BackgroundPrevious studies have shown beneficial effects of mesenchymal stem cell (MSC) transplantation in central nervous system (CNS) injuries, including traumatic brain injury (TBI). Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs. However, few studies have simultaneously focused on the effects of MSCs on immune cells and inflammation-associated cytokines in CNS injury, especially in an experimental TBI model. In this study, we investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation by systemic transplantation of MSCs into a rat TBI model.Methods/resultsMSCs were transplanted intravenously into rats 2 h after TBI. Modified neurologic severity score (mNSS) tests were performed to measure behavioral outcomes. The effect of MSC treatment on neuroinflammation was analyzed by immunohistochemical analysis of astrocytes, microglia/macrophages, neutrophils and T lymphocytes and by measuring cytokine levels [interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-α, interferon-γ, RANTES, macrophage chemotactic protein-1, macrophage inflammatory protein 2 and transforming growth factor-β1] in brain homogenates. The immunosuppression-related factors TNF-α stimulated gene/protein 6 (TSG-6) and nuclear factor-κB (NF-κB) were examined by reverse transcription-polymerase chain reaction and Western blotting. Intravenous MSC transplantation after TBI was associated with a lower density of microglia/macrophages and peripheral infiltrating leukocytes at the injury site, reduced levels of proinflammatory cytokines and increased anti-inflammatory cytokines, possibly mediated by enhanced expression of TSG-6, which may suppress activation of the NF-κB signaling pathway.ConclusionsThe results of this study suggest that MSCs have the ability to modulate inflammation-associated immune cells and cytokines in TBI-induced cerebral inflammatory responses. This study thus offers a new insight into the mechanisms responsible for the immunomodulatory effect of MSC transplantation, with implications for functional neurological recovery after TBI.

Cerebral vascular endothelial cell (CEC) degeneration significantly contributes to blood-brain barrier (BBB) breakdown and neuronal loss after cerebral ischemia. Recently, emerging data suggest that peroxisome proliferator-activated receptor ␦ (PPAR␦) activation has a potential neuroprotective role in ischemic stroke. Here we report for the first time that PPAR␦ is significantly reduced in oxygen-glucose deprivation (

The release of amyloid precursor protein (APP) intracellular domain (AICD) may be triggered by extracellular cues through γ-secretase-dependent cleavage. AICD binds to Fe65, which may have a role in AICD-dependent signalling; however, the functional ligand has not been characterized. In this study, we have identified TAG1 as a functional ligand of APP. We found that, through an extracellular interaction with APP, TAG1 increased AICD release and triggered Fe65-dependent activity in a γ-secretasedependent manner. TAG1, APP and Fe65 colocalized in the neural stem cell niche of the fetal ventricular zone. Neural precursor cells from TAG1 -/-, APP -/-and TAG1 -/-;APP -/-mice had aberrantly enhanced neurogenesis, which was significantly reversed in TAG1 -/-mice by TAG1 or AICD but not by AICD mutated at the Fe65 binding site. Notably, TAG1 reduced normal neurogenesis in Fe65 +/+ mice. Abnormally enhanced neurogenesis also occurred in Fe65 -/-mice but could not be reversed by TAG1. These results describe a TAG1-APP signalling pathway that negatively modulates neurogenesis through Fe65.The γ-secretase proteolytic complex cleaves a wide spectrum of type-1 transmembrane protein substrates, including Notch and APP, by regulated intramembrane proteolysis (RIP) to release their intracellular domains 1 . Ligand-binding to the substrate protein is one mechanism by which this cleavage is regulated. When a ligand binds to Notch, RIP stimulates the release of the intracellular domain of Notch (NICD), which interacts with the transcription factor CSL (CBF1, Suppressor of Hairless and Lag1; ref. 1). Similar transcriptional activity or regulation has been proposed for the intracellular domains cleaved from other γ-secretase substrates, including AICD, which is cleaved from APP 1 . It is therefore important to understand the physiological mechanisms regulating cleavage of AICD.Glycophosphatidylinositol (GPI)-linked proteins are anchored to the outer leaflet of the plasma membrane and mediate the dynamic remodelling of membranes during cell-cell interactions. In the central nervous system (CNS), GPI-linked recognition molecules, such as TAG1, NB-3 and F3, have been implicated in key developmental events, including selective axonal fasciculation, neural cell adhesion and migration, and neurite outgrowth 2 . Recently, we identified F3 and its homologue NB-3 as functional ligands for the Notch receptor and we showed that their interaction with each other is involved in oligodendrocyte differentiation through activation of the transcriptional factor Deltex1 (refs 3, 4). Given that RIP processing of APP is strikingly similar to that of the Notch receptor 5 , knowledge of the interaction between F3 and the Notch receptor has led us to ask whether members of the F3 family may act as APP ligands. RESULTS TAG1 and APP bind to each otherTo investigate the potential interaction between APP and members of the F3 subfamily, cell adhesion assays were performed. When F3-transfected CHO (CHOF3) cells or non-transfected CHO cells were seeded onto c...