Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury

Abstract

BACKGROUND: Previous 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/RESULTS: MSCs 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. CONCLUSIONS: The 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.