Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination

Jayshree Samanta, Ethan M. Grund, Hernandez M. Silva, Juan J. Lafaille, Gordon Fishell, James L. Salzer

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)448-452
Number of pages5
JournalNature
Volume526
Issue number7573
DOIs
StatePublished - Oct 15 2015

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Neural Stem Cells
Adult Stem Cells
Lateral Ventricles
Oligodendroglia
Demyelinating Diseases
Autoimmune Experimental Encephalomyelitis
Myelin Sheath
Prosencephalon
Nervous System Diseases
Multiple Sclerosis
Cell Differentiation
Stem Cells
Pharmacology
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Samanta, J., Grund, E. M., Silva, H. M., Lafaille, J. J., Fishell, G., & Salzer, J. L. (2015). Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature, 526(7573), 448-452. https://doi.org/10.1038/nature14957

Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. / Samanta, Jayshree; Grund, Ethan M.; Silva, Hernandez M.; Lafaille, Juan J.; Fishell, Gordon; Salzer, James L.

In: Nature, Vol. 526, No. 7573, 15.10.2015, p. 448-452.

Research output: Contribution to journalArticle

Samanta, J, Grund, EM, Silva, HM, Lafaille, JJ, Fishell, G & Salzer, JL 2015, 'Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination', Nature, vol. 526, no. 7573, pp. 448-452. https://doi.org/10.1038/nature14957
Samanta J, Grund EM, Silva HM, Lafaille JJ, Fishell G, Salzer JL. Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature. 2015 Oct 15;526(7573):448-452. https://doi.org/10.1038/nature14957
Samanta, Jayshree ; Grund, Ethan M. ; Silva, Hernandez M. ; Lafaille, Juan J. ; Fishell, Gordon ; Salzer, James L. / Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. In: Nature. 2015 ; Vol. 526, No. 7573. pp. 448-452.
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