An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors

Molecular Neurodegeneration

Stephen A Back¹  Larry S Sherman³  Anthony P Barnes²  Marnie Preston³  Kelly D Hansen²  Jennifer Maire²  Art Riddle²  Justin M Dean² 

[1] Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA;Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA;Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Ave, Portland, OR 97006, USA

关键词: slice culture;    hyaluronan;    astrocyte;    gliosis;    oligodendrocyte;    white matter;   

Others  :  865810
DOI  :  10.1186/1750-1326-6-46

 received in 2011-05-11, accepted in 2011-07-05,  发布年份 2011

【 摘 要 】

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/mm², 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.

【 授权许可】

   
2011 Dean et al; licensee BioMed Central Ltd.

【 图 表 】

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