Lack of Neuroprotection with a Single Intravenous Infusion of Human Amnion Epithelial Cells after Severe Hypoxia–Ischemia in Near-Term Fetal Sheep

Abstract

Background: Hypoxic–ischemic encephalopathy (HIE) around the time of birth results from loss of oxygen (hypoxia) and blood supply (ischemia). Exogenous infusion of multi-potential cells, including human amnion epithelial cells (hAECs), can reduce hypoxic–ischemic (HI) brain injury. However, there are few data on treatment of severe HI in large animal paradigms at term. The aim of the current study was to determine whether infusion of hAECs early after injury may reduce brain damage after ischemia in near-term fetal sheep. Methods: Chronically instrumented fetal sheep (0.85 gestation) received 30 min of global cerebral ischemia followed by intravenous infusion of hAECs from 2 h after the end of ischemia (ischemia-hAEC, n = 6) or saline (ischemia-vehicle, n = 7). Sham control animals received sham ischemia with vehicle infusion (sham control, n = 8). Results: Ischemia was associated with significant suppression of EEG power and spectral edge frequency until the end of the experiment and a secondary rise in cortical impedance from 24 to 72 h, which were not attenuated by hAEC administration. Ischemia was associated with loss of neurons in the cortex, thalamus, striatum and hippocampus, loss of white matter oligodendrocytes and increased microglial numbers in the white matter, which were not affected by hAEC infusion. Conclusions: A single intravenous administration of hAECs did not reduce electrographic or histological brain damage after 30 min of global cerebral ischemia in near-term fetal sheep.

Therapeutic Hypothermia Attenuates Cortical Interneuron Loss after Cerebral Ischemia in Near-Term Fetal Sheep

“…It should be noted that the correlations between interneuron survival and EEG power were modest and were only observed for the GAD + and parvalbumin + populations. This likely reflects our previous findings of more widespread neuronal and glial cell death in this experimental model, including within multiple populations of neurons in the cerebral cortex, striatum, and hippocampus [ 42 , 43 , 44 , 45 , 46 ], as well as oligodendrocyte cell death and axonal injury in the white matter [ 46 ].…”

Advances in neonatal cell therapies: Proceedings of the First Neonatal Cell Therapies Symposium (2022)

“…The efficacy of hAECs in HI injury was assessed in fetal sheep models of preterm HI injury to examine this question. 71 – 73 Preterm animals were given a single intracerebroventricular hAEC infusion (1 × 10 6 ), at either 2 or 24 h post-HI injury induced by umbilical cord occlusion. The histological effects at 1 week after injury were similar after both dosing time points.…”

“… 72 In contrast to these studies, intravenous hAECs given 2 hours post insult did not confer neuroprotection or anti-inflammatory effects in term rodent models of perinatal HI injury. 73 Neuroprotection failure may relate to age, route of administration, or nature of the insult, but these data raise the intriguing possibility that early cell treatment may not be optimal.…”