Human Amniotic Epithelial Cell Therapy for Neuroprotection and Neuro-repair after Perinatal Asphyxial Brain Injury

Abstract

The primary purpose of this thesis was to investigate the effects of human amniotic epithelial cells (hAECs) on preterm and term brain injury after hypoxic-ischaemic (HI) insults. I also examined the long-term effects of asphyxia on the neural development, and the pre-HI conditioning of inflammation on the preterm fetal responses to asphyxia. A secondary aim was to assess the effect of hAECs on the recovery of fetal EEG, cardiovascular and cerebrovascular activity, biochemistry and cytokines after HI insults. In chapter 3, I tested the hypothesis that acute-on-chronic exposure to LPS would exacerbate white matter injury after subsequent asphyxia in preterm fetal sheep. Contrary to this hypothesis, the combination of acute-on-chronic LPS with subsequent asphyxia reduced neuroinflammation and white matter injury. In chapters 4 and 5, I examined the effect of hAECs given i.c.v. at 2 and 24 hours post- asphyxia in preterm fetal sheep, with outcomes studied at 7 days. HAEC treatment in both groups significantly reduced neuronal injury in selected subcortical regions, and improved CNPase positive cells in selected regions. These changes were associated with a significant reduction in microglia and astrocytes in both groups, and reduced plasma pro-inflammatory and increased anti-inflammatory cytokines and modulated seizure activity in the 2 hour, but not the 24 hour study. In chapter 6, I investigated the 21 day recovery of preterm fetal sheep after asphyxia, and observed that inflammation does not resolve. HAEC treatment via intranasal administration at 1, 3 and 10 days after asphyxia significantly reduced neuronal injury, white matter hypomyelination, neural inflammation, and improved EEG maturation. In chapter 7, I examined the effects of hAECs given intravenously on injury after cerebral ischaemia with a 7 day follow-up. HAECs did not improve neuronal or glia cell loss, or reduce inflammation. Treatment was associated with an earlier onset of seizures. My data demonstrate, for the first time, that hAECs are neuroprotective after an HI insult in preterm, but not term fetal sheep. Treatment efficacy is in part due to immunomodulation. We did not observe an effect on cardiovascular or cerebrovascular variables suggesting the treatment is safe.