Cerebral Ischemia or Intrauterine Inflammation Promotes Differentiation of Oligodendroglial Precursors in Preterm Ovine Fetuses: Possible Cellular Basis for White Matter Injury

Abstract

White matter injury in premature infants is known to be major cause of long-term neurocognitive disability, but the pathogenic mechanism remains unclear, hampering our ability to develop preventions. Periventricular leukomalacia is a severe form of white matter injury. In the present study, we explored the effects of cerebral ischemia and/or intrauterine inflammation on the development of oligodendroglia in the cerebral white matter using chronically instrumented fetal sheep. Each fetus received one of three insults: hemorrhage, inflammation and their combination. In the hemorrhage group, 40% of the fetoplacental blood volume was acutely withdrawn, and 24 hours after removal, the blood was returned to the fetus. The inflammation group received intravenous granulocyte-colony stimulating factor and intra-amniotic endotoxin and thus suffered from necrotizing funisitis and chorioamnionitis. The inflammatory hemorrhage group underwent acute hemorrhage under the inflammatory state. The sham group received no insults. Importantly, periventricular leukomalacia was not detected in the sham and the inflammation groups. Differentiating oligodendroglia at various developmental stages were identified by immunohistochemical analysis with specific antibodies. No difference in the density of oligodendroglial progenitors was detected among the four groups, whereas oligodendroglial precursors were significantly reduced in the three insult groups, compared to sham control. Moreover, the density of immature oligodendroglia was higher in the inflammation group and the inflammatory hemorrhage group, while the density of mature oligodendroglia was highest in the hemorrhage group. We propose that cerebral ischemia or intrauterine inflammation induces the differentiation of oligodendroglial precursors in preterm fetuses, eventually resulting in their exhaustion.

Akt/mTOR Pathway Agonist SC79 Inhibits Autophagy and Apoptosis of Oligodendrocyte Precursor Cells Associated with Neonatal White Matter Dysplasia

“…The observed decrease in mean MBP + immunofluorescence intensity and CNPase + optical density of white matter of the LPS group therefore indicate that LPS inhibits OPC maturation and myelination. The mechanism by which intrauterine inflammation leads to white matter maturation disorders is complex, and abnormal OPC apoptosis is considered one of the main causes of WMI [8,23,24,26]. Our group previously demonstrated that in the early stages of WMI in neonatal rats, induced by intrauterine inflammation, significant up-regulation of Akt phosphorylation can reduce the number of apoptotic OPCs and protect against white matter damage [27].…”

“…Intrauterine endotoxin exposure can lead to continuous activation of microglia in the neonatal periventricular white matter [7]. Numerous proinflammatory cytokines are released from activated microglia and induce apoptosis of oligodendrocyte precursor cells (OPCs), thereby impairing the proliferation, differentiation, migration, and maturation of oligodendrocyte lineage cells in the white matter [8]. Promoting WMD recovery is an method to rescue white matter damage.…”

Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

“…The white matter is particularly vulnerable to ischemia and injury because of the very low pressure of perfusion [46]. Ischemia and intrauterine inflammation may cause premature differentiation of the oligodendrocytes, thereby increasing vulnerability to fatal insults [47]. Correspondingly, chorioamnionitis predisposes preterm neonates to periventricular leukomalacia [48], periventricular hemorrhagic infarction [49], cerebral palsy [50], and to many other permanent cerebral deficits such as chronic epilepsy and intellectual disability [45,51].…”