Intravenous Multipotent Adult Progenitor Cell Therapy Attenuates Activated Microglial/Macrophage Response and Improves Spatial Learning After Traumatic Brain Injury

Abstract

We previously demonstrated that the intravenous delivery of multipotent adult progenitor cells (MAPCs) after traumatic brain injury (TBI) in rodents provides neuroprotection by preserving the blood-brain barrier and systemically attenuating inflammation in the acute time frame following cell treatment; however, the long-term behavioral and anti-inflammatory effects of MAPC administration after TBI have yet to be explored. We hypothesized that the intravenous injection of MAPCs after TBI attenuates the inflammatory response (as measured by microglial morphology) and improves performance at motor tasks and spatial learning (Morris water maze [MWM]). MAPCs were administered intravenously 2 and 24 hours after a cortical contusion injury (CCI). We tested four groups at 120 days after TBI: sham (uninjured), injured but not treated (CCI), and injured and treated with one of two concentrations of MAPCs, either 2 million cells per kilogram (CCI-2) or 10 million cells per kilogram (CCI-10). CCI-10 rats showed significant improvement in left hind limb deficit on the balance beam. On the fifth day of MWM trials, CCI-10 animals showed a significant decrease in both latency to platform and distance traveled compared with CCI. Probe trials revealed a significant decrease in proximity measure in CCI-10 compared with CCI, suggesting improved memory retrieval. Neuroinflammation was quantified by enumerating activated microglia in the ipsilateral hippocampus. We observed a significant decrease in the number of activated microglia in the dentate gyrus in CCI-10 compared with CCI. Our results demonstrate that intravenous MAPC treatment after TBI in a rodent model offers long-term improvements in spatial learning as well as attenuation of neuroinflammation. STEM CELLS TRANSLATIONAL MEDICINE 2013;2:953-960

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

“…Thirty-eight studies met inclusion criteria and underwent data extraction and quality assessment. Of these studies, some reported more than one pertinent outcome measure so that a total of 10 studies presented data for RR outcomes (16–25), 14 presented data on LV outcomes (23, 26–38), 21 assessed NSS outcomes (17–21, 23–26, 28, 29, 31, 36, 38–53), and 13 presented data on MWM testing (17, 18, 24, 26, 28, 29, 36, 38, 49–53). Specific study characteristics are listed in Table 1.…”

Propranolol and Mesenchymal Stromal Cells Combine to Treat Traumatic Brain Injury

“…A decrease in body temperature, known to decrease inflammatory responses, resulted in an increase in cellular proliferation frequency of dentate gyrus DCX‐immunoreactive cells 7 days post‐trauma [67]. Given the immunomodulatory potential of MSC in TBI [26, 33], it is conceivable that the anti‐inflammatory effects of MSCs contribute to neurogenesis in our model.…”

“…Stimulation of the thalamic region years after TBI improves arousal level, motor control, and behavioral responses [81], supporting preservation of the thalamus as a new and promising target to improve TBI outcome. Lastly, the reduction in neuroinflammatory responses holds promise in other neurodegenerative diseases besides TBI [26, 33, 37], such as Alzheimer's disease [82] and multiple sclerosis [83].…”

Clinical trials in traumatic brain injury: cellular therapy and outcome measures

“…Pati and colleagues have shown that MSCs prevent Evans blue dye extravasation (preserved BBB) after TBI and that this effect is due to up regulation and organization of the tight junctional proteins, VE‐cadherin and β‐catenin. These data have been replicated using different cell types (MAPC and bone marrow mononuclear cells [BMMNCs]) using similar TBI models and various methods to evaluate permeability . The reproducibility in multiple laboratories with various cell types and injuries support that this is one of the principal beneficial mechanisms of action with these cell types.…”