Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function

Duncan, Ian D.; Marik, Rachel L.; Broman, Aimee Teo; Heidari, Mohsen

doi:10.1073/pnas.1714183114

Cited by 66 publications

(50 citation statements)

References 56 publications

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“…Around 40% of axons of all calibers had thin myelin sheaths, as previously reported (1). The pattern seen on recovery, which is a mixture of mature and remyelinated myelin sheaths, persisted over time (30). In one animal examined 2.5 y after termination of the irradiated diet, the pattern of mixed distribution of remyelinated and mature myelin sheaths remained in the ventral column ( Fig.…”

Section: Scattered Demyelination and Remyelination Lead To A MIX Of Rsupporting

confidence: 80%

“…1). Examination of longitudinal sections through these areas of white matter showed that there were many short internodes on thinly myelinated (remyelinated) axons (30). In contrast to the lateral and ventral column, remyelination of the dorsal column resulted in large areas of homogeneously thin myelin sheaths ( Fig.…”

Section: Scattered Demyelination and Remyelination Lead To A MIX Of Rmentioning

confidence: 98%

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The adult oligodendrocyte can participate in remyelination

Duncan

Radcliff

Heidari

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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207

155

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Endogenous remyelination of the CNS can be robust and restore function, yet in multiple sclerosis it becomes less complete with time. Promoting remyelination is a major therapeutic goal, both to restore function and to protect axons from degeneration. Remyelination is thought to depend on oligodendrocyte progenitor cells, giving rise to nascent remyelinating oligodendrocytes. Surviving, mature oligodendrocytes are largely regarded as being uninvolved. We have examined this question using two large animal models. In the first model, there is extensive demyelination and remyelination of the CNS, yet oligodendrocytes survive, and in recovered animals there is a mix of remyelinated axons interspersed between mature, thick myelin sheaths. Using 2D and 3D light and electron microscopy, we show that many oligodendrocytes are connected to mature and remyelinated myelin sheaths, which we conclude are cells that have reextended processes to contact demyelinated axons while maintaining mature myelin internodes. In the second model in vitamin B 12 -deficient nonhuman primates, we demonstrate that surviving mature oligodendrocytes extend processes and ensheath demyelinated axons. These data indicate that mature oligodendrocytes can participate in remyelination.adult oligodendrocyte | remyelination | large animal models

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Section: Scattered Demyelination and Remyelination Lead To A MIX Of Rsupporting

confidence: 80%

Section: Scattered Demyelination and Remyelination Lead To A MIX Of Rmentioning

confidence: 98%

The adult oligodendrocyte can participate in remyelination

Duncan

Radcliff

Heidari

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

207

155

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“…This is supported by the significant albeit incomplete recovery of electrophysiological properties over the affected wrist segment following surgical decompression. Persistence of thin myelin sheets after remyelination as shown in experimental models 26,27 may account for the continuing conduction slowing.…”

Section: Discussionmentioning

confidence: 92%

Molecular and cellular correlates of human nerve regeneration: ADCYAP1 encoding PACAP enhances sensory neuron outgrowth

Schmid

Baskozos

Windsor

et al. 2019

Preprint

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We only have a rudimentary understanding of the molecular and cellular determinants of human nerve regeneration. Here, we use carpal tunnel syndrome (CTS) as a human model system to prospectively evaluate correlates of neural regeneration and their relationship with clinical recovery after decompression surgery. At 6 months post-surgery, we noted a significant improvement of median nerve neurophysiological and somatosensory function. Serial skin biopsies revealed a partial recovery of intraepidermal innervation, whose extent correlated with symptom improvement. In myelinated afferents, nodal length increased postoperatively.Transcriptional profiling of the skin revealed 23 differentially expressed genes following decompression, with ADCYAP1 (encoding PACAP) being the most strongly upregulated and showing an association with regeneration of intraepidermal nerve fibres. Using human induced pluripotent stem cell-derived sensory neurons, we confirmed that PACAP significantly enhances axon outgrowth in vivo. Since PACAP signals through G-protein receptors, this pathway provides an interesting therapeutic target for human sensory nerve regeneration.

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“…Myelin sheath thickness is a parameter of considerable interest in neuroscience. It is an important factor in signal conduction velocity [41] and may be used as a marker for disease [42]. Together with the axon diameter it determines the g-ratio.…”

Section: Discussionmentioning

confidence: 99%

A semi-automated approach to dense segmentation of 3D white matter electron microscopy

Kleinnijenhuis

Johnson

Mollink

et al. 2020

Preprint

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PurposeNeuroscience methods working on widely different scales can complement and inform each other. At the macroscopic scale, magnetic resonance imaging methods that estimate microstructural measures have much to gain from ground truth validation and models based on accurate measurement of that microstructure. We present an approach to generate rich and accurate geometric models of white matter microstructure through dense segmentation of 3D electron microscopy (EM).MethodsVolumetric data of the white matter of the genu of the corpus callosum of the adult mouse brain were acquired using serial blockface scanning electron microscopy (SBF-SEM). A segmentation pipeline was developed to separate the 3D EM data into compartments and individual cellular and subcellular constituents, making use of established tools as well as newly developed algorithms to achieve accurate segmentation of various compartments.ResultsThe volume was segmented into six compartments comprising myelinated axons (axon, myelin sheath, nodes of Ranvier), oligodendrocytes, blood vessels, mitochondria, and unmyelinated axons. The myelinated axons had an average inner diameter of 0.56 μm and an average outer diameter of 0.87 μm. The diameter of unmyelinated axons was 0.43 μm. A mean g-ratio of 0.61 was found for myelinated axons, but the g-ratio was highly variable between as well as within axons.ConclusionThe approach for segmentation of 3D EM data yielded a dense annotation of a range of white matter compartments that can be interrogated for their properties and used for in silico experiments of brain structure. We provide the resulting dense annotation as a resource to the neuroscience community.

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Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function

Cited by 66 publications

References 56 publications

The adult oligodendrocyte can participate in remyelination

The adult oligodendrocyte can participate in remyelination

Molecular and cellular correlates of human nerve regeneration: ADCYAP1 encoding PACAP enhances sensory neuron outgrowth

A semi-automated approach to dense segmentation of 3D white matter electron microscopy

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