Human Amnion Epithelial Cells Reduce Fetal Brain Injury in Response to Intrauterine Inflammation

Abstract

Intrauterine infection, such as occurs in chorioamnionitis, is a principal cause ofpreterm birth and is a strong risk factor for neurological morbidity and cerebral palsy. 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 intra-amniotic administration of lipopolysaccharide (LPS) in preterm fetal sheep. Pregnant ewes underwent surgery at approximately 110 days of gestation (term is approx. 147 days) for implantation of catheters into the amniotic cavity, fetal trachea, carotid artery and jugular vein. LPS was administered at 117 days; hAECs were labeled with carboxyfluorescein succinimidyl ester and administered at 0, 6 and 12 h, relative to LPS administration, into the fetal jugular vein, trachea or both. Control fetuses received an equivalent volume of saline. Brains were collected 7 days later for histological assessment of brain injury. Microglia (Iba-1-positive cells) were present in the brain of all fetuses and were significantly increased in the cortex, subcortical and periventricular white matter in fetuses that received LPS, indicative of inflammation. Inflammation was reduced in fetuses that received hAECs. In LPS fetuses, the number of TUNEL-positive cells was significantly elevated in the cortex, periventricular white matter, subcortical white matter and hippocampus compared with controls, and reduced in fetuses that received hAECs in the cortex and periventricular white matter. Within the fetal brains studied there was a significant positive correlation between the number of Iba-1-immunoreactive cells and the number of TUNEL-positive cells (R² = 0.19, p < 0.001). The administration of hAECs protects the developing brain when administered concurrently with the initiation of intrauterine inflammation.

Human Amnion Epithelial Cells Modulate Ventilation-Induced White Matter Pathology in Preterm Lambs

“…Prior studies exploring the protective effects of hAECs in lamb models of inflammation-induced lung and brain injury have clearly demonstrated their anti-inflammatory and reparative effects over a period of 1 week [19,21]. The lack of such effects in our study is probably due to the timing of cell administration or the short duration of the experiment.…”

“…Fetal lung inflammation induced by intra-amniotic lipopolysaccharide injection is attenuated by hAEC administration [19], and ventilation-induced abnormal lung remodelling in fetal sheep is also reduced [20]. The neuroprotective capacity of hAECs has not been extensively studied; however, hAECs are capable of reducing brain inflammation and injury in preterm fetal sheep exposed to intra-amniotic lipopolysaccharide [21]. …”

Respiratory support for premature neonates in the delivery room: effects on cardiovascular function and the development of brain injury

“…This can result in increased number of infiltrating inflammatory cells, activation of resident microglia (which causes local amplification of proinflammatory cytokines), increased oxidative stress, and subsequent diffuse white matter gliosis within the periventricular white matter, subcortical white matter, and corpus callosum (Figure 4) (4,58,59). This brain inflammatory environment, notably an increase in activated microglial cells, is a prominent feature of neuropathologies and can be correlated with brain cell death (60). As a clinical correlate, diffuse "microstructural" white matter injury within the corpus callosum in infants born at <33 wk gestation is clinically associated with poor cognitive function at 19 years of age (61).…”

Ventilation-Induced Brain Injury in Preterm Neonates: A Review of Potential Therapies

“…They express neural genes and secrete multiple neurotransmitters [66,67]. Only one study to date has demonstrated neuroprotective and anti-inflammatory responses after intravenous and intratracheal hAEC administration in the neonatal brain following inflammation-induced brain injury in fetal sheep [68]. Given that hAEC are able to protect the preterm lung from in utero ventilation- and inflammation-induced lung injury [63,64], and that they protect the brain from in utero inflammation-induced damage [68], they may also have the potential to protect against ventilation-induced brain injury as a postnatal treatment.…”

“…Only one study to date has demonstrated neuroprotective and anti-inflammatory responses after intravenous and intratracheal hAEC administration in the neonatal brain following inflammation-induced brain injury in fetal sheep [68]. Given that hAEC are able to protect the preterm lung from in utero ventilation- and inflammation-induced lung injury [63,64], and that they protect the brain from in utero inflammation-induced damage [68], they may also have the potential to protect against ventilation-induced brain injury as a postnatal treatment. We observed an apparent beneficial effect of hAEC on brain inflammation as a result of high V T ventilation; hAEC (administered both intravenously and intratracheally) reduced microgliosis and vascular protein extravasation in the brain 2 h after of ventilation onset [9].…”