Controlling hedgehogs to cause remyelination

Samanta J et al. Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination Nature (30 September 2015) | doi:10.1038/nature14957

Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.

Sonic hedgehog is a protein that in humans is encoded by the SHH (“sonic hedgehog”) gene. Sonic hedgehog is one of three proteins in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog (DHH) and Indian hedgehog (IHH). SHH is the best studied ligand of the hedgehog signaling pathway. It plays a key role in regulating the formation of organs (organogenesis), such as in the growth of finger/toes and organization of the brain. Sonic hedgehog is the best established example of a morphogen as defined by Lewis Wolpert‘s French flag model—a molecule that diffuses to form a concentration gradient (low amounts to high amounts) and has different effects on the cells of the developing embryo depending on its concentration. SHH remains important in the adult. It controls cell division of adult stem cells.

The hedgehog gene (hh) was first identified in the fruit-fly Drosophila melanogaster and identified genes that control the segmentation pattern of the fly embryos. The hh loss of function mutant phenotype causes the embryos to be covered with denticles (small pointy projections), resembling a hedgehog. Sonic was named after the game character

In the study, mice with chemically damaged brain myelin were given GANT61, which blocks the action of a key protein, Gli1, which is involved in so-called sonic hedgehog signaling. Results showed that mice that received the drug had eight times more neural stem cells that migrated to myelin-damaged areas of the brain and eventually developed into myelin producing oligodendrocytes and had 50 percent more myelin at the end of treatment than did untreated mice.

So if we look at the effect in EAE (above) you can see there is no affect on the first phase of the disease but the animals accumulate less deficit. This is so much more convincing to me than some, OK most, of the other experiments where the remyelinating drugs are wiping out the severity of the attacks. It took along time to see an effect. 

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  • I found this study also very interesting … From what I understand from what I read such a strategy would be possible to be used in already consolidated injuries?

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