Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord

Lesions appearing in the CNS of patients in the chronic phase of the inflammatory, demyelinating disease multiple sclerosis often fail to repair, resulting in neurological dysfunction. This failure of remyelination appears, in many cases, to be due not to the destruction of the local oligodendrocyte precursor population, a source for new myelin-forming cells, but to the failure of the precursor cells to proliferate and differentiate, at least in brain lesions. The spinal cord is also a prominent site for lesions in multiple sclerosis, but nothing is known about the fate of the oligodendrocyte precursor population in this area. The present study has therefore analysed spinal cord samples with demyelination from 16 subjects with longstanding multiple sclerosis for the presence of oligodendrocyte precursor cells. Immunolabellings of 10 microm thick sections with the O4/anti-galactocerebroside (GalC) antibody combination, to visualize O4-positive, GalC-negative oligodendrocyte precursor cells, revealed that such cells were prevalent in many spinal cord lesions, with densities of up to 35 cells/mm(2). Six of the spinal cord lesions contained < or =3 O4-positive, GalC-negative cells/mm(2), but such cells were widespread in brain lesions from these multiple sclerosis cases that were available for study (8-26 cells/mm(2)). The density of the O4-positive, GalC-negative oligodendrocyte precursor cells in all spinal cord and brain lesions studied thus far (n = 41) decreased significantly with declining numbers of debris-laden macrophages. In addition, lesions lacking macrophages tended to be derived from the older patients and there was a negative correlation between the density of the oligodendrocyte precursor cells and clinical age of the multiple sclerosis subject at death, and disease duration. The analysis further revealed that lesions from subjects with primary progressive and secondary progressive multiple sclerosis contained, on average, similar numbers of oligodendrocyte precursor cells/mm(2) and that immature oligodendrocytes were only present in significant numbers in lesions with high precursor densities. Taken together, the present data suggest that there is a gradual reduction in the size of the O4-positive, GalC- negative oligodendrocyte precursor population with increasing age of the lesion, that the generation of new oligodendrocytes becomes increasingly more impaired and that lesions are not repopulated to a significant extent by migratory oligodendrocyte precursor cells present in the adjacent unaffected tissue. Hence, strategies intended to promote endogenous remyelination in multiple sclerosis patients should focus on both enhancing the long-term survival of oligodendrocyte precursor cells and on stimulating these cells to proliferate and differentiate into remyelinating oligodendrocytes.