Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis.
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-gamma was unique in inducing Shh expression in astroglia and NSCs, while paradoxically suppressing Gli1 expression in NSCs and inhibiting Shh-mediated NSC differentiation.


CONCLUSIONS
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.
Wang
Yue
Y
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Imitola
Jaime
J
Rasmussen
Stine
S
O'Connor
Kevin C
KC
Khoury
Samia J
SJ
D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D004622:Embryo, Mammalian; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma