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PPARg activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage

ABSTRACT: PPARg activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage

PROVIDER: PRJNA757533 | ENA |

REPOSITORIES: ENA

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PPARg activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage

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

Microglial-oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury

Project description:Microglial-oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury

| PRJNA821869 | ENA

Microglial-oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury

Project description:Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia-OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-CreERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-CreERT2;Nhe1flox/flox, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes were recapitulated in C57BL6J wild-type mice which were subjected to TBI and received treatment of a potent NHE1 inhibitor HOE642 for 1-7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation and oligodendrogenesis, which contributes to accelerated white matter repair and neurological function recovery after TBI.

2022-04-03 | GSE199869 | GEO

The effect of PPARG inhibition on human angiomyolipoma cells

Project description:Angiomyolipoma (AML), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While mTORC1 activation is involved in its growth, mTORC1 inhibitors fail to eradicate AML, highlighting the need for new therapies. Moreover, the identity of the AML cell of origin is obscure. AML research, however, is hampered by the lack of in-vivo models. Here, we establish a human AML-xenograft (Xn) model in mice, recapitulating AML at the histological and molecular levels. Microarray analysis demonstrated tumor growth in-vivo to involve robust PPARG-pathway activation. Similarly, immunostaining revealed strong PPARG expression in human AML specimens. Accordingly, we demonstrate that while PPARG agonism accelerates AML growth, PPARG antagonism is inhibitory, strongly suppressing AML proliferation and tumor-initiating capacity, via an anti-TGFb mechanism. Finally, we show striking similarity between AML cell lines and multipotent mesenchymal stromal cells (MSCs) in terms of antigen and gene expression and differentiation potential. Altogether, we establishment the first in-vivo human AML model, provide evidence that AML may originate in a PPARG-activated renal MSC lineage that is skewed towards adipocytes and smooth muscle and away from osteoblasts, and uncover PPARG as a regulator of AML growth, which could serve as an attractive therapeutic target.

2017-02-04 | GSE94461 | GEO

Germinalmatrix-Intraventricular Hemorrhage induced Early Gene Expression Profile in Subventricular zone (SVZ) of developing rabbit forebrain

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

Germinalmatrix-Intraventricular Hemorrhage induced Early Gene Expression Profile in Subventricular zone (SVZ) of developing rabbit forebrain

2022-12-31 | GSE185438 | GEO

Intraventricular hemorrhage induces deposition of proteoglycans in premature rabbits, but their in vivo degradation with chondroitinase does not restore myelination, ventricle size and neurological recovery.

Project description: Not available

| S-EPMC3742687 | biostudies-literature

Placental PPARg-Regulated Genes

2012-07-10 | GSE39233 | GEO

Placental PPARg-Regulated Genes

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). [Placentas] Three pools of three WT placentas, each vs a litter-matched pool of three Pparg-null placentas Three pools of three WT placentas, each vs a litter-matched pool of three Rxra-null placentas Three pools of three WT placentas, each vs a litter-matched pool of three Med1-null placentas Three pools of three WT placentas, each vs a litter-matched pool of three Ncoa6-null placentas [Trophoblast stem cells (TSC)] Three independent WT TSC lines differentiated for two and four days in the presence or absence of Rosi vs two independent Pparg-null TSC lines differntiated for the same durations in the presence of Rosi

2012-07-09 | E-GEOD-39233 | biostudies-arrayexpress

PPARg and IL-4-induced gene expression data from PPARg +/- LysCre and PPARg fl/- LysCre mouse bone marrow-derived macrophages

Project description:Conditional macrophage-specific PPARg knockout mice were generated on C57Bl/6 background by breeding PPARg fl/- (one allele is floxed, the other is null) and lysozyme Cre transgenic mice. PPARg and IL-4 signaling was analyzed on bone marrow-derived macrophages. Bone marrow of 3 mice per group was isolated and differentiated to macrophages with M-CSF (20 ng/ml). 20 ng/ml IL-4 was used to induce alternative macrophage activation and 1 uM Rosiglitazone (RSG) was used to activate PPARg. From each mouse 4 samples were generated: 1. M-CSF, 2. M-CSF+RSG, 3. IL-4 and 4. IL-4+RSG. All compounds were added throughout the whole differentiation process, and fresh media was added every other day. Control cells were treated with vehicle (DMSO:ethanol). After 10 days, RNA was isolated and gene expression profiles were analyzed using Mouse Genome 430 2.0 microarrays from Affymetrix. 3 PPARg +/- LysCre and 3 PPARg fl/- LysCre mice were used to isolate bone marrow and from each macrophages were differentiated with or without IL-4 and simultaneously treated with vehicle or RSG. Altogether we analyzed 24 samples with 3 biological replicates as below.

2010-11-18 | E-GEOD-25123 | biostudies-arrayexpress

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