Abstract
Following CNS demyelination, oligodendrocyte progenitor cells (OPCs) are able to differentiate into either remyelinating oligodendrocytes (OLs) or remyelinating Schwann cells (SCs). However, the signals that determine which type of remyelinating cell is generated and the underlying mechanisms involved have not been identified. Here, we show that distinctive microenvironments created in discrete niches within demyelinated white matter determine fate decisions of adult OPCs. By comparative transcriptome profiling we demonstrate that an ectopic, injury-induced perivascular niche is enriched with secreted ligands of the BMP and Wnt signalling pathways, produced by activated OPCs and endothelium, whereas reactive astrocyte within non-vascular area express the dual BMP/Wnt antagonist Sostdc1. The balance of BMP/Wnt signalling network is instructive for OPCs to undertake fate decision shortly after their activation: disruption of the OPCs homeostasis during demyelination results in BMP4 upregulation, which, in the absence of Socstdc1, favours SCs differentiation.
Highlights
CNS remyelination is mediated by a specialized type of adult multipotent progenitor cells, commonly referred to oligodendrocyte progenitor cells or OPCs, that are able to differentiate into new myelin-forming oligodendrocytes (OLs) following primary demyelination
Different cellular compositions define discrete niches within areas of CNS demyelination To get insight into molecular composition of post-injury niches we used a well-established model of demyelination induced by a stereotactic injection of ethidium bromide (EB) into the caudal cerebellar peduncle (CCP) of adult rats (Woodruff and Franklin, 1999)
We characterized the spatial distribution of oligodendrocyte lineage cells in the lesion using antibodies to the transcription factor Olig2 and found them preferentially distributed around blood vessels, visualized with agglutinin RCA120, which binds to endothelial cells and their basement membrane (Figure 1B)
Summary
CNS remyelination is mediated by a specialized type of adult multipotent progenitor cells, commonly referred to oligodendrocyte progenitor cells or OPCs, that are able to differentiate into new myelin-forming oligodendrocytes (OLs) following primary demyelination. This regenerative process can involve the generation of remyelinating Schwann cells (SCs), the myelin-forming cells of the peripheral nervous system (PNS). The contribution of SCs to CNS remyelination have been reported in several clinical conditions including traumatic spinal cord injury, leukodystrophies (Bunge et al, 1993; Guest et al, 2005), and most frequently in severe forms of multiple sclerosis (MS) (Itoyama et al, 1983). We have previously shown using a genetic fate mapping
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