NG2-proteoglycan-dependent contributions of oligodendrocyte progenitors and myeloid cells to myelin damage and repair.
NG2-proteoglycan-dependent contributions of oligodendrocyte progenitors and myeloid cells to myelin damage and repair.
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DOI：
10.1186/s12974-015-0385-6
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发表时间：
2015-09-04
影响因子：
9.3
通讯作者：
Stallcup WB
中科院分区：
文献类型：
--
作者：
Kucharova K;Stallcup WB
NG 2蛋白聚糖由脱髓鞘病变中的几种细胞类型表达，并对这些细胞的生物学具有重要影响。在这里，我们确定了NG 2在少突胶质祖细胞（OPC）和髓样细胞脱髓鞘和髓鞘再生中的作用。我们已经使用Cre-Lox技术来剖析NG 2对髓鞘损伤和修复的细胞类型特异性贡献。通过将1%溶血素微量注射到对照、OPC特异性NG 2缺失（OPC-NG 2ko）和骨髓特异性NG 2缺失（My-NG 2ko）小鼠的脊髓白色物质中来诱导脱髓鞘。通过光学、免疫荧光、共聚焦和电子显微镜评估OPC、髓样细胞、轴突和髓鞘的状态。在OPC-NG 2ko小鼠中，注射溶血素1周后，OPC有丝分裂指数降低40%，导致损伤后1周时OPC减少25%，损伤后6周时成熟少突胶质细胞减少28%。在OPC-NG 2ko小鼠中，初始脱髓鞘病变大小不受影响，但少突胶质细胞的产生减少延迟了病变修复。相比之下，My-NG 2ko小鼠中脱髓鞘的初始程度和病变修复的动力学均降低。令人惊讶的是，在My-NG 2ko小鼠中，损伤后1周的OPC有丝分裂指数也降低（48%），导致OPC在损伤后1周降低35%，随后成熟少突胶质细胞在损伤后6周降低34%。髓磷脂碎片的清除在My-NG 2ko小鼠中也减少了40%。髓鞘形成缺陷的髓鞘碱性蛋白的免疫染色检测证实甲苯胺蓝染色和电子显微镜。除了髓鞘修复减少，在OPC-NG 2ko和My-NG 2ko小鼠中的6周损伤中发现较少的轴突，强调了髓鞘形成对神经元存活的重要性。OPC-NG 2ko小鼠中OPC和少突胶质细胞的生成减少与髓鞘修复减少相关。My-NG 2ko小鼠中脱髓鞘减少可能源于骨髓细胞向病变募集的减少（约70%）。减少的巨噬细胞/小胶质细胞数量然后可通过减少髓鞘碎片的清除和减少对OPC的刺激作用而导致髓鞘修复减少。
The NG2 proteoglycan is expressed by several cell types in demyelinated lesions and has important effects on the biology of these cells. Here we determine the cell-type-specific roles of NG2 in the oligodendrocyte progenitor cell (OPC) and myeloid cell contributions to demyelination and remyelination. We have used Cre-Lox technology to dissect the cell-type-specific contributions of NG2 to myelin damage and repair. Demyelination is induced by microinjection of 1 % lysolecithin into the spinal cord white matter of control, OPC-specific NG2-null (OPC-NG2ko), and myeloid-specific NG2-null (My-NG2ko) mice. The status of OPCs, myeloid cells, axons, and myelin is assessed by light, immunofluorescence, confocal, and electron microscopy. In OPC-NG2ko mice 1 week after lysolecithin injection, the OPC mitotic index is reduced by 40 %, resulting in 25 % fewer OPCs at 1 week and a 28 % decrease in mature oligodendrocytes at 6 weeks post-injury. The initial demyelinated lesion size is not affected in OPC-NG2ko mice, but lesion repair is delayed by reduced production of oligodendrocytes. In contrast, both the initial extent of demyelination and the kinetics of lesion repair are decreased in My-NG2ko mice. Surprisingly, the OPC mitotic index at 1 week post-injury is also reduced (by 48 %) in My-NG2ko mice, leading to a 35 % decrease in OPCs at 1 week and a subsequent 34 % reduction in mature oligodendrocytes at 6 weeks post-injury. Clearance of myelin debris is also reduced by 40 % in My-NG2ko mice. Deficits in myelination detected by immunostaining for myelin basic protein are confirmed by toluidine blue staining and by electron microscopy. In addition to reduced myelin repair, fewer axons are found in 6-week lesions in both OPC-NG2ko and My-NG2ko mice, emphasizing the importance of myelination for neuron survival. Reduced generation of OPCs and oligodendrocytes in OPC-NG2ko mice correlates with reduced myelin repair. Diminished demyelination in My-NG2ko mice may stem from a reduction (approximately 70 %) in myeloid cell recruitment to lesions. Reduced macrophage/microglia numbers may then result in decreased myelin repair via diminished clearance of myelin debris and reduced stimulatory effects on OPCs.