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An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors
BACKGROUND: CNS myelination disturbances commonly occur in chronic white matter lesions in neurodevelopmental and adult neurological disorders. Recent studies support that myelination failure can involve a disrupted cellular repair mechanism where oligodendrocyte (OL) progenitor cells (OPCs) prolife...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163199/ https://www.ncbi.nlm.nih.gov/pubmed/21729326 http://dx.doi.org/10.1186/1750-1326-6-46 |
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author | Dean, Justin M Riddle, Art Maire, Jennifer Hansen, Kelly D Preston, Marnie Barnes, Anthony P Sherman, Larry S Back, Stephen A |
author_facet | Dean, Justin M Riddle, Art Maire, Jennifer Hansen, Kelly D Preston, Marnie Barnes, Anthony P Sherman, Larry S Back, Stephen A |
author_sort | Dean, Justin M |
collection | PubMed |
description | BACKGROUND: CNS myelination disturbances commonly occur in chronic white matter lesions in neurodevelopmental and adult neurological disorders. Recent studies support that myelination failure can involve a disrupted cellular repair mechanism where oligodendrocyte (OL) progenitor cells (OPCs) proliferate in lesions with diffuse astrogliosis, but fail to fully differentiate to mature myelinating OLs. There are no in vitro models that reproduce these features of myelination failure. RESULTS: Forebrain coronal slices from postnatal day (P) 0.5/1 rat pups were cultured for 1, 5, or 9 days in vitro (DIV). Slices rapidly exhibited diffuse astrogliosis and accumulation of the extracellular matrix glycosaminoglycan hyaluronan (HA), an inhibitor of OPC differentiation and re-myelination. At 1 DIV ~1.5% of Olig2(+ )OLs displayed caspase-3 activation, which increased to ~11.5% by 9 DIV. At 1 DIV the density of PDGFRα(+ )and PDGFRα(+)/Ki67(+ )OPCs were significantly elevated compared to 0 DIV (P < 0.01). Despite this proliferative response, at 9 DIV ~60% of white matter OLs were late progenitors (preOLs), compared to ~7% in the postnatal day 10 rat (P < 0.0001), consistent with preOL maturation arrest. Addition of HA to slices significantly decreased the density of MBP(+ )OLs at 9 DIV compared to controls (217 ± 16 vs. 328 ± 17 cells/mm(2), respectively; P = 0.0003), supporting an inhibitory role of HA in OL lineage progression in chronic lesions. CONCLUSIONS: Diffuse white matter astrogliosis and early OPC proliferation with impaired OL maturation were reproduced in this model of myelination failure. This system may be used to define mechanisms of OPC maturation arrest and myelination failure related to astrogliosis and HA accumulation. |
format | Online Article Text |
id | pubmed-3163199 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-31631992011-08-29 An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors Dean, Justin M Riddle, Art Maire, Jennifer Hansen, Kelly D Preston, Marnie Barnes, Anthony P Sherman, Larry S Back, Stephen A Mol Neurodegener Research Article BACKGROUND: CNS myelination disturbances commonly occur in chronic white matter lesions in neurodevelopmental and adult neurological disorders. Recent studies support that myelination failure can involve a disrupted cellular repair mechanism where oligodendrocyte (OL) progenitor cells (OPCs) proliferate in lesions with diffuse astrogliosis, but fail to fully differentiate to mature myelinating OLs. There are no in vitro models that reproduce these features of myelination failure. RESULTS: Forebrain coronal slices from postnatal day (P) 0.5/1 rat pups were cultured for 1, 5, or 9 days in vitro (DIV). Slices rapidly exhibited diffuse astrogliosis and accumulation of the extracellular matrix glycosaminoglycan hyaluronan (HA), an inhibitor of OPC differentiation and re-myelination. At 1 DIV ~1.5% of Olig2(+ )OLs displayed caspase-3 activation, which increased to ~11.5% by 9 DIV. At 1 DIV the density of PDGFRα(+ )and PDGFRα(+)/Ki67(+ )OPCs were significantly elevated compared to 0 DIV (P < 0.01). Despite this proliferative response, at 9 DIV ~60% of white matter OLs were late progenitors (preOLs), compared to ~7% in the postnatal day 10 rat (P < 0.0001), consistent with preOL maturation arrest. Addition of HA to slices significantly decreased the density of MBP(+ )OLs at 9 DIV compared to controls (217 ± 16 vs. 328 ± 17 cells/mm(2), respectively; P = 0.0003), supporting an inhibitory role of HA in OL lineage progression in chronic lesions. CONCLUSIONS: Diffuse white matter astrogliosis and early OPC proliferation with impaired OL maturation were reproduced in this model of myelination failure. This system may be used to define mechanisms of OPC maturation arrest and myelination failure related to astrogliosis and HA accumulation. BioMed Central 2011-07-05 /pmc/articles/PMC3163199/ /pubmed/21729326 http://dx.doi.org/10.1186/1750-1326-6-46 Text en Copyright ©2011 Dean et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Dean, Justin M Riddle, Art Maire, Jennifer Hansen, Kelly D Preston, Marnie Barnes, Anthony P Sherman, Larry S Back, Stephen A An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors |
title | An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors |
title_full | An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors |
title_fullStr | An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors |
title_full_unstemmed | An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors |
title_short | An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors |
title_sort | organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163199/ https://www.ncbi.nlm.nih.gov/pubmed/21729326 http://dx.doi.org/10.1186/1750-1326-6-46 |
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