Myelin loss stimulates endogenous repair strategies, including the recruitment of neural stem cells (NSCs) from the subventricular zone (SVZ) to sites of demyelination and NSC differentiation into myelinating oligodendrocytes; however, in diseases such as multiple sclerosis (MS), this endogenous response is insufficient for functional recovery. Understanding the signals that drive endogenous remyelination may allow for the development of strategies to enhance endogenous repair. Here, Samanta et al. show that inhibition of the transcription factor GLI1 promotes the recruitment and differentiation of SVZ NSCs after demyelination.
During development, sonic hedgehog (SHH) signalling can enhance the generation of oligodendrocyte precursor cells (OPCs), suggesting that it might have a role in remyelination. SHH drives the expression of GLI1, thus to investigate the potential role of SHH signalling in remyelination, the authors generated transgenic mice in which GLI1-expressing (GLI1+) NSCs and their progeny were labelled with green fluorescent protein (GFP). The animals were subjected to cuprizone- or lysophosphatidylcholine-driven demyelination of the corpus callosum, and the fates of GLI1+ cells were tracked. GLI1+ cells were recruited to the sites of demyelination and subsequently differentiated into glia, most of which were oligodendrocytes. The presence of GFP-labelled processes surrounding axons indicated that the newly generated cells contributed to remyelination.
“in mice lacking functional GLI1, recruitment of NSCs to lesion sites was greater than in control mice”
The authors showed that GLI1 is expressed at high levels in the SVZ but is not expressed in OPCs and oligodendrocytes in the corpus callosum, regardless of myelination status. Thus, the recruited and differentiating cells seem to downregulate GLI1, leading the authors to consider whether enhancing this downregulation could improve remyelination. They found that, in mice lacking functional GLI1, recruitment of NSCs to lesion sites was greater than in control mice and more of the cells differentiated into oligodendrocytes. Mice in which canonical SHH signalling was augmented through the expression of an activated form of the receptor smoothened exhibited increased numbers of OPCs in the corpus callosum following demyelination, as predicted; however, when this manipulation was combined with the loss of GLI1, 16-fold more oligodendrocytes were generated.
These findings suggested that loss of GLI1 can promote endogenous remyelination. Next, the authors examined the effects of a small-molecule inhibitor of GLI1, GANT61, on remyelination. Infusion of GANT61 into the lateral ventricle during and after cuprizone-mediated demyelination resulted in enhanced recruitment and differentiation of GLI1+ cells in the corpus callosum. Furthermore, daily oral treatment with GANT61 improved functional outcomes in relapsing-remitting experimental autoimmune encephalitis, a mouse model that replicates some of the features of MS.
This study identifies GLI1 downregulation as a key event that drives the endogenous response of SVZ NSCs to demyelination and suggests that strategies to inhibit GLI1 may enhance remyelination. Identifying the signals that are important for the mobilization of other pools of endogenous repair cells, such as parenchymal OPCs, may complement these findings and lead to even better strategies for repair.
Samanta, J. et al. Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature http://dx.doi.org/10.1038/nature14957, (2015)