Activation of oligodendroglial Stat3 is required for efficient remyelination

NEUROBIOLOGY OF DISEASE

卷:91

Article

Steelman, Andrew J.^1,3,5  Zhou, Yun¹  Koito, Hisami¹  Kim, SunJa^1,3  Payne, H. Ross²  Lu, Q. Richard⁴  Li, Jianrong^1,3 

[1] Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA

[2] Coll Vet Med & Biomed Sci, Dept Vet Pathobiol, College Stn, TX 77843 USA

[3] Texas A&M Univ, Inst Neurosci, Mail Stop 4458, College Stn, TX 77843 USA

[4] Cincinnati Childrens Hosp Med Ctr, Brain Tumor Ctr, Dept Pediat, Cincinnati, OH 45229 USA

[5] Univ Illinois, Dept Anim Sci, Champaign, IL USA

关键词: Oligodendrocyte maturation;    Stat3 signaling;    Myelination;    Remyelination;    CNTF;   

DOI  :  10.1016/j.nbd.2016.03.023

来源: Elsevier

【 摘 要 】

Multiple sclerosis is the most prevalent demyelinating disease of the central nervous system (CNS) and is histologically characterized by perivascular demyelination as well as neurodegeneration. While the degree of axonal damage is correlated with clinical disability, it is believed that remyelination can protect axons from degeneration and slow disease progression. Therefore, understanding the intricacies associated with myelination and remyelination may lead to therapeutics that can enhance the remyelination process and slow axon degeneration and loss of function. Ciliary neurotrophic factor (CNTF) family cytokines such as leukemia inhibitory factor (LIF) and interleukin 11 (IL-11) are known to promote oligodendrocyte maturation and remyelination in experimental models of demyelination. Because CNTF family member binding to the gp130 receptor results in activation of the JAK2/Stat3 pathway we investigated the necessity of oligodendroglial Stat3 in transducing the signal required for myelination and remyelination. We found that Stat3 activation in the CNS coincides with myelination during development. Stimulation of oligodendrocyte precursor cells (OPCs) with CNTF or LIF promoted OPC survival and final differentiation, which was completely abolished by pharmacologic blockade of Stat3 activation with JAK2 inhibitor. Similarly, genetic ablation of Stat3 in oligodendrocyte lineage cells prevented CNTF-induced OPC differentiation in culture. In vivo, while oligodendroglial Stat3 signaling appears to be dispensable for developmental CNS myelination, it is required for oligodendrocyte regeneration and efficient remyelination after toxin-induced focal demyelination in the adult brain. Our data suggest a critical function for oligodendroglial Stat3 signaling in myelin repair. (C) 2016 Elsevier Inc. All rights reserved.

【 授权许可】

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