Abstract
BackgroundThe 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.MethodsWe 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.ResultsIn 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.ConclusionsReduced 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.
Highlights
The NG2 proteoglycan is expressed by several cell types in demyelinated lesions and has important effects on the biology of these cells
Cell-type-specific ablation of NG2 Previously, we found that germline ablation of NG2 affected the behavior of three different cell types during spinal cord demyelination and remyelination
Recruitment and abundance of oligodendrocyte progenitors (OPCs), pericytes, and macrophages/microglia were all diminished in germline NG2-null mice [15]
Summary
The NG2 proteoglycan is expressed by several cell types in demyelinated lesions and has important effects on the biology of these cells. We determine the cell-type-specific roles of NG2 in the oligodendrocyte progenitor cell (OPC) and myeloid cell contributions to demyelination and remyelination. New oligodendrocytes for myelin repair are generated by so-called adult oligodendrocyte progenitor cells (OPCs) [3, 4] that represent the largest cycling population in the mature CNS [5,6,7,8]. Adult OPCs are effective in generating myelinating oligodendrocytes to repair lesions in experimental demyelination models and in the early stages of demyelinating pathologies. Remyelination in chronic stages of multiple sclerosis (MS) is less impressive [9, 10], partly due to several factors in addition to OPCs and neurons that contribute to the disease process. A more complete understanding of MS requires delineation of the respective contributions of these various cell types to the disease process
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