The new population of oligodendrocytes remyelinating an experimental demyelinating optic nerve lesion has been tracked backwards in time. Using autoradiography combined with electron microscopy and immunocytochemistry, serial sections of optic nerves from young adult cats were studied from 42 h (2 days) post-injection to 93 h (4 days) post-injection. The remyelinating oligodendrocyte lineage was found to commence with the single division of a resting progenitor cell residing in a central fascicular location outside the demyelinative lesion. The division of the founding progenitor cell occurs at 2 days post-lesion and results in two motile daughter cells. These cells, previously described by us as precursor cells, migrate to the lesion, closely appose demyelinated axons, produce axon wrapping processes and differentiate to become remyelinating oligodendrocytes. This study confirms that remyelinating oligodendrocytes originate from resting progenitor cells outside the lesion and not from mature oligodendrocytes, and implies that repeated demyelinative injury could exhaust the reparative capacity of such a region.

The source of the new population of oligodendrocytes which successfully remyelinates experimentally induced demyelination of the cat optic nerve was studied with a combination of techniques. These included correlative light microscopy, immunocytochemistry, electron microscopy and autoradiography in transverse and longitudinal sections. Extending the analysis from the newly generated oligodendrocyte back to the very early demyelinative phase of the lesion enabled the identification of a glial precursor cell (GPC) outside the lesion which appeared to be readily recruitable and motile. This cell is likely to be the product of the division of a putative resting progenitor cell residing in a central fascicular location of the normal optic nerve surrounding the lesion. On arriving at the fringe of the lesion, GPCs are transformed into vimentin-positive small glial cells (SGCs) possibly by signals from demyelinated axons to which the SGCs become closely apposed. Small glial cells, which together with GPCs share several features in common with O-2A perinatal progenitors of the rodent optic nerve, then differentiate into oligodendrocytes. Together these findings suggest that the events leading to remyelination of adult mammalian optic nerve commence soon after the demyelinating injury and might recapitulate the principal events of developmental myelinogenesis.

The origin of the remyelinating oligodendrocyte in a focal antigalactocerebroside-induced demyelinating lesion of the cat optic nerve was studied with detailed correlative electron microscopy and immunocytochemistry using a panel of antigenic markers. Within 10 days of the destruction of all endogenous oligodendrocytes and demyelination of all axons in the lesion, a new population of small glial cells appeared coincident with division of the residual astrocytes and developed a process-bearing axon-embracing morphology. The processes of these small glial cells (SGCs) contained intermediate filaments composed not of glial fibrillary acidic protein but of vimentin and over the ensuing 14 days these cells confirmed their oligodendrocyte destiny by differentiating to lose the intermediate filaments, form myelin and acquire the acquire the typical oligodendrocyte antigenic phenotype. It is suggested that the extensive remyelination of this lesion is sponsored by the new population of SGCs which in turn are generated either by dedifferentiated reactive astrocytes or by as yet unidentified precursor cells.

No abstract

In multiple sclerosis (MS), one strategy to reduce disability is enhancement of endogenous repair by remyelinating oligodendrocytes derived from oligodendrocyte progenitor cells (OP). An important prerequisite is determining the abundance of OP relative to oligodendrocytes in normal human central nervous system (CNS), which, in turn, requires reliable OP identification. To achieve this, cat and human optic nerves (ON) were subjected to varied preparation protocols, and the resultant neuroglial staining profiles correlated to generate an antigenic phenotype for OP applicable to human autopsy specimens. OP, interchangeably called NG2cells due to universal NG2 expression, were shown to comprise a separate class of neuroglial cells, related to oligodendrocytes by expression of the oligodendrocyte lineage transcription factors, Olig1 and Olig2. Despite their morphological complexity, including contact with axons and other neuroglia, NG2cells all appear capable of responding as OP to counter local oligodendrocyte loss. However, quantification revealed that NG2cells comprised less than 5% of the neuroglia and had a ratio to oligodendrocytes of about 1:10, not only in human and cat ON but also in white and gray-matter regions of cat spinal cord. The finding that NG2cells are not abundant, particularly relative to oligodendrocytes, may have implications for efforts to enhance endogenous repair in MS.