Region and dynamic specificities of adult neural stem cells and oligodendrocyte precursors in myelin regeneration in the mouse brain.

Béatrice Brousse,Myriam Cayre,Karine Magalon,Pascale Durbec

doi:10.1242/bio.012773

Abstract

ABSTRACTMyelin regeneration can occur in the brain following demyelination. Parenchymal oligodendrocyte progenitors (pOPC) are known to play a crucial role in this process. Neural stem cells (NSC) residing in the ventricular-subventricular zone (V-SVZ) also have the ability to generate oligodendrocytes but their contribution to endogenous myelin repair was so far considered to be negligible. Here, we addressed the relative contribution of pOPC and V-SVZ-derived neural progenitors (SVZdNP) to remyelination in cuprizone mouse models of acute or chronic corpus callosum (CC) demyelination. Using genetic tracing, we uncover an unexpected massive and precocious recruitment of SVZdNP in the anterior CC after acute demyelination. These cells very quickly adopt an oligodendrocytic fate and robustly generate myelinating cells as efficiently as pOPC do. In more posterior areas of the CC, SVZdNP recruitment is less important whereas pOPC contribute more, underlining a regionalization in the mobilization of these two cell populations. Strikingly, in a chronic model when demyelination insult is sustained in time, SVZdNP minimally contribute to myelin repair, a failure associated with a depletion of NSC and a drastic drop of progenitor cell proliferation in V-SVZ. In this context, pOPC remain reactive, and become the main contributors to myelin regeneration. Altogether our results highlight a region and context-dependent contribution of SVZdNP to myelin repair that can equal pOPC. They also raise the question of a possible exhaustion of V-SVZ proliferation potential in chronic pathologies.

Highlights

Since the discovery of ongoing neurogenesis throughout life in most mammals including humans, the idea that the adult brain may be endowed with regenerative capacities has been largely explored
In a chronic model when demyelination insult is sustained in time, SVZ-derived neural progenitors (SVZdNP) minimally contribute to myelin repair, a failure associated with a depletion of Neural stem cells (NSC) and a drastic drop of progenitor cell proliferation in ventricularsubventricular zone (V-SVZ)
Several recent studies demonstrated that beside pOPC, progenitors located in the V-SVZ could be mobilized after demyelination and generate new oligodendrocytes (Jablonska et al, 2010; Menn et al, 2006)

Summary

Introduction

Since the discovery of ongoing neurogenesis throughout life in most mammals including humans, the idea that the adult brain may be endowed with regenerative capacities has been largely explored. Post-mortem observations of multiple sclerosis (MS) patient brains long since suggested that demyelination lesions could undergo spontaneous. Parenchymal oligodendrocyte precursor cells ( pOPC) were soon identified as the cell population responsible for myelin repair (Franklin et al, 1997; Gensert and Goldman, 1997). This was confirmed by the development of genetic tracing approaches (Zawadzka et al, 2010). POPC located close to the lesion proliferate, migrate and undergo terminal differentiation to replace lost oligodendrocytes. After demyelination insult even SVZ-derived neuroblasts can generate new oligodendrocytes (Jablonska et al, 2010)

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