Autologous bone marrow mononuclear cells therapy attenuates activated microglial/macrophage response and improves spatial learning after traumatic brain injury

Abstract

Background Autologous bone marrow-derived mononuclear cells (AMNC) have shown therapeutic promise for central nervous system insults such as stroke and traumatic brain injury (TBI). We hypothesized that intravenous injection of AMNC provides neuroprotection which leads to cognitive improvement after TBI. Methods A controlled cortical impact (CCI) rodent traumatic brain injury (TBI) model was used to examine blood-brain barrier permeability (BBB), neuronal and glial apoptosis and cognitive behavior. Two groups of rats underwent CCI with (CCI-Autologous) or without AMNC treatment (CCI-Alone), consisting of 2 million AMNC/kilogram body weight harvested from the tibia and intravenously injected 72 hr after injury. CCI-Alone animals underwent sham harvests and received vehicle injections. Results 96 hr after injury, AMNC significantly reduced the BBB permeability in injured animals, and there was an increase in apoptosis of pro-inflammatory activated microglia in the ipsilateral hippocampus. At 4 weeks after injury, we examined changes in spatial memory after TBI due to AMNC treatment. There was a significant improvement in probe testing of CCI-Autologous group in comparison to CCI-Alone in the Morris Water Maze paradigm. Conclusions Our data demonstrate that the intravenous injection of AMNC after TBI leads to neuroprotection by preserving early BBB integrity and increasing activated microglial apoptosis. In addition, AMNC also improves cognitive function.

Autologous Bone Marrow Mononuclear Cells Exert Broad Effects on Short- and Long-Term Biological and Functional Outcomes in Rodents with Intracerebral Hemorrhage

“…MNCs are a heterogeneous population of cells that include mesenchymal stem cells, hematopoietic progenitor cells, endothelial progenitor cells, and several different committed cells of various lineages. Previous reports have demonstrated that MNCs conferred beneficial effects against various types of brain damage, including models of focal cerebral ischemia, transient global cerebral ischemia, chronic cerebral ischemia, and traumatic brain injury [9,[31][32][33]. In this study, we now show that intravenous administration of autologous MNCs reduces injury and enhances recovery in the autologous blood injection ICH model.…”

Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis

“…These important variables can be concordant but not merged for a meta-analysis. For example Evans Blue dye extravasation can show a 40% reduction in blood-brain barrier permeability with bone marrow derived mononuclear cells (52), and similar results can be obtained using an Alexa-Fluor fluorescent dye with permeability mapping (75). However, accuracy is lost in trying to harmonize the effect magnitude using different measurement techniques.…”

Strategies for CNS repair following TBI

“…Additional animal models have shown that administration of bone marrow derived stem cells is able to illicit an increase in the regulatory T cell response following injury (see figure 4) and increase the M2:M1 ratio of macrophages and microglia in the acute phase (Walker et al, 2012a). This alteration has also been shown with BM-MNC and may be due to a proapoptotic CC3 dependent pathway that is selective for the activated microglial population (Bedi et al, 2013b). While attenuation of the inflammatory response occurs acutely, the duration of this change is unknown and other experiments have shown the prolonged M1 response found in TBI to be associated with white matter injury .…”

“…Finally, preservation or restoration of the blood brain barrier by cell therapies could have beneficial effects on the inflammatory response to injury. Multiple studies in animal models have shown intravenous administration of BM-MNC, MAPC and MSC to preserve blood brain barrier integrity (Bedi et al, 2013b;Menge et al, 2012;Walker et al, 2012a;Walker et al, 2010b). …”