Analysis of regeneration- and myelination-associated proteins in human neuroma in continuity and discontinuity

Dömer, Patrick; Kewitz, Bettina; Heinen, Christian; Janssen‐Bienhold, Ulrike; Kretschmer, Thomas

doi:10.1007/s00701-018-3544-6

Cited by 3 publications

(10 citation statements)

References 61 publications

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“…Nevertheless, with increasing neuroma age, a decline in βIII tubulin positive axons in the entire nerve was noticed (Fig. 1D) in line with previous reports (Domer et al, 2018; Ebenezer et al, 2007; Wilcox et al ., 2020).…”

Section: Resultssupporting

confidence: 92%

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Nerve injury converts Schwann cells in a persisting repair state in human neuroma tissue

Deininger,

Schumacher,

Blechschmidt

et al. 2024

Preprint

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Peripheral nerve injury (PNI) induces neuroma formation at the severed nerve stump resulting in impaired nerve regeneration and functional recovery in patients. So far, molecular mechanisms and cell types present in the neuroma impeding on regeneration have only sparsely been analyzed. Herein we compare resected human neuroma tissue with intact donor nerves from the same patient. Neuroma from several post-injury timepoints (1-13 months) were included, thereby allowing for temporal correlation with molecular and cellular processes. We observed reduced axonal area and percentage of myelin producing Schwann cells (SCs) compared to intact nerves. However, total SOX10 positive SC numbers were comparable. Notably, markers for SCs in a repair mode including c-JUN and SHH (sonic hedgehog) and SC proliferation (pH3) were upregulated in neuroma, suggesting presence of SCs in repair rather than differentiated status. In agreement, in neuroma, pro-regenerative markers such as phosphorylated i.e. activated CREB (pCREB), ATF3, GAP43 and SCG10 were upregulated. Neuroma tissue was infiltrated by several types of macrophages. Finally, when taken in culture, neuroma SCs were indistinguishable from controls SCs with regard to proliferation and morphology. However, cultured neuroma SCs retained a different molecular signature from control SCs including increased inflammation and reduced gene expression for differentiation markers such as myelin genes. In summary, human neuroma tissue consists of SCs with a repair status and is infiltrated strongly by several types of macrophages.

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Section: Resultssupporting

confidence: 92%

“…5D) compared to sural nerve (Fig. 5C; G) in line with previous reports (Domer et al, 2018;Gilmer-Hill et al, 2002).…”

Section: Neuroma Tissue Reveals Upregulation Of Pro-regenerative Markerssupporting

confidence: 92%

Nerve injury converts Schwann cells in a persisting repair state in human neuroma tissue

Deininger,

Schumacher,

Blechschmidt

et al. 2024

Preprint

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“…Dömer et al reported regenerating axons in both terminal neuromas and neuromas-in-continuity, indicating that these axons maintain their regenerative capacity. 29 Based on the results of our IHC and immunofluorescence staining analysis with NF-200, which is considered an important part of axonal growth, 2 we found no significant differences between the INS group and CON1 and CON2. The application of INS had little effect on axonal regeneration in this model; in other words, neuromas-in-continuity did not affect axonal regeneration.…”

Section: Axonal Regeneration and Remyelinationmentioning

confidence: 72%

“…Therefore, our findings showed that axonal outgrowth was accompanied by remyelination in neuromas. 29 In addition, muscle atrophy was not significantly different between the INS group and CON1 on the basis of the wet weight data for the gastrocnemius muscle. We conclude that INS had little effect on remyelination in this model.…”

Section: Axonal Regeneration and Remyelinationmentioning

confidence: 82%

A new insight on peripheral nerve repair: the technique of internal nerve splinting

Luo

Zhang

et al. 2022

Journal of Neurosurgery

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OBJECTIVE Neuropathic pain produced by symptomatic neuromas is an important problem after peripheral nerve injury (PNI). End-to-end anastomosis of the nerve stump for PNI is well established but cannot efficiently prevent neuroma-in-continuity formation. METHODS Sciatic nerve injury was used in the experimental model. Seventy-two rats were randomly divided into four groups: rats with nerve anastomosis sites supported with silicone tubes represented the internal nerve splinting (INS) group (n = 18); rats with end-to-end nerve anastomosis represented control group 1 (CON1) (n = 18); rats with INS and the nerve anastomosis site represented control group 2 (CON2) (n = 18); and rats that underwent the same surgical procedures for skin and muscle operations but without sciatic nerve injury represented the normal group (n = 18). RESULTS Gross evaluations of the nerve anastomosis sites, gastrocnemius muscle atrophy, axonal regeneration and remyelination, neuropathic pain, and scar hyperplasia of the neuromas were performed, as well as motor function evaluations. Axonal regeneration, remyelination, and gastrocnemius muscle atrophy were similar between the INS group and CON1 (p > 0.05). However, neuropathic pain and scar hyperplasia—as evaluated according to the expression of anti–sigma-1 receptor antibody and anti–α-smooth muscle actin, respectively—and the weight ratios of the neuromas were reduced in the INS group compared with those of CON1 and CON2 (p < 0.05). CONCLUSIONS Application of INS in nerve repair effectively prevented traumatic neuroma-in-continuity formation and inhibited neuropathic pain without influencing nerve regeneration in rats.

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“…46 Some studies found that overexpression of GAP43 promoted nerve growth in transgenic mice and method outgrowth in civilized cells. 47,48 In addition, proof within the past few years showed that it should be helpful to act GAP43 as an associate in nursing adapter macromolecule due to the association and potential binding of GAP43 with a variety of various molecules, together with PKC, PIP2, actin, synaptophysin, and so forth. [49][50][51][52] However, there was no study to show the association with AQP4.…”

Section: Upregulated Gap43 Might Be Involved In the Mechanism Of The ...mentioning

confidence: 99%

AQP4 knockout promotes neurite outgrowth via upregulating GAP43 expression in infant rats with hypoxic‐ischemic brain injury

Dan

Tan

et al. 2022

Ibrain

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Neonatal hypoxic‐ischemic encephalopathy (NHIE) induces severe cerebral damage and neurological dysfunction, with seldom effective therapy. Aquaporin‐4 (AQP4) is involved in aggravating brain damage induced by NHIE. This study aimed to investigate the role of AQP4 underlying the pathogenesis of NHIE. Neonatal Sprague–Dawley rats were used to establish neonatal hypoxic‐ischemic (HI) models, and the expression of AQP4 in the cortex, hippocampus, and lung tissues was detected by real‐time quantitative polymerase chain reaction as well as Western blot. Primary cortical neurons were cultured for the oxygen‐glucose deprivation (OGD) model, and siRNA was used to silence the expression of AQP4. Immunostaining of Tuj1 was performed to observe the axonal growth. CRISPER/Cas9 technology was used to knock out AQP4. The results demonstrated that AQP4 was upregulated in the cortex, hippocampus, and lung tissues in neonatal rats with HI and OGD neurons. Besides, silencing AQP4 promoted axonal growth of OGD neurons, and AQP4 knockout notably improved long‐term neurobehavioral impairment. Furthermore, GAP43 was found closely correlated with AQP4 via GeneMANIA prediction. Significant downregulation of GAP43 was induced in OGD neurons, while AQP4 knockout markedly upregulated its expression in rats. This indicated that the depletion of AQP4 may enhance axonal regeneration and promote the long‐term neurobehavioral recovery associated with the upregulation of GAP43 expression.

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Analysis of regeneration- and myelination-associated proteins in human neuroma in continuity and discontinuity

Cited by 3 publications

References 61 publications

Nerve injury converts Schwann cells in a persisting repair state in human neuroma tissue

Nerve injury converts Schwann cells in a persisting repair state in human neuroma tissue

A new insight on peripheral nerve repair: the technique of internal nerve splinting

AQP4 knockout promotes neurite outgrowth via upregulating GAP43 expression in infant rats with hypoxic‐ischemic brain injury

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