title: Activation of oligodendroglial Stat3 is required for efficient remyelination.
abstract: 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.
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, United States; Institute for Neuroscience, Texas A&M University, College Station, TX 77843, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Steelman
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, United States.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, United States.
authors.forename: Hisami
authors.initials: H
authors.lastname: Koito
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, United States; Institute for Neuroscience, Texas A&M University, College Station, TX 77843, United States.
authors.forename: SunJa
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, United States.
authors.forename: H Ross
authors.initials: HR
authors.lastname: Payne
authors.affiliation: Department of Pediatrics, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, United States.
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
authors.affiliation: Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, United States; Institute for Neuroscience, Texas A&M University, College Station, TX 77843, United States. Electronic address: jrli@cvm.tamu.edu.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000473:pathology*; D051379:Mice; D009103:Multiple Sclerosis / Q000473:pathology; D009186:Myelin Sheath / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D000074586:Remyelination / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat
keywords: CNTF; Myelination; Oligodendrocyte maturation; Remyelination; Stat3 signaling