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Abstract
Microglia are the primary immunocompetent cells in brain tissue and microglia-mediated inflammation is associated with the pathogenesis of various neuronal disorders. Recently, many studies have shown that mesenchymal stem cells (MSCs) display a remarkable ability to modulate inflammatory and immune responses through the release of a variety of bioactive molecules, thereby protecting the central nervous system. Previously, we reported that MSCs have the ability to modulate inflammatory responses in a traumatic brain injury model and that the potential mechanisms may be partially attributed to upregulated TNF-α stimulated gene/protein 6 (TSG-6) expression. However, whether TSG-6 exerts an anti-inflammatory effect by affecting microglia is not fully understood. In this study, we investigated the anti-inflammatory effects of MSCs and TSG-6 in an in vitro lipopolysaccharide (LPS)-induced BV2 microglial activation model. We found that MSCs and TSG-6 significantly inhibited the expression of pro-inflammatory mediators in activated microglia. However, MSC effects on microglia were attenuated when TSG-6 expression was silenced. In addition, we found that the activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways in LPS-stimulated BV2 microglial cells was significantly inhibited by TSG-6. Furthermore, we found that the presence of CD44 in BV2 microglial cells was essential for MSC- and TSG-6-mediated inhibition of pro-inflammatory gene expression and of NF-κB and MAPK activation in BV2 microglial cells. The results of this study suggest that MSCs can modulate microglia activation through TSG-6 and that TSG-6 attenuates the inflammatory cascade in activated microglia. Our study indicates that novel mechanisms are responsible for the immunomodulatory effect of MSCs on microglia and that MSCs, as well as TSG-6, might be promising therapeutic agents for the treatment of neurotraumatic injuries or neuroinflammatory diseases associated with microglial activation.
Highlights
Microglia, which are derived from primitive myeloid progenitor cells, are the resident immune cells of the central nervous system (CNS) [1]
We found that the presence of CD44 in BV2 microglial cells was essential for Mesenchymal stem cell (MSC)- and tumor necrosis factor (TNF)-α stimulated gene/protein 6 (TSG-6)-mediated inhibition of pro-inflammatory gene expression and of Nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) activation in BV2 microglial cells
Our study indicates that novel mechanisms are responsible for the immunomodulatory effect of MSCs on microglia and that MSCs, as well as TSG-6, might be promising therapeutic agents for the treatment of neurotraumatic injuries or neuroinflammatory diseases associated with microglial activation
Summary
Microglia, which are derived from primitive myeloid progenitor cells, are the resident immune cells of the central nervous system (CNS) [1]. Mesenchymal stem cells (MSCs) are a population of heterogeneous multipotent cells that reside primarily in bone marrow but can be found in various postnatal organs and tissues, such as adipose tissue [10], umbilical cord blood [11], and amniotic fluid [12]. These cells are relatively easy to isolate, expand rapidly in culture, and differentiate into several cellular phenotypes in vitro and in vivo. MSCs may promote functional neurological recovery, decrease apoptosis levels, foster endogenous neurogenesis, improve angiogenesis, and reduce lesion size [13]
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