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

Abstract

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.

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

“…NOD-scid mice were selected to enable comparison between in vitro (Figs. [1][2][3][4][5][6][7][8] and in vivo (Figs. 9, 10) data, in which donor human cells were xenografted into the mouse spinal cord.…”

“…The immunomodulatory effects of donor stem cells on the host have been studied extensively, particularly in the case of mesenchymal stem cell populations, but also in the context of NSC populations (8)(9)(10)(11)(12). The converse, that is the effect of the host cellular immune response on donor stem cells, has received less attention.…”

Calcitriol modulates the effects of the supernatants of bone-marrow–derived mesenchymal stem cells on neutrophil functions

“…They also have potent immunomodulatory properties and may be valuable tools for cell-based immunotherapy (Meirelles Lda et al, 2009;Ghannam et al, 2010;Zhang et al, 2013). MSCs in bone marrow and tissue form a niche that has inevitable interactions with hematopoietic cells including neutrophils (Raffaghello et al, 2008;Maqbool et al, 2011).…”

Autologous Bone Marrow Mononuclear Cells Reduce Therapeutic Intensity for Severe Traumatic Brain Injury in Children

“…In 2008, we completed a two year Phase I trial with ten children using autologous BMMNCs delivered intravenously within 48 hours of injury and found this approach to be safe, though a secondary finding with underlying mechanistic potential was preservation of selected brain structures on follow-up MRI 38 . Concurrent preclinical rodent experiments demonstrated that cell based therapies could reduce the amount of locoregional brain edema in the acute post injury period, suggesting that therapy allows for preservation or recovery of the blood brain barrier [39][40][41] . We thus questioned whether or not this preclinical acute treatment associated effect could be retrospectively demonstrated in our human trials.…”