tissue regeneration and reduce inflammation. Studies demonstrated that MSCs have complex paracrine machineries involving shedding of cell-derived microvesicles (MVs), which entail part of the regulatory and regenerative activity of MSCs, as observed in animal models. We proposed MSC-derived MVs as potent regulators of microglia activation and used an in vitro model of stimulation for BV-2 cells, a microglia cell line, with lipopolysaccharides (LPS). Here we demonstrated that presence of MSCs-derived MVs (MSC-MVs) prevents Tumor necrosis factor-α, Interleukin (IL)-1β and IL-6 upregulation by BV-2 cells and primary microglia cells toward LPS. Also, inducible isoform of nitric oxide synthases and Prostaglandin-endoperoxide synthase 2 upregulation were hampered in presence of MSC-MVs. Higher levels of the M2 microglia marker chemokine ligand-22 were detectable in BV-2 cells after coculture with MSC-MVs in presence and absence of LPS. Moreover, upregulation of the activation markers CD45 and CD11b by BV-2 cells was prevented when cocultured with MSC-MVs. Furthermore, MSC-MVs suppressed the phosphorylation of the extracellular signal kinases 1/2, c-Jun N-terminal kinases and the p38 MAP kinase (p38) molecules. Consequently, MSC-MVs might represent a modulator of microglia activation with future therapeutic impact. Stem Cells 2017;35:812-823.

Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells

“…A variety of trophic factors and cytokines with immunomodulatory, anti‐inflammatory, and anti‐apoptotic activity has been identified as a result (Drago et al, ; Konala et al, ). MSC‐derived microvesicles show strong and acute immune modulatory activity, reducing MAPK and STAT activity within hours (Jaimes, Naaldijk, Wenk, Leovsky, & Emmrich, ). In other studies, TNFα‐stimulated gene‐6 (TSG6), identified as an active component of the MSC secretome, shows an anti‐inflammatory effect in LPS‐stimulated microglia and reduces phosphorylation of STAT1 (Liu et al, ; Mittal et al, ).…”

“…Previously, we have shown that the MSC‐derived microvesicles significantly reduced levels of inflammatory cytokines of the hyperoxia‐induced injured lungs and also contains several beneficial anti‐inflammatory factors for wound healing (Ahn et al, ; Sung et al, ). It has been also known that MSC‐derived microvesicles have potency to modulate microglial activation by suppressing MAPK (Jaimes et al, ). These findings suggest that microvesicles included in MSC‐CM in this study might have a seminal role for strong and acute immune modulatory effects on microglia showing reduced MAPK and STAT activity within hours.…”

“…MSC-derived microvesicles show strong and acute immune modulatory activity, reducing MAPK and STAT activity within hours (Jaimes, Naaldijk, Wenk, Leovsky, & Emmrich, 2017). In other studies, TNFαstimulated gene-6 (TSG6), identified as an active component of the MSC secretome, shows an anti-inflammatory effect in LPS-stimulated microglia and reduces phosphorylation of STAT1 (Liu et al, 2014;Mittal et al, 2016).…”

Oral Mesenchymal Stem/Progenitor Cells: The Immunomodulatory Masters

“…Additionally, BM-MSC-derived microvesicles downregulated the level of IL-1β, IL-6, TNF-α, iNOS, and PTGS2, produced by microglia cells, when cocultured in LPS inflammatory environment. Moreover, the phosphorylation of ERK, JNK, and p38 molecules in microglia cells was also suppressed by BM-MSC-derived microvesicles [111]. In an uninflamed environment, DPSCs were shown to induce the production of TNF-α by macrophages via PKR-rich microvesicles [112].…”

Mesenchymal stem cells in the pathogenesis and treatment of bronchopulmonary dysplasia: a clinical review

“…Target cells of MSC-derived exosomes include fibroblasts, MSCs, epithelial cells, and immune cells (24). It is partially through this exosome-mediated mechanism that MSCs exert their anti-inflammatory effect in vitro (24,25). The role of exosomes in the treatment of lung disease is an area of active pre-clinical study.…”