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MicroRNAs participate in the murine oligodendroglial response to perinatal hypoxia-ischemia.

ABSTRACT: Hypoxic-ischemic injury (HI) to preterm brain results in white matter loss. The endogenous oligodendroglial response to perinatal HI is characterized by increased oligodendroglial progenitor cells (OPCs). MicroRNAs (miRs) are important post-transcriptional regulators of gene expression, and a few miRs have been shown to regulate differentiation of OPCs into mature oligodendroglia. We tested the hypothesis that miRs play a role in the increase in OPCs in response to perinatal HI.We inducibly deleted the miR-processing enzyme Dicer in OPCs using a tamoxifen-inducible NG2CreER(T2) transgene in Dicer(fl/fl) mice. After HI, mice were analyzed for OPC differentiation using immunofluorescence and for white matter formation by Luxol fast blue (LFB) staining. Functional recovery from injury was investigated using digital gait analysis. We also tested whether HI changed miRs known to regulate OPC differentiation using quantitative RT-PCR.Perinatal HI induced significant increases in miR-138 and miR-338, two miRs known to regulate OPC differentiation. Knockdown of Dicer increased myelin basic protein and LFB staining within the corpus callosum after HI. In addition, there was significant improvement in motor function 14 and 24 d post lesion.Changes in specific mature miRs expressed in OPCs following HI may contribute to white matter injury.

SUBMITTER: Birch D

PROVIDER: S-EPMC4167925 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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MicroRNAs participate in the murine oligodendroglial response to perinatal hypoxia-ischemia.

Birch Derin D Britt Blair C BC Dukes Silena C SC Kessler John A JA Dizon Maria L V ML

Pediatric research 20140708 4

<h4>Background</h4>Hypoxic-ischemic injury (HI) to preterm brain results in white matter loss. The endogenous oligodendroglial response to perinatal HI is characterized by increased oligodendroglial progenitor cells (OPCs). MicroRNAs (miRs) are important post-transcriptional regulators of gene expression, and a few miRs have been shown to regulate differentiation of OPCs into mature oligodendroglia. We tested the hypothesis that miRs play a role in the increase in OPCs in response to perinatal H ...[more]

PMID: 25003912

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Project description:Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near-term lambs (n = 27) were resuscitated after the induction of 5 min of asystole. Following recovery, lambs were assessed to define neurodevelopmental outcomes. At the end of this period, lambs were euthanized, and brains were harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enabled identification of animals that recover significant neurological function. Approximately 35% of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matters, oligodendrocyte loss, neuronal loss, and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex, they demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.

Dataset Information

MicroRNAs participate in the murine oligodendroglial response to perinatal hypoxia-ischemia.

Publications

MicroRNAs participate in the murine oligodendroglial response to perinatal hypoxia-ischemia.

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