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Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog‐gli1 in autoimmune encephalomyelitis and multiple sclerosis
Author(s) -
Wang Yue,
Imitola Jaime,
Rasmussen Stine,
O'Connor Kevin C.,
Khoury Samia J.
Publication year - 2008
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21457
Subject(s) - sonic hedgehog , experimental autoimmune encephalomyelitis , gli1 , multiple sclerosis , neural stem cell , hedgehog signaling pathway , immunology , biology , olig2 , microbiology and biotechnology , central nervous system , oligodendrocyte , cancer research , medicine , neuroscience , stem cell , myelin , signal transduction
Objective 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. Methods 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. Results 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. Interpretation 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