Department of Pediatrics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
Mol Neurodegener. 2011 Jul 5;6:46. doi: 10.1186/1750-1326-6-46.
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.
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.
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.
中枢神经系统髓鞘形成障碍常见于神经发育和成人神经紊乱的慢性白质病变中。最近的研究支持髓鞘形成失败可能涉及一种受损的细胞修复机制，其中少突胶质细胞（OL）祖细胞（OPC）在弥漫性星形胶质细胞增生的病变中增殖，但未能完全分化为成熟的髓鞘形成 OL。目前还没有能够复制这些髓鞘形成失败特征的体外模型。
从出生后第 0.5/1 天的大鼠幼崽的前脑冠状切片在体外培养 1、5 或 9 天（DIV）。切片迅速表现出弥漫性星形胶质细胞增生和细胞外基质糖胺聚糖透明质酸（HA）的积累，HA 是 OPC 分化和再髓鞘形成的抑制剂。在 1 DIV 时，约有 1.5%的 Olig2+ OL 显示出半胱天冬酶-3 的激活，到 9 DIV 时增加到约 11.5%。在 1 DIV 时，与 0 DIV 相比，PDGFRα+和 PDGFRα+/Ki67+ OPC 的密度显著升高（P < 0.01）。尽管有这种增殖反应，但在 9 DIV 时，约 60%的白质 OL 是晚期祖细胞（preOL），而在出生后第 10 天的大鼠中，这一比例约为 7%（P < 0.0001），与 preOL 成熟停滞一致。与对照组相比，HA 添加到切片中显著降低了 9 DIV 时 MBP+ OL 的密度（分别为 217 ± 16 与 328 ± 17 个细胞/mm2；P = 0.0003），支持 HA 在慢性病变中对 OL 谱系进展的抑制作用。
在这个髓鞘形成失败的模型中，重现了弥漫性白质星形胶质细胞增生和 OPC 早期增殖，而 OL 成熟受损。该系统可用于定义与星形胶质细胞增生和 HA 积累相关的 OPC 成熟停滞和髓鞘形成失败的机制。
