Window of opportunity for human amnion epithelial stem cells to attenuate astrogliosis after umbilical cord occlusion in preterm fetal sheep

• Published in: Stem cells translational medicine Vol. 10; no. 3; pp. 427 - 440
• Main Authors: Davidson, Joanne O., Heuij, Lotte G., Fraser, Mhoyra, Wassink, Guido, Miller, Suzanne L., Lim, Rebecca, Wallace, Euan M., Jenkin, Graham, Gunn, Alistair J., Bennet, Laura
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.03.2021; Oxford University Press
• Subjects: Amnion; Amniotic fluid; Anesthesia; asphyxia; Asphyxia neonatorum; Astrocytes; Brain injury; Brain research; Bupivacaine; Carotid arteries; Catheters; Cerebral blood flow; EEG; Electroencephalography; Epithelial cells; Ethics; Ethylenediaminetetraacetic acid; Fetuses; Gestation; Gliosis; Heart rate; Hypoxia; Inflammation; Intracerebroventricular administration; Ischemia; Microglia; Myelination; Neostriatum; Neuroprotection; Newborn babies; Oligodendrocytes; Oxytetracycline; Penicillin G; Pluripotent Stem Cells; preterm birth; Sheep; Stem cell research; Stem cells; Substantia alba; Substantia grisea; Surgery; Thalamus; Umbilical cord; Uterus; Veins & arteries; Ventilation; New Zealand; California; Australia; United States; United States > US; preterm birth; stem cells; inflammation; neuroprotection; asphyxia
• ISSN: 2157-6564; 2157-6580; 2157-6580
• DOI: 10.1002/sctm.20-0314

There is increasing evidence that administration of many types of stem cells, including human amnion epithelial cells (hAECs), can reduce hypoxic‐ischemic injury, including in the perinatal brain. However, the therapeutic window for single dose treatment is not known. We compared the effects of early and delayed intracerebroventricular administration of hAECs in fetal sheep at 0.7 gestation on brain injury induced by 25 minutes of complete umbilical cord occlusion (UCO) or sham occlusion. Fetuses received either 1 × 106 hAECs or vehicle alone, as an infusion over 1 hour, either 2 or 24 hours after UCO. Fetuses were killed for brain histology at 7 days post‐UCO. hAEC infusion at both 2 and 24 hours had dramatic anti‐inflammatory and anti‐gliotic effects, including significantly attenuating the increase in microglia after UCO in the white and gray matter and the number of astrocytes in the white matter. Both protocols partially improved myelination, but had no effect on total or immature/mature numbers of oligodendrocytes. Neuronal survival in the hippocampus was increased by hAEC infusion at either 2 or 24 hours, whereas only hAECs at 24 hours were associated with improved neuronal survival in the striatum and thalamus. Neither protocol improved recovery of electroencephalographic (EEG) power. These data suggest that a single infusion of hAECs is anti‐inflammatory, anti‐gliotic, and neuroprotective in preterm fetal sheep when given up to 24 hours after hypoxia‐ischemia, but was associated with limited white matter protection after 7 days recovery and no improvement in the recovery of EEG power. Human amnion epithelial cells normalize microgliosis and astrogliosis after asphyxia.