PPARg activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage
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ABSTRACT:
PROVIDER: PRJNA757533 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15602500_1.fastq.gz | Fastqsanger.gz | |||
| SRR15602500_2.fastq.gz | Fastqsanger.gz | |||
| SRR15602501_1.fastq.gz | Fastqsanger.gz | |||
| SRR15602501_2.fastq.gz | Fastqsanger.gz | |||
| SRR15602502_1.fastq.gz | Fastqsanger.gz |
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Project description:We hypothesized that activation of PPARg would enhance myelination, reduce hydrocephalus, and promote neurological recovery in newborns with IVH. These hypotheses were tested in preterm rabbit model of IVH; autopsy brain samples from premature infants with and without IVH were analyzed. We found that IVH augmented PPARg expression in microglia of both preterm human infants and rabbit kits. The treatment with PPARg agonist or PPARg overexpression by adenovirus delivery further elevated PPARg levels in microglia, reduced pro-inflammatory cytokines, increased microglial phagocytosis, and improved oligodendrocyte progenitor cell (OPC) maturation in kits with IVH. Transcriptomic analyses of OPCs identified previously unrecognized PPARg-induced novel genes for purinergic signaling, cAMP generation, and antioxidant production, which would reprogram these progenitors toward promoting myelination. RNA-seq analyses of microglia revealed PPARg-triggered downregulation of several pro-inflammatory genes and transcripts having roles in Parkinson’s disease and amyotrophic lateral sclerosis, contributing to neurological recovery in kits with IVH. Accordingly, PPARg activation enhanced myelination and neurological function in kits with IVH.
2021-08-27 | GSE182718 | GEO
Project description:Intraventricular hemorrhage (IVH) results in white matter injury and hydrocephalus in premature infants. Chondroitin sulfate proteoglycans (CSPGs)-neuorcan, brevican, versican, aggrecan and phosphacan-are unregulated in the extracellular matrix after brain injury, and their degradation enhances plasticity of the brain. Therefore, we hypothesized that CSPG levels were elevated in the forebrain of premature infants with IVH and that in vivo degradation of CSPGs would enhance maturation of oligodendrocyte, augment myelination, promote neurological recovery, and minimize hydrocephalus. We found that levels of neurocan, brevican, aggrecan, phosphacan, and versican were elevated, whereas NG2 expression was reduced in premature rabbit pups and human infants with IVH compared to controls. Intracerebroventricular chondroitinase ABC (ChABC) reduced the expression of neuorcan, brevican, versican and aggrecan, but not NG2. However, ChABC treatment did not enhance maturation of oligodendrocytes, myelination, or neurological recovery in the pups with IVH. Moreover, ChABC did not reduce gliosis or ventriculomegaly. Our results demonstrate that IVH induces distinct changes in the components of CSPGs, and that reversing these changes by in vivo ChABC treatment neither promotes clinical recovery, myelination, nor reduces ventriculomegaly in preterm rabbit pups.
| S-EPMC3742687 | biostudies-literature
Project description:Intraventricular hemorrhage (IVH) remains a major neurological complication of prematurity that results in cerebral palsy, hydrocephalus, and cognitive deficits. No effective therapy exists to prevent these disorders in infants with IVH. IVH triggers inflammation, cellular infiltration and white matter injury following neurobehavioural deficits.
2022-12-31 | GSE185438 | GEO
Project description:Intraventricular hemorrhage (IVH) remains a major neurological complication of prematurity that results in cerebral palsy, hydrocephalus, and cognitive deficits. No effective therapy exists to prevent these disorders in infants with IVH. IVH triggers inflammation, cellular infiltration and white matter injury following neurobehavioural deficits.
2022-12-31 | GSE198497 | GEO
Project description:Intraventricular hemorrhage (IVH) is a significant complication of premature infants. With improved preterm infant survival, there is increased incidence of severe IVH, and the potential for lifelong neurodevelopmental deficits. Neurological complications are high in babies that develop hydrocephalus as a result of IVH and require a permanent ventriculoperitoneal (VP) shunt. Spina bifida is a congenital disorder caused by the incomplete closure of the neural tube. Hydrocephalus is also a common complication of spina bifida, presenting in 15 to 25% of cases. Often, when spina bifida is identified and surgically repaired, CSF shunting mechanisms are placed in a high percentage of cases. A better understanding of the events leading to the development of hydrocephalus will help clinicians make more informed decisions about the need for CSF shunting and other interventions. Extracellular RNAs (exRNAs) may be indicators of the multiple pathological events surrounding the development of hydrocephalus in subjects with intraventricular hemorrhage or spina bifida. exRNAs may also be indicators for the presence and magnitude of neurodevelopmental outcomes. Under that premise, we sequenced the total exRNA in CSF from children that had IVH or spina bifida, some of which developed hydrocephalus and/or had reported developmental delays.
2018-10-27 | GSE121867 | GEO
Project description:Intraventricular hemorrhage (IVH) remains a major cause of white matter injury in preterm infants with no viable therapeutic strategy to restore myelination. Maturation of oligodendrocytes and myelination is influenced by thyroid hormone (TH) signaling, which is mediated by TH receptor ? (TR?) and TR?. In the brain, cellular levels of TH are regulated by deiodinases, with deiodinase-2 mediating TH activation and deiodinase-3 TH inactivation. Therefore, we hypothesized that IVH would decrease TH signaling via changes in the expression of deiodinases and/or TRs, and normalization of TH signaling would enhance maturation of oligodendrocytes and myelination in preterm infants with IVH. These hypotheses were tested using both autopsy materials from human preterm infants and a rabbit model of IVH. We found that deiodinase-2 levels were reduced, whereas deiodinase-3 levels were increased in brain samples of both humans and rabbits with IVH compared with controls without IVH. TR? expression was also increased in human infants with IVH. Importantly, treatment with TH accelerated the proliferation and maturation of oligodendrocytes, increased transcription of Olig2 and Sox10 genes, augmented myelination, and restored neurological function in pups with IVH. Consistent with these findings, the density of myelinating oligodendrocytes was almost doubled in TH-treated human preterm infants compared with controls. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TR?. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH.
| S-EPMC3812500 | biostudies-literature
Project description:Intraventricular hemorrhage (IVH) results in neural cell death and white matter injury in premature infants. No therapeutic strategy is currently available against this disorder. Bone morphogenetic protein (BMP) signaling suppresses oligodendrocyte development through basic-helix-loop-helix (bHLH) transcription factors and promotes astrocytosis. Therefore, we hypothesized that IVH in premature newborns initiates degeneration and maturation arrest of oligodendrocyte lineage and that BMP inhibition alleviates hypomyelination, gliosis, and motor impairment in the survivors of IVH. To test the hypotheses, a rabbit model of IVH was used in which premature rabbit pups (E29) are treated with intraperitoneal glycerol at 2 h of age to induce IVH; and the pups with IVH exhibit hypomyelination and gliosis at 2 weeks of postnatal age. Maturation of oligodendrocyte lineage was evaluated by specific markers, and the expression of bHLH transcription factors was assessed. BMP levels were measured in both premature rabbit pups and autopsy materials from premature infants. Recombinant human noggin was used to suppress BMP action; and neurobehavioral performance, myelination and gliosis were assessed in noggin-treated pups compared with untreated controls. We found that IVH resulted in apoptosis and reduced proliferation of oligodendrocyte progenitors, as well as arrested maturation of preoligodendrocytes in rabbits. BMP4 levels were significantly elevated in both rabbit pups and human premature infants with IVH compared with controls. Importantly, BMP inhibition by recombinant human noggin restored the levels of phospho-Smad1/5/8, Olig2 transcription factor, oligodendrocyte maturation, myelination, astrocyte morphology, and motor function in premature pups with IVH. Hence, BMP inhibition might enhance neurological recovery in premature infants with IVH.
| S-EPMC3167068 | biostudies-literature
Project description:Intraventricular hemorrhage (IVH) in premature infants results in inflammation, arrested oligodendrocyte progenitor cell (OPC) maturation, and reduced myelination of the white matter. Hyaluronan (HA) inhibits OPC maturation and complexes with the heavy chain (HC) of glycoprotein inter-α-inhibitor to form pathological HA (HC-HA complex), which exacerbates inflammation. Therefore, we hypothesized that IVH would result in accumulation of HA, and that either degradation of HA by hyaluronidase treatment or elimination of HCs from pathological HA by HA oligosaccharide administration would restore OPC maturation, myelination, and neurological function in survivors with IVH. To test these hypotheses, we used the preterm rabbit model of glycerol-induced IVH and analyzed autopsy samples from premature infants. We found that total HA levels were comparable in both preterm rabbit pups and human infants with and without IVH, but HA receptors--CD44, TLR2, TLR4--were elevated in the forebrain of both humans and rabbits with IVH. Hyaluronidase treatment of rabbits with IVH reduced CD44 and TLR4 expression, proinflammatory cytokine levels, and microglia infiltration. It also promoted OPC maturation, myelination, and neurological recovery. HC-HA and tumor necrosis factor-stimulated gene-6 were elevated in newborns with IVH; and depletion of HC-HA levels by HA oligosaccharide treatment reduced inflammation and enhanced myelination and neurological recovery in rabbits with IVH. Hence, hyaluronidase or HA oligosaccharide treatment represses inflammation, promotes OPC maturation, and restores myelination and neurological function in rabbits with IVH. These therapeutic strategies might improve the neurological outcome of premature infants with IVH. Significance statement: Approximately 12,000 premature infants develop IVH every year in the United States, and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The onset of IVH induces inflammation of the periventricular white matter, which results in arrested maturation of OPCs and myelination failure. HA is a major component of the extracellular matrix of the brain, which regulates inflammation through CD44 and TLR2/4 receptors. Here, we show two mechanism-based strategies that effectively enhanced myelination and neurological recovery in preterm rabbit model of IVH. First, degrading HA by hyaluronidase treatment reduced CD44 and TLR4 expression, proinflammatory cytokines, and microglial infiltration, as well as promoted oligodendrocyte maturation and myelination. Second, intraventricular injection of HA oligosaccharide reduced inflammation and enhanced myelination, conceivably by depleting HC-HA levels.
| S-EPMC4719021 | biostudies-literature
Project description:Intraventricular hemorrhage is a common cause of morbidity and mortality in premature infants. The rupture of the germinal zone into the ventricles entails loss of neural stem cells and disturbs the normal cytoarchitecture of the region, compromising late neurogliogenesis. Here we demonstrate that neural stem cells can be easily and robustly isolated from the hemorrhagic cerebrospinal fluid obtained during therapeutic neuroendoscopic lavage in preterm infants with severe intraventricular hemorrhage. Our analyses demonstrate that these neural stem cells, although similar to human fetal cell lines, display distinctive hallmarks related to their regional and developmental origin in the germinal zone of the ventral forebrain, the ganglionic eminences that give rise to interneurons and oligodendrocytes. These cells can be expanded, cryopreserved, and differentiated in vitro and in vivo in the brain of nude mice and show no sign of tumoral transformation 6 months after transplantation. This novel class of neural stem cells poses no ethical concerns, as the fluid is usually discarded, and could be useful for the development of an autologous therapy for preterm infants, aiming to restore late neurogliogenesis and attenuate neurocognitive deficits. Furthermore, these cells represent a valuable tool for the study of the final stages of human brain development and germinal zone biology.
2020-06-01 | GSE124361 | GEO
Project description:Robust identification of placental PPARg target genes via mutliple PPARg-dependence criteria. Integration of differential expression data from Pparg-null, Rxra-null, Med1-nul and Ncoa6-null placentas and from WT and Pparg-null Trophoblast stem cells (TSC) differentiated for 2 or 4 days in the presence or absence of the PPARg agonist Rosiglitazone (Rosi).
2012-07-10 | GSE39233 | GEO