Identification of the adult resting progenitor cell by autoradiographic tracking of oligodendrocyte precursors in experimental CNS demyelination

Abstract

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.

In vivo proliferation of oligodendrocyte progenitors expressing PDGF?R during early remyelination

“…However, these previous studies demonstrated that proliferation occurs prior to remyelination and the proliferation that we observed was not in oligodendrocytes, using PLP mRNA as a marker of mature myelinating oligodendrocytes. The present findings are consistent with recent demonstrations that oligodendrocyte lineage cells proliferate prior to remyelination and that mature oligodendrocytes are postmitotic (Keirstead and Blakemore, 1997;Carroll et al, 1998). In addition, our findings are consistent with many studies which have concluded that proliferation of a progenitor population serves as a source of remyelinating oligodendrocytes (Ludwin, 1979;Godfraind et al, 1989;Prayoonwiwat and Rodriguez, 1993;Gensert and Goldman, 1997;Carroll et al, 1998;Keirstead et al, 1998).…”

“…Cell proliferation, as detected by immunostaining for BrdU, was increased within and near remyelinating lesions compared to nondemyelinated or control white matter. This distribution of BrdUϩ cells is consistent with recruitment of remyelinating cells from the local periphery Carroll et al, 1998;Keirstead et al, 1998). As expected from previous studies of MHV-A59 -lesioned tissue Armstrong et al, 1990b), a component of the proliferating cell population appeared to be astrocytes with large, oval nuclei.…”

The In Vivo PDGF Response During Remyelination in Mouse Spinal Cord Following Murine Hepatitis Virus Strain AS9-Induced Transient Demyelination

“…The present findings are consistent with recent demonstrations that oligodendrocyte lineage cells 116 pr!Jliferate prior to remyelination and that mature oligodendrocytes are post-mitotic (Keirstead and Blakemore, 1997;Carroll et at., 1998). In addition, our findings are consistent with many studies which have concluded that proliferation of a progenitor population serves as a source of remyelinating oligodendrocytes (Ludwin, 1979;Godfraind et al, 1989;Prayoonwiwat and Rodriguez, 1993;Gensert and Goldman, 1997;Carroll et al, 1998;Keirstead et al, 1998). The continuity from an endogenous cycling progenitor to a remyelinating cell has been demonstrated by retrovirallabeling prior to lysolecithin-induced demyelination and subsequently observing remyelinating oligodendrocytes (Gensert and Goldman, 1997).…”

Extensive remyelination of the CNS leads to functional recovery

“…Thus, endogenous cells in the cat may respond quickly to demyelination. Although the source of these cells is unknown, there is good evidence (14,15) that an OPC exists in the adult cat CNS, in the optic nerve in particular, and is highly likely the source of remyelinating oligodendrocytes in focal lesions. Here, however, there appears to be little cell death, with only occasional TUNEL-labeled cells, so the question arises as to whether mature oligodendrocytes, stripped of their myelin sheaths, play any role in repair.…”