Potential conflict of interest: Nothing to report.
Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-gli1 in autoimmune encephalomyelitis and multiple sclerosis†
Article first published online: 7 NOV 2008
Copyright © 2008 American Neurological Association
Annals of Neurology
Volume 64, Issue 4, pages 417–427, October 2008
How to Cite
Wang, Y., Imitola, J., Rasmussen, S., O'Connor, K. C. and Khoury, S. J. (2008), Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann Neurol., 64: 417–427. doi: 10.1002/ana.21457
- Issue published online: 7 NOV 2008
- Article first published online: 7 NOV 2008
- Manuscript Accepted: 4 JUN 2008
- Manuscript Revised: 30 MAY 2008
- Manuscript Received: 7 SEP 2007
- NIAID. Grant Numbers: AI043496, AI071448
- National Multiple Sclerosis Society. Grant Number: RG3945
- Fidelity Foundation
- Cereer Transition Fellow of the NMSS
Neurovascular niches have been proposed as critical components of the neural stem cell (NSC) response to acute central nervous system injury; however, it is unclear whether these potential reparative niches remain functional during chronic injury. Here, we asked how central nervous system inflammatory injury regulates the intrinsic properties of NSCs and their niches.
We investigated the sonic hedgehog (Shh)-Gli1 pathway, an important signaling pathway for NSCs, in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS), and its regulation by inflammatory cytokines.
We show that Shh is markedly upregulated by reactive and perivascular astroglia in areas of injury in MS lesions and during EAE. Astroglia outside the subventricular zone niche can support NSC differentiation toward neurons and oligodendrocytes, and Shh is a critical mediator of this effect. Shh induces differential upregulation of the transcription factor Gli1, which mediates Shh-induced NSC differentiation. However, despite the increase in Shh and the fact that Gli1 was initially increased during early inflammation of EAE and active lesions of MS, Gli1 was significantly decreased in spinal cord oligodendrocyte precursor cells after onset of EAE, and in chronic active and inactive lesions from MS brain. The Th1 cytokine interferon-γ was unique in inducing Shh expression in astroglia and NSCs, while paradoxically suppressing Gli1 expression in NSCs and inhibiting Shh-mediated NSC differentiation.
Our data suggest that endogenous repair potential during chronic injury appears to be limited by inflammation-induced alterations in intrinsic NSC molecular pathways such as Gli1. Ann Neurol 2008;64:417–427