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TGFß1 Stimulates the Over-Production of White Matter Astrocytes from Precursors of the “Brain Marrow” in a Rodent Model of Neonatal Encephalopathy

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 oligodendrocyte...

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Detalles Bibliográficos
Autores principales: Bain, Jennifer M., Ziegler, Amber, Yang, Zhengang, Levison, Steven W., Sen, Ellora
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832687/
https://www.ncbi.nlm.nih.gov/pubmed/20221422
http://dx.doi.org/10.1371/journal.pone.0009567
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author Bain, Jennifer M.
Ziegler, Amber
Yang, Zhengang
Levison, Steven W.
Sen, Ellora
author_facet Bain, Jennifer M.
Ziegler, Amber
Yang, Zhengang
Levison, Steven W.
Sen, Ellora
author_sort Bain, Jennifer M.
collection PubMed
description 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 TGFß 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 TGFß1 reconstituted the increased astrogliogenesis. TGFß1-induced Smad 2/3 phosphorylation and the combination of EGF, LIF and TGFß1 synergistically increased STAT3 phosphorylation over single or double cytokine combinations. Pharmacologically inhibiting ALK5 signaling in vitro antagonized the TGFß1-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.
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spelling pubmed-28326872010-03-11 TGFß1 Stimulates the Over-Production of White Matter Astrocytes from Precursors of the “Brain Marrow” in a Rodent Model of Neonatal Encephalopathy Bain, Jennifer M. Ziegler, Amber Yang, Zhengang Levison, Steven W. Sen, Ellora PLoS One Research Article 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 TGFß 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 TGFß1 reconstituted the increased astrogliogenesis. TGFß1-induced Smad 2/3 phosphorylation and the combination of EGF, LIF and TGFß1 synergistically increased STAT3 phosphorylation over single or double cytokine combinations. Pharmacologically inhibiting ALK5 signaling in vitro antagonized the TGFß1-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. Public Library of Science 2010-03-05 /pmc/articles/PMC2832687/ /pubmed/20221422 http://dx.doi.org/10.1371/journal.pone.0009567 Text en Bain et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bain, Jennifer M.
Ziegler, Amber
Yang, Zhengang
Levison, Steven W.
Sen, Ellora
TGFß1 Stimulates the Over-Production of White Matter Astrocytes from Precursors of the “Brain Marrow” in a Rodent Model of Neonatal Encephalopathy
title TGFß1 Stimulates the Over-Production of White Matter Astrocytes from Precursors of the “Brain Marrow” in a Rodent Model of Neonatal Encephalopathy
title_full TGFß1 Stimulates the Over-Production of White Matter Astrocytes from Precursors of the “Brain Marrow” in a Rodent Model of Neonatal Encephalopathy
title_fullStr TGFß1 Stimulates the Over-Production of White Matter Astrocytes from Precursors of the “Brain Marrow” in a Rodent Model of Neonatal Encephalopathy
title_full_unstemmed TGFß1 Stimulates the Over-Production of White Matter Astrocytes from Precursors of the “Brain Marrow” in a Rodent Model of Neonatal Encephalopathy
title_short TGFß1 Stimulates the Over-Production of White Matter Astrocytes from Precursors of the “Brain Marrow” in a Rodent Model of Neonatal Encephalopathy
title_sort tgfß1 stimulates the over-production of white matter astrocytes from precursors of the “brain marrow” in a rodent model of neonatal encephalopathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832687/
https://www.ncbi.nlm.nih.gov/pubmed/20221422
http://dx.doi.org/10.1371/journal.pone.0009567
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