Abstract
BackgroundCNS 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.ResultsForebrain 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.ConclusionsDiffuse 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.
Highlights
Disturbances in CNS myelination are a central feature of numerous neurodevelopmental and adult neurological disorders, and are widely recognized to occur in areas of reactive astrogliosis
HA and its receptor CD44 are robustly expressed in white matter lesions with diffuse astrogliosis, consistent with the response observed in demyelinating lesions, traumatic spinal cord injury, vascular brain injury associated with dementia, and ischemic lesions in adult humans and rodents [14,16,17]
Organotypic slice cultures display progressive diffuse astrogliosis and HA accumulation Intact whole coronal forebrain slices containing white matter and overlying cortex were cultured from postnatal day 0.5/1 (P0.5/1) rats
Summary
Disturbances in CNS myelination are a central feature of numerous neurodevelopmental and adult neurological disorders, and are widely recognized to occur in areas of reactive astrogliosis. In chronic white matter lesions, OPCs proliferate but fail to fully differentiate to mature myelinating OLs, The mechanisms that mediate inhibition of OL maturation following CNS insults are largely unknown. The molecular mechanisms by which HA inhibits OL maturation are largely unknown, and as yet, there are no well-established in vitro models that reproduce the major features of chronic white matter lesions. 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
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