Dataset Information

TGFbeta1 stimulates the over-production of white matter astrocytes from precursors of the "brain marrow" in a rodent model of neonatal encephalopathy.

ABSTRACT:

Background

In children born prematurely and those surviving cerebral ischemia there are white matter abnormalities that correlate with neurological dysfunction. Since this injury occurs in the immature brain, when the majority of subventricular zone (SVZ) cells generate white matter oligodendrocytes, we sought to study the effect this injury has on gliogenesis from the SVZ. We hypothesized that there is aberrant glial cell generation from the SVZ after neonatal hypoxia ischemia (H/I) that contributes to an increased astrogliogenesis with concomitant oligodendroglial insufficiency. Mechanistically we hypothesized that an increase in specific locally produced cytokines during recovery from injury were modifying the differentiation of glial progenitors towards astrocytes at the expense of the more developmentally-appropriate oligodendrocytes.

Methodology/principal finding

For these studies we used the Vannucci H/I rat model where P6 rats are subjected to unilateral common carotid ligation followed by 75 min of systemic hypoxia. Retroviral lineage tracing studies combined with morphological and immunohistochemical analyses revealed the preferential generation of SVZ-derived white matter astrocytes instead of oligodendrocytes post hypoxia/ischemia. Microarray and QRT-PCR analyses of the damaged SVZ showed increased expression of several cytokines and receptors that are known to promote astrocyte differentiation, such as EGF, LIF and TGFbeta1 signaling components. Using gliospheres to model the neonatal SVZ, we evaluated the effects of these cytokines on signal transduction pathways regulating astrocyte generation, proliferation and differentiation. These studies demonstrated that combinations of EGF, LIF and TGFbeta1 reconstituted the increased astrogliogenesis. TGFbeta1-induced Smad 2/3 phosphorylation and the combination of EGF, LIF and TGFbeta1 synergistically increased STAT3 phosphorylation over single or double cytokine combinations. Pharmacologically inhibiting ALK5 signaling in vitro antagonized the TGFbeta1-induced increase in astrocyte generation and antagonizing ALK5 signaling in vivo similarly inhibited astrogliogenesis within the SVZ during recovery from H/I.

Conclusion/significance

Altogether, these data indicate that there is aberrant specification of glial precursors within the neonatal SVZ during recovery from neonatal H/I that is a consequence of altered cytokine signaling. Our studies further suggest that antagonizing the ALK5 receptor will restore the normal pattern of cell differentiation after injury to the immature brain.

SUBMITTER: Bain JM

PROVIDER: S-EPMC2832687 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Publications

TGFbeta1 stimulates the over-production of white matter astrocytes from precursors of the "brain marrow" in a rodent model of neonatal encephalopathy.

Bain Jennifer M JM Ziegler Amber A Yang Zhengang Z Levison Steven W SW Sen Ellora E

PloS one 20100305 3

<h4>Background</h4>In children born prematurely and those surviving cerebral ischemia there are white matter abnormalities that correlate with neurological dysfunction. Since this injury occurs in the immature brain, when the majority of subventricular zone (SVZ) cells generate white matter oligodendrocytes, we sought to study the effect this injury has on gliogenesis from the SVZ. We hypothesized that there is aberrant glial cell generation from the SVZ after neonatal hypoxia ischemia (H/I) tha ...[more]

PMID: 20221422

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Project description:Highlights • Cases were children cooled for neonatal encephalopathy, without cerebral palsy.• Controls were matched for age, sex and socioeconomic status.• In cases, tract-level fractional anisotropy correlated with motor performance.• Graph-theoretic properties of structural networks correlated with motor performance.• Connections to frontal lobe regions were associated with motor performance. Therapeutic hypothermia reduces the incidence of severe motor disability, such as cerebral palsy, following neonatal hypoxic-ischaemic encephalopathy. However, cooled children without cerebral palsy at school-age demonstrate motor deficits and altered white matter connectivity. In this study, we used diffusion-weighted imaging to investigate the relationship between white matter connectivity and motor performance, measured using the Movement Assessment Battery for Children-2, in children aged 6–8 years treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy at birth, who did not develop cerebral palsy (cases), and matched typically developing controls. Correlations between total motor scores and diffusion properties in major white matter tracts were assessed in 33 cases and 36 controls. In cases, significant correlations (FDR-corrected P < 0.05) were found in the anterior thalamic radiation bilaterally (left: r = 0.513; right: r = 0.488), the cingulate gyrus part of the left cingulum (r = 0.588), the hippocampal part of the left cingulum (r = 0.541), and the inferior fronto-occipital fasciculus bilaterally (left: r = 0.445; right: r = 0.494). No significant correlations were found in controls. We then constructed structural connectivity networks, for 22 cases and 32 controls, in which nodes represent brain regions and edges were determined by probabilistic tractography and weighted by fractional anisotropy. Analysis of whole-brain network metrics revealed correlations (FDR-corrected P < 0.05), in cases, between total motor scores and average node strength (r = 0.571), local efficiency (r = 0.664), global efficiency (r = 0.677), clustering coefficient (r = 0.608), and characteristic path length (r = -0.652). No significant correlations were found in controls. We then investigated edge-level association with motor function using the network-based statistic. This revealed subnetworks which exhibited group differences in the association between motor outcome and edge weights, for total motor scores (P = 0.0109) as well as for balance (P = 0.0245) and manual dexterity (P = 0.0233) domain scores. All three of these subnetworks comprised numerous frontal lobe regions known to be associated with motor function, including the superior frontal gyrus and middle frontal gyrus. The subnetwork associated with total motor scores was highly left-lateralised. These findings demonstrate an association between impaired motor function and brain organisation in school-age children treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy.

Dataset Information

TGFbeta1 stimulates the over-production of white matter astrocytes from precursors of the "brain marrow" in a rodent model of neonatal encephalopathy.

Background

Methodology/principal finding

Conclusion/significance

Publications

TGFbeta1 stimulates the over-production of white matter astrocytes from precursors of the "brain marrow" in a rodent model of neonatal encephalopathy.

Similar Datasets

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