Neuropathology in intrauterine growth restricted newborn piglets is associated with glial activation and proinflammatory status in the brain

Abstract

BackgroundThe fetal brain is particularly vulnerable to intrauterine growth restriction (IUGR) conditions evidenced by neuronal and white matter abnormalities and altered neurodevelopment in the IUGR infant. To further our understanding of neurodevelopment in the newborn IUGR brain, clinically relevant models of IUGR are required. This information is critical for the design and implementation of successful therapeutic interventions to reduce aberrant brain development in the IUGR newborn. We utilise the piglet as a model of IUGR as growth restriction occurs spontaneously in the pig as a result of placental insufficiency, making it a highly relevant model of human IUGR. The purpose of this study was to characterise neuropathology and neuroinflammation in the neonatal IUGR piglet brain.MethodsNewborn IUGR (< 5th centile) and normally grown (NG) piglets were euthanased on postnatal day 1 (P1; < 18 h) or P4. Immunohistochemistry was utilised to examine neuronal, white matter and inflammatory responses, and PCR for cytokine analysis in parietal cortex of IUGR and NG piglets.ResultsThe IUGR piglet brain displayed less NeuN-positive cells and reduced myelination at both P1 and P4 in the parietal cortex, indicating neuronal and white matter disruption. A concurrent decrease in Ki67-positive proliferative cells and increase in cell death (caspase-3) in the IUGR piglet brain was also apparent on P4. We observed significant increases in the number of both Iba-1-positive microglia and GFAP-positive astrocytes in the white matter in IUGR piglet brain on both P1 and P4 compared with NG piglets. These increases were associated with a change in activation state, as noted by altered glial morphology. This inflammatory state was further evident with increased expression levels of proinflammatory cytokines (interleukin-1β, tumour necrosis factor-α) and decreased levels of anti-inflammatory cytokines (interleukin-4 and -10) observed in the IUGR piglet brains.ConclusionsThese findings suggest that the piglet model of IUGR displays the characteristic neuropathological outcomes of neuronal and white matter impairment similar to those reported in the IUGR human brain. The activated glial morphology and elevated proinflammatory cytokines is indicative of an inflammatory response that may be associated with neuronal damage and white matter disruption. These findings support the use of the piglet as a pre-clinical model for studying mechanisms of altered neurodevelopment in the IUGR newborn.

RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer’s disease

“…Injection of MSC-Exo and MSC-RVG-Exo could significantly attenuate the expression of GFAP in the brain. GFAP is just not an astrocyte marker, but also the marker of astrocyte activation because of the morphologic changes of astrocyte could be observed after immunostaining of GFAP [17–19]. The processes of astrocytes in AD group become thicker and the number of processes was increased when visualized with antibodies against GFAP.…”

Neurovascular effects of umbilical cord blood-derived stem cells in growth-restricted newborn lambs

“…Animal models of FGR show that neuroinflammation is upregulated in areas of white and gray matter that are vulnerable to damage [25][26][27]. Cerebral inflammation can disrupt neuronal and oligodendrocyte development [28] leading to life-long neurological deficits.…”

TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model

“…A significant proportion of activated microglia had an amoeboid morphology which was characterized by darker cell bodies and thickened retracted processes, indicating a phagocytic phenotype (41). Additionally, the ramified/resting microglia were characterized by light round or oval cell bodies with fine symmetrical extended processes that were easy to distinguish (42). Few activated microglia were found at 1 d after ischemia, but a strong response was visible in the penumbra at 3 d, occurring in both the TMEM16F knockdown group and untreated animals ( Figure 5A).…”