Myelinating Glia-Specific Deletion of Fbxo7 in Mice Triggers Axonal Degeneration in the Central Nervous System Together with Peripheral Neuropathy

Joseph, Sabitha; Vingill, Siv; Jahn, Olaf; Fledrich, Robert; Werner, Hauke; Katona, István; Möbius, Wiebke; Mitkovski, Mišo; Huang, Yu‐Hao; Weis, Joachim; Sereda, Michael W.; Schulz, Jörg B.; Nave, Klaus‐Armin; Stegmüller, Judith

doi:10.1523/jneurosci.3094-18.2019

Cited by 12 publications

(10 citation statements)

References 73 publications

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“…Moreover, various studies have shown that persistent demyelination may result in axonal damage and neuron degeneration [7,8]. Indeed, therapeutical approaches promoting timely recovery of damaged myelin sheath is an urgent medical need for many neurological disorders, but to the best of our knowledge, progression has been limited.…”

mentioning

confidence: 99%

Bone Marrow Mesenchymal Stem Cells Promote Remyelination in Spinal Cord by Driving Oligodendrocyte Progenitor Cell Differentiation Via Tnfα/Relb-Hes1 Pathway: A Rat Model Study of 2,5-Hexanedione-Induced Neurotoxicity

Guan

Zhang³

et al. 2021

Preprint

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Background: N-hexane, with its metabolite 2,5-hexanedine (HD), is a hazardous material widely used in industry and chronic exposure causes nerve demyelination. Demyelinating conditions are difficult to treat and frequently cause disabilities. Stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising novel strategy. Our previous study found that BMSCs promoted significant recovery of motor dysfunction in rats modelling N-hexane neurotoxicity. The present study aimed to explore the underlying mechanisms and focused on the changes in spinal cord. Methods: Sprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). BMSCs (5×107cells/kg) were administrated by tail vein injection. Demyelination and remyelination of the spinal cord before and after BMSC treatment were examined microscopically. Cultured oligodendrocyte progenitor cells (OPCs) were incubated with HD +/- BMSCs-derived conditional medium (BMSC-CM). OPC differentiation was studied by immunostaining and quantitative imaging analysis. The expressional changes of Hes1, a key transcription factor negatively regulating OPC-differentiation, were studied. The upstream Notch1 and TNFα/RelB pathways were studied and some key signaling molecules in these pathways were measured. The correlation between neurotrophin NGF and TNFα was also investigated. Statistical significance was evaluated using one-way ANOVA test and performed using SPSS 13.0. Results: The demyelinating damage by HD and remyelination by BMSCs were evidenced by electron microscopy, LFB staining and NG2/MBP immunohistochemistry. In vitro cultured OPCs showed more differentiation after incubation with BMSC-CM. Hes1 expression was found to be significantly increased by HD and decreased by BMSC or BMSC-CM. The change of Hes1 was found, however, independent on Notch1 activation, but dependent on TNFα/RelB signaling. HD was found to increase TNFα, RelB and Hes1 expression and BMSCs was found to have the opposite effect. Addition of recombinant TNFα to OPCs or RelB overexpression similarly caused upregulation of Hes1 expression. The secretion of NGF by BMSC and activation of NGF receptor was found important for suppression of TNFα production in OPCs. Conclusions: Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNFα/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease.

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confidence: 99%

Bone Marrow Mesenchymal Stem Cells Promote Remyelination in Spinal Cord by Driving Oligodendrocyte Progenitor Cell Differentiation Via Tnfα/Relb-Hes1 Pathway: A Rat Model Study of 2,5-Hexanedione-Induced Neurotoxicity

Guan

Zhang³

et al. 2021

Preprint

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“…Our data in Cnp-Mek1DD mice revealed significant improvement in EAE clinical score compared to controls, yet data using tamoxifen-inducible Plp-Mek1DD or Pdgfrα-Mek1DD mice did not support the conclusion that MEK1DD expression in the OL lineage provides a protective or reparative functional benefit. These data were surprising, given that Cnp-Cre has previously been reported to cause recombination specifically in the OL lineage in the CNS (Nishizawa et al., 1985; Trapp et al., 1988; Lappe-Siefke et al., 2003; Madsen et al., 2016; Mei et al., 2016; Joseph et al., 2019; Y. Yue et al., 2019).…”

Section: Resultsmentioning

confidence: 93%

CnpPromoter-Driven Sustained ERK1/2 Activation Increases B-Cell Activation and Suppresses Experimental Autoimmune Encephalomyelitis

et al. 2020

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The ERK1/2 signaling pathway promotes myelin wrapping during development and remyelination, and sustained ERK1/2 activation in the oligodendrocyte (OL) lineage results in hypermyelination of the CNS. We therefore hypothesized that increased ERK1/2 signaling in the OL lineage would 1) protect against immune-mediated demyelination due to increased baseline myelin thickness and/or 2) promote enhanced remyelination and thus functional recovery after experimental autoimmune encephalomyelitis (EAE) induction. Cnp-Cre;Mek1DD-eGFP/+ mice that express a constitutively active form of MEK1 (the upstream activator of ERK1/2) in the OL lineage, exhibited a significant decrease in EAE clinical severity compared to controls. However, experiments using tamoxifen-inducible Plp-CreERT;Mek1DD-eGFP/+ or Pdgfrα-CreERT;Mek1DD-eGFP mice revealed this was not solely due to a protective or reparative effect resulting from MEK1DD expression specifically in the OL lineage. Because EAE is an immune-mediated disease, we examined Cnp-Cre; Mek1DD-eGFP/+ splenic immune cells for recombination. Surprisingly, GFP+ recombined CD19+ B-cells, CD11b+ monocytes, and CD3+ T-cells were noted when Cre expression was driven by the Cnp promoter. While ERK1/2 signaling in monocytes and T-cells is associated with proinflammatory activation, fewer studies have examined ERK1/2 signaling in B-cell populations. After in vitro stimulation, MEK1DD-expressing B-cells exhibited a 3-fold increase in CD138+ plasmablasts and a 5-fold increase in CD5+CD1dhi B-cells compared to controls. Stimulated MEK1DD-expressing B-cells also exhibited an upregulation of IL-10, known to suppress the initiation of EAE when produced by CD5+CD1dhi regulatory B-cells. Taken together, our data support the conclusion that sustained ERK1/2 activation in B-cells suppresses immune-mediated demyelination via increasing activation of regulatory B10 cells.

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“…The beam was connected to a darkened box of 13 x 22 cm, which had an entrance hole of 5 x 6 cm (Fig. 2) [14]. Footprints test.…”

Section: Obtaining Of Mmscs From Adipose Tissuementioning

confidence: 99%

The effects of adipose-derived multipotent mesenchymal stromal cells transplantation on motor activity and function of the sciatic nerve in mice with peripheral neuropathy

Rubtsov¹,

Govbach²,

Ustymenko³

et al. 2020

COT

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The Charcot–Marie–Tooth disease type 1A (SHMT1A) is one of the most common hereditary motor-sensory peripheral neuropathies, which is caused by demyelination of motor and sensory nerve fibers and leads to nerve dysfunction. There are currently no effective treatments for hereditary neuropathies, but recent studies indicate a number of potentially effective therapeutic agents, including multipotent mesenchymal stromal cells (MMSCs). The aim of the study was to evaluate the effect of adipose-derived MMSCc transplantation on motor activity and sciatic nerve function of transgenic mice with peripheral neuropathy. Materials and methods. The transgenic B6.Cg-Tg(PMP22)C3Fbas/J mice with peripheral neuropathy were injected intramuscularly with MMSCs, which were isolated from the adipose tissue of FVB-Cg-Tg(GFPU) mice transgenic by GFP. Motor activity of experimental animals was investigated in dynamics after 2, 4, 6, 8 and 10 weeks using the behavioral balance beam test. The functions of the sciatic nerve were analyzed according to the footprint test by calculating the sciatic functional index (SFI). Results. For 2-10 weeks in animals with neuropathy, disease progression was observed, which was expressed in an increasing increase in the number of slidings of the hind limbs from the beam and the time required to walking the distance. SFI in animals of this group decreased and at the 10th week was -47.0 ± 2 units. In contrast, from the 2nd week of the experiment, mice with neuropathy after MMSCs transplantation performed 20 % fewer slidings and spent 11 % less time in the balance beam test compared to animals without cell transplantation. In the same period, an increase of SFI up to -30.2 ± 2 versus -34.6 ± 0.9 units was observed, respectively. At the 10th week after the injection of MMSC, the SFI value was -10.1 ± 2.3 units and correlated with a decrease in the number of slidings and the time spent on the balance beam test. Conclusions. MMSCs transplantation improves the sciatic functional index and fine motor skills in mice with peripheral neuropathy. MMSCs have the potential to be an effective therapeutic agent in the treatment of peripheral neuropathy at Charcot-Marie-Tooth disease.

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Myelinating Glia-Specific Deletion of Fbxo7 in Mice Triggers Axonal Degeneration in the Central Nervous System Together with Peripheral Neuropathy

Cited by 12 publications

References 73 publications

Bone Marrow Mesenchymal Stem Cells Promote Remyelination in Spinal Cord by Driving Oligodendrocyte Progenitor Cell Differentiation Via Tnfα/Relb-Hes1 Pathway: A Rat Model Study of 2,5-Hexanedione-Induced Neurotoxicity

Bone Marrow Mesenchymal Stem Cells Promote Remyelination in Spinal Cord by Driving Oligodendrocyte Progenitor Cell Differentiation Via Tnfα/Relb-Hes1 Pathway: A Rat Model Study of 2,5-Hexanedione-Induced Neurotoxicity

CnpPromoter-Driven Sustained ERK1/2 Activation Increases B-Cell Activation and Suppresses Experimental Autoimmune Encephalomyelitis

The effects of adipose-derived multipotent mesenchymal stromal cells transplantation on motor activity and function of the sciatic nerve in mice with peripheral neuropathy

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