Abstract
BackgroundTraumatic brain injury (TBI) is a major cause of death and disability. TBI results in a prolonged secondary central neuro-inflammatory response. Previously, we have demonstrated that multiple doses (2 and 24 h after TBI) of multipotent adult progenitor cells (MAPC) delivered intravenously preserve the blood-brain barrier (BBB), improve spatial learning, and decrease activated microglia/macrophages in the dentate gyrus of the hippocampus. In order to determine if there is an optimum treatment window to preserve the BBB, improve cognitive behavior, and attenuate the activated microglia/macrophages, we administered MAPC at various clinically relevant intervals.MethodsWe administered two injections intravenously of MAPC treatment at hours 2 and 24 (2/24), 6 and 24 (6/24), 12 and 36 (12/36), or 36 and 72 (36/72) post cortical contusion injury (CCI) at a concentration of 10 million/kg. For BBB experiments, animals that received MAPC at 2/24, 6/24, and 12/36 were euthanized 72 h post injury. The 36/72 treated group was harvested at 96 h post injury.ResultsAdministration of MAPC resulted in a significant decrease in BBB permeability when administered at 2/24 h after TBI only. For behavior experiments, animals were harvested post behavior paradigm. There was a significant improvement in spatial learning (120 days post injury) when compared to cortical contusion injury (CCI) in groups when MAPC was administered at or before 24 h. In addition, there was a significant decrease in activated microglia/macrophages in the dentate gyrus of hippocampus of the treated group (2/24) only when compared to CCI.ConclusionsIntravenous injections of MAPC at or before 24 h after CCI resulted in improvement of the BBB, improved cognitive behavior, and attenuated activated microglia/macrophages in the dentate gyrus.
Highlights
Traumatic brain injury (TBI) is a major cause of death and disability
We have demonstrated that multiple doses of multipotent adult progenitor cells [MAPC (2/24 h after TBI)] at 10 million/kg body weight reduced blood-brain barrier (BBB) permeability and reduced the number of activated microglia/macrophages in the dentate gyrus
There was a trend in reduction in the integrated signal between cortical contusion injury (CCI) and CCI-6/24 at 10–60K (p < 0.06, Fig. 1b), and there was a significant difference between sham and CCI at 10–60K (p < 0.01, Fig. 1a)
Summary
Traumatic brain injury (TBI) is a major cause of death and disability. TBI results in a prolonged secondary central neuro-inflammatory response. We have demonstrated that multiple doses (2 and 24 h after TBI) of multipotent adult progenitor cells (MAPC) delivered intravenously preserve the blood-brain barrier (BBB), improve spatial learning, and decrease activated microglia/macrophages in the dentate gyrus of the hippocampus. Intravenous delivery of MAPC after TBI results in an increase in splenocyte and plasma T regulatory cell populations, with an increase in locoregional antiinflammatory microglia/macrophages [12]. Multipotent adult progenitor cells treatment after cortical contusion injury (CCI) resulted in a significant increase in anti-inflammatory cytokine interleukin-10 (IL-10) [3]. In the absence of spleen, there is no effect of MAPC after TBI on microglia [3], thereby necessitating the involvement of spleen These cells do not require honing to the brain to exert paracrine effect. Similar results have been demonstrated with other cell types in TBI [13]
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