Long-term administration of amnion-derived cellular cytokine suspension promotes functional recovery in a model of penetrating ballistic-like brain injury.

Abstract

Previous work has shown that human amnion-derived progenitor (AMP) cell therapy is neuroprotective in a penetrating ballistic-like brain injury (PBBI) model. However, the neuroprotective capacity of AMP cells seemed to be mediated by the sustained secretion of AMP cell-derived neurotrophic factors, which are abundant in the amnion-derived cellular cytokine suspension (ACCS). To test this theory, the current study assessed the neuroprotective efficacy of long-term ACCS delivery in the PBBI model. Experiment 1 assessed the bioactive stability and neuroprotective capacity of ACCS in an in vitro model of neurodegeneration. Experiment 2 evaluated the therapeutic effects of ACCS delivery initiated 15 minutes after PBBI and continued for 2 weeks after injury. Experiment 3 was designed to identify the therapeutic window for long-term ACCS delivery in the PBBI model. Outcome metrics included neurobehavioral assessments and neuropathologic measures of neuroinflammation and axonal/neuronal degeneration. Experiment 1 demonstrated that ACCS is thermally stable for 1 week at 37°C and that ACCS treatment protected neurite against staurosporine toxicity. Experiment 2 identified the optimal infusion rate of ACCS (1 μL/h) and demonstrated that long-term infusion of ACCS was capable of promoting significant protection against PBBI-induced neuropathology and motor abnormalities, but was not sufficient for reducing cognitive deficits. Finally, the results of Experiment 3 showed that ACCS is effective in promoting significant neuroprotection even when onset of treatment is delayed out to 24 hours (but not 48 hours) after PBBI. Collectively, our results support the hypothesis that the neuroprotective effects of AMP cells are mediated through a sustained delivery of ACCS, which implicates ACCS as a promising neuroprotection agent for clinical study.