Abrogation of  -Catenin Signaling in Oligodendrocyte Precursor Cells Reduces Glial Scarring and Promotes Axon Regeneration after CNS Injury

Rodriguez, Justin P.; Coulter, Michael; Miotke, Jill; Meyer, Ronald L.; Takemaru, Ken‐Ichi; Levine, Joel M.

doi:10.1523/jneurosci.4915-13.2014

Cited by 94 publications

(90 citation statements)

References 79 publications

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“…35,37 Although astrocytes secrete critical growth factors for neurons, the glial scar presents a physical barrier to regeneration and plasticity. 38,39 It is a source of multiple inhibitory factors that may limit neuroplasticity. Thus, a better control of astrocytes proliferation after SCI and identify of proteins involved in this process will be helpful in aiding the regeneration of the spinal cord following injury.…”

Section: Discussionmentioning

confidence: 99%

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

et al. 2015

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Department of Stomatology; Affiliated Hospital of Nantong University, Nantong; Nantong University; 226001, Nantong, Jiangsu, PR China y These authors equally contributed to this work, and should be considered as joint first authors.Keywords: astrocyte proliferation, b-catenin, p27, PKM2, spinal cord injuryAbbreviations: CNS, Central nervous system; CDKs, cyclin-dependent kinases; CAK, CDK activating kinase; E2F, E2 promoter-binding protein dimerization partners; GFAP, Glial fibrillary acidic protein; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; NeuN, Neuronal nuclei; PCNA, Proliferating cell nuclear antigen; PEP, phosphoenolpyruvate; PK, Pyruvate kinase; PKM2, pyruvate kinase M2; pRb, protein retinoblastoma; SCI, Spinal cord injury; EGFR, Epidermal growth factor receptor.Aberrant functionality of the cell cycle has been implicated in the pathology of traumatic SCI. Although it has been reported that the expressions of various cell cycle related proteins were altered significantly following SCI, detailed information on the subject remains largely unclear. The embryonic pyruvate kinase M2 (PKM2) is an important metabolic kinase in aerobic glycolysis or the warburg effect, however, its functions in central nervous system (CNS) injury remains elusive. Here we demonstrate that PKM2 was not only significantly upregulated by western blot and immunohistochemistry but certain traumatic stimuli also induced translocation of PKM2 into the nucleus in astrocytes following spinal cord injury (SCI). Furthermore, the expression levels and localization of p-b-catenin, p27, cyclin D1 and PCNA were correlated with PKM2 after SCI. In vitro, we also found that PKM2 co-immunoprecipitation with p-b-catenin and p27 respectively. Knockdown of PKM2 apparently decreased the level of PCNA, cyclinD1, p27 in primary astrocyte cells. Taken together, our findings indicate that nuclear translocation of PKM2 promotes astrocytes proliferation after SCI through modulating cell cycle signaling. These discoveries firstly uncovered the role of PKM2 in spinal cord injury and provided a potential therapeutic target for CNS injury and repair.

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Section: Discussionmentioning

confidence: 99%

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

et al. 2015

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“…There is increasing evidence that astrogliosis is a principal consequence of the chronic immune response in the CNS in EAE and MS. 37 A significant increase in GFAP + (an astrocyte marker) immunoreactivity was observed throughout the gray and white matter of spinal cords from PBS-, FTY720-, or NSC-treated EAE mice (Figure 5B). Quantification of GFAP immunoreactivity revealed a 2.8-fold reduction in reactive astrogliosis after treatment with FTY720 in combination with NSCs ( Figure 5E).…”

Section: Wwwmoleculartherapyorgmentioning

confidence: 97%

Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

Zhang

Ćirić

et al. 2017

Molecular Therapy

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Inflammatory demyelination and axonal damage of the CNS are hallmarks of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Fingolimod (FTY720), the first FDA-approved oral medication for MS, suppresses acute disease but is less effective at the chronic stage, and whether it has a direct effect on neuroregeneration in MS and EAE remains unclear. Here we show that FTY720, at nanomolar concentrations, effectively protected survival of neural stem cells (NSCs) and enhanced their development into mature oligodendrocytes (OLGs) in vitro, primarily through the S1P3 and S1P5 receptors. In vivo, treatment with either FTY720 or NSCs alone had no effect on the secondary progressive stage of remitting-relapsing EAE, but a combination therapy with FTY720 and NSCs promoted significant recovery, including ameliorated clinical signs and CNS inflammatory demyelination, enhanced MBP synthesis and remyelination, inhibited axonal degeneration, and reduced astrogliosis. Moreover, FTY720 significantly improved incorporation and survival of transplanted NSCs in the CNS and drove their differentiation into more OLGs but fewer astrocytes, thus promoting remyelination and CNS repair processes in situ. Our data demonstrate a novel effect of FTY720 on NSC differentiation and remyelination, broadening its possible application to NSC-based therapy in the secondary progressive stage of MS.

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“…61 In turn, neurons/axons may signal to oligodendrocyte lineage cells. For example, laminin is known as pro-myelination signals from neurons to determine proper myelin thickness.…”

Section: Oligodendrocyte-neuron Interactionmentioning

confidence: 99%

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Shindo

Liang

Maki

et al. 2015

J Cereb Blood Flow Metab

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Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.

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Abrogation of -Catenin Signaling in Oligodendrocyte Precursor Cells Reduces Glial Scarring and Promotes Axon Regeneration after CNS Injury

Cited by 94 publications

References 79 publications

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

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