Introduction: Intrauterine inflammation is recognized as a major cause of preterm birth and neurological complications in the developing brain. This study aims to examine whether human Amnion Epithelial Cells (hAECs) can be used as a potential therapeutic agent to reduce brain injury induced by inflammation (lipopolysaccharide, LPS) in preterm fetal sheep.
Methods: Pregnant ewes underwent surgery at ~105 days of gestation (term is ~ 147 days) for implantation of catheters into the fetal brachial artery and femoral vein. LPS was administered at 109, 110 and 111 d via the femoral vein and fluorescent-labeled hAECs were administered at 110, 111, and 112 d via the brachial artery. Control fetuses received saline. Brains were collected at 114 d gestation for histological assessment of brain injury.
Results: hAECs were observed throughout the brain, with large numbers (up to 30 ± 5 cells/mm2) identified in the white matter, cortex and the hippocampus. Pyknotic degenerating cells were evident and increased within LPS brains; in the thalamus (100-fold increase vs control), and hippocampal CA1 region (80-fold increase vs control). hAECs administration significantly reduced pyknotic cell numbers in the thalamus and the hippocampus compared to LPS alone. The number of neurons within the CA1 region of the hippocampus was significantly reduced in the LPS brains (57 ± 20 cells/mm2) compared to control and LPS+hAECs (761 ± 13 cells/mm2) -treated animals. Circulating fetal cytokine concentrations have been evaluated and it appears that hAECs reduce TNF-a levels 6 hours following LPS administration.
Conclusion: hAEC administration to fetuses in an LPS model of fetal inflammation reduces neuronal cell loss, which is likely mediated by dampening the fetal inflammatory response.