Generation of oligodendroglial progenitors in acute inflammatory demyelinating lesions of the rat brain stem is associated with demyelination rather than inflammation.
Remyelination is an extremely efficient process in the adult rodent central nervous system yet the source of new oligodendroglia that appear following primary demyelination is still subject to much debate. Using a reliable marker for oligodendroglial progenitor cells in vivo, the NG2 chondroitin sulphate proteoglycan, we have evaluated the response of endogenous NG2(+) cells in the adult rat brain stem and cerebellum to inflammatory demyelinating lesions in an experimentally induced animal model of multiple sclerosis (MS), antibody augmented experimental allergic encephalomyelitis (ADEAE). We have manipulated T-cell mediated EAE in Lewis rats by injecting in addition, either anti-myelin/oligodendroglial glycoprotein (MOG) antibodies to induce inflammatory demyelination, or non-specific mouse immunoglobulins to induce an inflammatory response without demyelination. We have examined the relationship of NG2(+) progenitor cells to microglia (OX-42(+)), astrocytes (GFAP(+)) and mature oligodendroglia (CNP(+)), in the normal and demyelinated CNS. In the normal CNS NG2-expressing cells are closely intermingled with other glia but represent a distinct cell population. A prominent inflammatory response, identified by the presence of large perivascular and periventricular accumulations of reactive OX42(+) macrophages/microglia, occurred in animals with ADEAE at 7-9 days post injection (DPI), coinciding with severe clinical symptoms. In animals injected with anti-MOG antibodies inflammation was followed by the appearance of large areas of demyelination at 11-14 DPI, at which point the animals had recovered clinically. The response of NG2(+) cells was different depending on whether the inflammation was accompanied by demyelination. In the presence of inflammation, NG2(+) cells responded by an increase in immunoreactivity and an alteration in their morphology, exhibiting enlarged cell bodies and an increased number of intensely stained processes. In areas of demyelination NG2(+) cells had fewer intensely stained processes reminiscent of progenitor cells seen during development. Quantitative analysis revealed a 3-fold increase in the number of NG2(+) cells in demyelinated lesions at 11 DPI, whereas no change was observed in areas of inflammation in the absence of demyelination. Mitotic figures were only seen in NG2(+) cells in areas of demyelination. NG2(+) cell numbers appeared to return to control levels following remyelination. These results suggest that endogenous oligodendroglial progenitors divide and/or migrate, in response to signals triggered by demyelinating rather than inflammatory events, to generate a large progenitor population sufficient to promote the rapid and successful remyelination observed in this model.
Di Bello
I C
IC
Department of Neurodegenerative Disorders, Division of Neuroscience, Imperial College School of Medicine, Charing Cross Hospital, London W6 8 RP, UK.
Dawson
M R
MR
Levine
J M
JM
Reynolds
R
R
D000818:Animals; D000911:Antibodies, Monoclonal; D001369:Axons / Q000737:chemistry / Q000276:immunology; D001933:Brain Stem / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D003711:Demyelinating Diseases / Q000276:immunology* / Q000473:pathology; D004660:Encephalitis / Q000276:immunology* / Q000473:pathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D017628:Microglia / Q000276:immunology; D018613:Microscopy, Confocal; D004676:Myelin Basic Protein / Q000032:analysis / Q000276:immunology; D009186:Myelin Sheath / Q000737:chemistry / Q000276:immunology; D016900:Neurofilament Proteins / Q000032:analysis / Q000276:immunology; D009836:Oligodendroglia / Q000166:cytology / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D013234:Stem Cells / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins