Efficient recolonisation of progenitor-depleted areas of the CNS by adult oligodendrocyte progenitor cells

Abstract

A widely quoted hypothesis for the failure of remyelination in multiple sclerosis (MS) is the exhaustion of the oligodendrocyte progenitor cell (OPC) pool that is strongly implicated as the source of remyelinating oligodendrocytes in demyelinating lesions. Despite this, little is known about the responses of adult OPCs to adjacent areas of the CNS from which their numbers are depleted. We have developed an experimental model to study the pattern and rate of repopulation of OPC-depleted zones, by endogenous OPCs in the adult rat spinal cord. By X-irradiating short lengths of the spinal cord with 40 Gy of X-irradiation, we were able to produce a highly localised depletion of OPCs that allowed us to study the responses of cells located in adjacent normal areas, to this local depletion. Using both NG2 immunohistochemistry and PDGFalphaR in situ hybridisation to identify OPCs, we demonstrate that endogenous OPCs repopulated the depleted areas slowly, but completely. This repopulation occurred at the rate of approximately 0.5 mm/week in the first month. Most cells at the leading edge of repopulation had complex, branching morphologies. The repopulation process was capable of restoring the density of progenitors in repopulated areas to that of normal tissue and was not associated with a secondary progenitor loss in tissue from which progenitor cells were generated. These findings indicate that depletion of the OPC population around lesions is not likely to be the primary explanation for remyelination failure in MS.