Stat1 integrates cytokine sensing to regulate neural stem cell function by transcriptional repression of Sox9 and Zic1
Author(s): ,
J. Imitola
Affiliations:
Neurology and Neuroscience, The Ohio State University, Columbus, OH
,
E. Hollingsworth
Affiliations:
Neurology and Neuroscience, The Ohio State University, Columbus, OH
,
F. Watanabe
Affiliations:
Neurology and Neuroscience, The Ohio State University, Columbus, OH
,
M. Olah
Affiliations:
Neurology, Harvard Medical School, Boston, MA, United States
,
W. Elyaman
Affiliations:
Neurology, Harvard Medical School, Boston, MA, United States
,
S.-C. Starossom
Affiliations:
Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
,
P. Kivisakk
Affiliations:
Neurology, Harvard Medical School, Boston, MA, United States
S. Khoury
Affiliations:
Neurology, Harvard Medical School, Boston, MA, United States; Abu Haidar Neuroscience Institute, American University of Beirut, Beirut, Lebanon
ECTRIMS Online Library. Imitola J. Oct 12, 2018; 228944; P1104
Jaime Imitola
Jaime Imitola
Contributions
Abstract

Abstract: P1104

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Repairing mechanisms

A central issue in regenerative medicine is understanding the mechanisms that regulate the self-renewal of stem cells in response to injury and disease. While interferons increase hematopoeitic stem cells during infection by activating STAT1, the role of STAT1 in neural stem cells (NSCs) under homeostatic and neuroinflammatory disease conditions remains unresolved. We observe the subventricular zone stem cell alteration in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is associated with upregulation of STAT1 in NSCs. Overexpressing STAT1 in murine NSCs decreases their self-renewal capacity. Normal niche cytokines increase STAT1 phosphorylation and Stat1-/- NSCs are resistant to these deleterious signals and show increased self-renewal, neurogenesis, and oligodendrogenesis. Notably, we find an increase in myelin-specific IFN-g, rather than IL17, T cells in the ventricles of EAE animals. IFN-g is superior to IL17 in reducing NSC proliferation, inducing STAT1 phosphorylation, and decreasing stem cell gene expression. Using CRISPR-Cas9 for targeted mutatagenesis of STAT1, we confirmed that human STAT1-/- NSCs are resistant to this IFN-g effect. Mechanistically, we identified that Stat1 exerts this robust neurogenic effect by transcriptional repression of Sox9 and Zic1. Altogether, our work indicates that Stat1 acts to limit homeostatic neural stem cell proliferation, however, during neuroinflammation, as it occurs in MS, this anti-self-renewal function is exacerbated by way of its dual role in cytokine sensing.
Disclosure: All authors: Nothing to disclose.
JI is supported by the Ohio State NRI.

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