Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord

Abstract

Elucidation of the response of oligodendrocyte progenitor cell populations to demyelination in the adult central nervous system (CNS) is critical to understanding why remyelination fails in multiple sclerosis. Using the anti-NG2 monoclonal antibody to identify oligodendrocyte progenitor cells, we have documented their response to antibody-induced demyelination in the dorsal column of the adult rat spinal cord. The number of NG2+ cells in the vicinity of demyelinated lesions increased by 72% over the course of 3 days following the onset of demyelination. This increase in NG2+ cell numbers did not reflect a nonspecific staining of reactive cells, as GFAP, OX-42, and Rip antibodies did not co-localise with NG2 + cells in double immunostained tissue sections. NG2 + cells incorporated BrdU 48-72 h following the onset of demyelination. After the onset of remyelination (10-14 days), the number of NG2+ cells decreased to 46% of control levels and remained consistently low for 2 months. When spinal cords were exposed to 40 Grays of x-irradiation prior to demyelination, the number of NG2+ cells decreased to 48% of control levels by 3 days following the onset of demyelination and remained unchanged at 3 weeks. Since 40 Grays of x-irradiation kills dividing cells, these studies illustrate a responsive and nonresponsive NG2+ cell population following demyelination in the adult spinal cord and suggest that the responsive NG2+ cell population does not renew itself.

Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination

“…The large accumulation of NG2ϩ oligodendrocyte progenitors in the demyelinating corpus callosum suggests that this increase may be due to migration of exogenous progenitors or activation and proliferation of local progenitors. There is evidence that some of the oligodendrocyte progenitors within demyelinated lesions are of local origin (Gensert and Goldman, 1997;Keirstead et al, 1998), whereas others suggest that oligodendrocyte progenitors migrate from the SVZ to demyelinated lesions within the brain (Nait- Oumesmar et al, 1999). Our data demonstrates that only few NG2ϩ progenitors proliferate within the demyelinating lesion, that is consistent with previous observations in the adolescent brain (Ludwin, 1979).…”

“…The oligodendrocyte progenitors located at the lesion begin to show a differentiated morphology just before the reappearance of the mature oligodendrocyte population, suggesting the differentiation of progenitor cells into mature oligodendrocytes. Our observation in this model supports previous work identifying progenitor involvement in the remyelination process (Gensert and Goldman, 1997;Keirstead et al, 1998). We acknowledge that the quantification of progenitor cell morphological or differentiation states (Fig.…”

“…The finding that oligodendrocyte progenitors accumulate during the depletion of mature oligodendrocytes, is consistent with previous observations using different methodology (Ludwin, 1979;Gensert and Goldman, 1997;Keirstead et al, 1998;Cammer and Zhang, 1999). The oligodendrocyte progenitors located at the lesion begin to show a differentiated morphology just before the reappearance of the mature oligodendrocyte population, suggesting the differentiation of progenitor cells into mature oligodendrocytes.…”

Model for focal demyelination of the spinal dorsal columns of transgenic MBP-LacZ mice by phototargeted ablation of oligodendrocytes

“…Ludwin (1979) demonstrated that mature oligodendrocytes were unable to divide and that new mature oligodendrocytes arose from the proliferation of oligodendrocyte progenitors within the CNS. Recent studies using injections of retroviral vectors, tritiated-thymidine, or BrdU to label dividing cells have similarly demonstrated the generation of oligodendrocytes from progenitors in the CNS (Prayoonwiwat and Rodriguez, 1993;Carroll and Jennings, 1994;Gensert and Goldman, 1997;Keirstead et al, 1998;Blakemore and Keirstead, 1999). In our study, BrdU was incorporated into ␤-galactosidasepositive cells within the treated zone, demonstrating the generation of new oligodendrocytes.…”

The remyelination Philosopher's Stone: stem and progenitor cell therapies for multiple sclerosis

“…Subsequent studies then revealed that so-called oligodendroglial precursor/progenitor cells (OPCs) are responsible for CNS remyelination (Ffrench-Constant and Raff 1986a;Ffrench-Constant and Raff 1986b). OPCs make up 5-8% of the glial cell population in the CNS (Levine et al 2001) and can be identified through the expression of specific markers such as a ganglioside antigen recognized by the A2B5 antibody (Wolswijk and Noble 1989), chondroitin sulfate NG2 (Dawson et al 2000;Keirstead et al 1998), platelet-derived growth factor (PDGF) receptor α (PDGFRα; Redwine and Armstrong 1998), or olig1 and olig2 transcription factors (Arnett et al 2004;Zhou and Anderson 2002). OPCs are the major source of new myelinating oligodendrocytes (Franklin and Kotter 2008) and therefore represent an important cell source for remyelination in the diseased CNS.…”