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

ABSTRACT: 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.

SUBMITTER: Davidson JO

PROVIDER: S-EPMC7900589 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Davidson Joanne O JO van den Heuij Lotte G LG Fraser Mhoyra M Wassink Guido G Miller Suzanne L SL Lim Rebecca R Wallace Euan M EM Jenkin Graham G Gunn Alistair J AJ Bennet Laura L

Stem cells translational medicine 20201026 3

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. Fetuse ...[more]

PMID: 33103374

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Project description:Introduction:Cerebral white matter injury is the most common neuropathology observed in preterm infants. However, there is increasing evidence that gray matter development also contributes to neurodevelopmental abnormalities. Fetal cerebral ischemia can lead to both neuronal and non-neuronal structural-functional abnormalities, but less is known about the specific effects on interneurons. Objective:In this study we used a well-established animal model of fetal asphyxia in preterm fetal sheep to study neuropathological outcome. We used comprehensive stereological methods to investigate the total number of oligodendrocytes, neurons and somatostatin (STT) positive interneurons as well as 3D morphological analysis of STT cells 14 days following umbilical cord occlusion (UCO) in fetal sheep. Materials and Methods:Induction of asphyxia was performed by 25 min of complete UCO in five preterm fetal sheep (98-100 days gestational age). Seven, non-occluded twins served as controls. Quantification of the number of neurons (NeuN), STT interneurons and oligodendrocytes (Olig2, CNPase) was performed on fetal brain regions by applying optical fractionator method. A 3D morphological analysis of STT interneurons was performed using IMARIS software. Results:The number of Olig2, NeuN, and STT positive cells were reduced in IGWM, caudate and putamen in UCO animals compared to controls. There were also fewer STT interneurons in the ventral part of the hippocampus, the subiculum and the entorhinal cortex in UCO group, while other parts of cortex were virtually unaffected (p > 0.05). Morphologically, STT positive interneurons showed a markedly immature structure, with shorter dendritic length and fewer dendritic branches in cortex, caudate, putamen, and subiculum in the UCO group compared with control group (p < 0.05). Conclusion:The significant reduction in the total number of neurons and oligodendrocytes in several brain regions confirm previous studies showing susceptibility of both neuronal and non-neuronal cells following fetal asphyxia. However, in the cerebral cortex significant dysmaturation of STT positive neurons occurred in the absence of cell loss. This suggests an abnormal maturation pattern of GABAergic interneurons in the cerebral cortex, which might contribute to neurodevelopmental impairment in preterm infants and could implicate a novel target for neuroprotective therapies.

Dataset Information

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

Publications

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

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