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A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
Human amnion epithelial cells reduce fetal brain injury in response to intrauterine inflammation
Tamara Yawno1, Joyce Schuilwerve, Timothy J M Moss
1The Ritchie Centre, Monash Institute of Medical Research, Clayton, Vic., Australia.
Insights
Human amnion epithelial cells (hAECs) can protect preterm fetal sheep brains from inflammation and injury caused by intrauterine infection. This finding offers a potential therapeutic strategy for preventing neurological damage in premature infants.
Area of Science:
- Neuroscience
- Developmental Biology
- Regenerative Medicine
Background:
- Intrauterine infection is a primary cause of preterm birth and subsequent neurological deficits, including cerebral palsy.
- Lipopolysaccharide (LPS) administration in fetal sheep models mimics intrauterine infection, inducing brain inflammation and injury.
- Human amnion epithelial cells (hAECs) are being investigated for their therapeutic potential in various conditions.
Purpose of the Study:
- To evaluate the efficacy of human amnion epithelial cells (hAECs) in mitigating lipopolysaccharide (LPS)-induced brain injury in preterm fetal sheep.
- To assess the impact of hAEC administration on inflammatory markers and cell death in the developing fetal brain.
Main Methods:
- Preterm fetal sheep underwent surgical catheter implantation for monitoring and administration of substances.
- Intra-amniotic lipopolysaccharide (LPS) was administered to induce inflammation, followed by intravenous or intratracheal administration of labeled hAECs at different time points.
- Brains were collected seven days post-LPS administration for histological analysis, including assessment of microglia (Iba-1) and apoptotic cells (TUNEL).
Main Results:
- LPS administration significantly increased microglia and TUNEL-positive cells in fetal sheep brains, indicating inflammation and cell death.
- Concurrent administration of hAECs reduced microglial activation and the number of TUNEL-positive cells in key brain regions, particularly the cortex and white matter.
- A positive correlation was observed between microglial presence and cell death, highlighting the link between inflammation and neuronal injury.
Conclusions:
- Human amnion epithelial cells (hAECs) demonstrate a protective effect against intrauterine inflammation-induced brain injury in a preterm fetal sheep model.
- hAEC administration can attenuate key markers of neuroinflammation and apoptosis in the developing brain.
- These findings suggest hAECs hold promise as a therapeutic agent to prevent neurological complications associated with preterm birth and intrauterine infection.
Abstract:
Intrauterine infection, such as occurs in chorioamnionitis, is a principal cause of preterm 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 (R(2) = 0.19, p < 0.001). The administration of hAECs protects the developing brain when administered concurrently with the initiation of intrauterine inflammation.
