Regeneration Of Myelin Sheaths Research Articles

Transplantation of Neural Stem Cells Loaded in an IGF-1 Bioactive Supramolecular Nanofiber Hydrogel for the Effective Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) leads to massive cell death, disruption, and demyelination of axons, resulting in permanent motor and sensory dysfunctions. Stem cell transplantation is a promising therapy for SCI. However, owing to the poor microenvironment that develops following SCI, the bioactivities of these grafted stem cells are limited. Cell implantation combined with biomaterial therapies is widely studied for the development of tissue engineering technology. Herein, an insulin-like growth factor-1 (IGF-1)-bioactive supramolecular nanofiber hydrogel (IGF-1 gel) is synthesized that can activate IGF-1 downstream signaling, prevent the apoptosis of neural stem cells (NSCs), improve their proliferation, and induce their differentiation into neurons and oligodendrocytes. Moreover, implantation of NSCs carried out with IGF-1 gels promotes neurite outgrowth and myelin sheath regeneration at lesion sites following SCI. In addition, IGF-1 gels can enrich extracellular vesicles (EVs) derived from NSCs or from nerve cells differentiated from these NSCs via miRNAs related to axonal regeneration and remyelination, even in an inflammatory environment. These EVs are taken up by autologous endogenous NSCs and regulate their differentiation. This study provides adequate evidence that combined treatment with NSCs and IGF-1 gels is a potential therapeutic strategy for treating SCI.

Study on the Role and Mechanism of Exosomes Derived from Dental Pulp Stem Cells in Promoting Regeneration of Myelin Sheath in Rats with Sciatic Nerve Injury.

The prognosis of peripheral nerve injury (PNI) is usually poor, and currently, there is no effective treatment for PNI. Studies have shown that exosomes derived from mesenchymal stem cells could promote nerve regeneration by optimizing the function of endogenous Schwann cells (SCs), while the mechanism is unclear. Autophagy, a highly conserved intracellular catabolic process responsible for maintaining cellular homeostasis, has been proved to be involved in the regulation of nerve repair after injury. We explored the effect of exosomes derived from dental pulp stem cells (DPSC-Exos) on the regeneration of myelin sheath in rats with sciatic nerve injury (SNI). In vitro and in vivo experiments were performed to clarify whether the effect of DPSC-Exos is associated with autophagy of SCs and to reveal the mechanism at the molecular level. Our results showed that the SCs of SNI rats exhibited the obvious autophagic characteristics, and the increase of P53 expression was an internal factor of autophagy. Our mechanism research indicated that DPSC-Exos could deliver miR-122-5p from DPSCs into SCs and suppressed the rapamycin (RAPA)-induced autophagy in SCs by inhibiting P53 expression. Rescue experiments showed that both the use of GW4869 and overexpression of exogenous P53 in SCs could reverse the inhibitory effect of DPSCs on the autophagy in SCs from co-culture system. In short, our study indicated that DPSC-Exos could promote the regeneration of the myelin sheath through suppressing the autophagy in SCs caused by PNI via miR-122-5p/P53 pathway; this provides researchers with another option for precise repair of PNI.

Modified FGF Hydrogel for Effective Axon Formation by Enhanced Regeneration of Myelin Sheath of Schwann Cells Using Rat Model

Modified FGF Hydrogel for Effective Axon Formation by Enhanced Regeneration of Myelin Sheath of Schwann Cells Using Rat Model

The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration

BackgroundMyelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target.MethodsBy analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination.ResultsStat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation.ConclusionOur findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases.

Time-Dependent Proregenerative Effects of Exogenous Melatonin on the Transected Sciatic Nerve

Microsurgical procedures are the treatment of choice of peripheral nerve injuries, but often fail to reach full functional recovery. Melatonin has neuroprotective actions and might be used as a possible proregenerative pharmacological support. Therefore, the aim of this study was to analyze the time-dependence of the neuroprotective effect of melatonin on the overall fascicular structures of both ends of the transected nerve. Sciatic nerve transection was performed in 34 adult male Wistar rats divided in four groups: two vehicle groups (N=7) treated intraperitoneally for 7 (V7) or 21 (V21) consecutive days with vehicle (5 % ethanol in Ringer solution) and two melatonin groups (N=10) administered intraperitoneally 30 mg/kg of melatonin for 7 (M7) or 21 (M21) consecutive days. At the end of the experiment, proximal stump neuroma and distal stump fibroma were excised and processed for qualitative and quantitative histological analysis. Intrafascicular neural structures were better preserved and the collagen deposition was reduced in the melatonin treated groups than in the vehicle groups. Myelin sheath regeneration observed through its thickness measurement was statistically significantly (p<0,05) more pronounced in the M21 (1,23±0,18 µm) vs. V21 group (0,98±0,13 µm). The mean volume density of the endoneurium was lower in both melatonin treated groups in comparison to the matching vehicle treated groups. Although not statistically different, the endoneural tube diameter was larger in both melatonin groups vs. vehicle groups, and the effect of melatonin was more pronounced after 21 days (24,97 % increase) vs. 7 days of melatonin treatment (18,8 % increase). Melatonin exerts a time-dependent proregenerative effect on nerve fibers in the proximal stump and an anti-scarring effect in both stumps.

Down-regulation miR-146a-5p in Schwann cell-derived exosomes induced macrophage M1 polarization by impairing the inhibition on TRAF6/NF-κB pathway after peripheral nerve injury

BackgroundBoth Schwann cell-derived exosomes (SC-Exos) and macrophagic sub-phenotypes are closely related to the regeneration and repair after peripheral nerve injury (PNI). However, the crosstalk between them is less clear. ObjectiveWe aim to investigate the roles and underlying mechanisms of exosomes from normoxia-condition Schwann cell (Nor-SC-Exos) and from post-injury oxygen-glucose-deprivation-condition Schwann cell in regulating macrophagic sub-phenotypes and peripheral nerve injury repair. MethodBoth Nor-SC-Exos and OGD-SC-Exos were extracted through ultracentrifugation, identified by transmission electron microscopy (TEM), Nanosight tracking analysis (NTA) and western blotting. High-throughput sequencing was performed to explore the differential expression of microRNAs in both SC-Exos. In vitro, RAW264.7 macrophage was treated with two types of SC-Exos, M1 macrophagic markers (IL-10, Arg-1, TGF-β1) and M2 macrophagic markers (IL-6, IL-1β, TNF-α) were detected by enzyme-linked Immunosorbent Assay (ELISA) or qRT-PCR, and the expression of CD206, iNOS were detected via cellular immunofluorescence (IF) to judge macrophage sub-phenotypes. Dorsal root ganglion neurons (DRGns) were co-cultured with RAW264.7 cells treated with Nor-SC-Exos and OGD-SC-Exos, respectively, to explore their effect on neuron growth. In vivo, we established a sciatic nerve crush injury rat model. Nor-SC-Exos and OGD-SC-Exos were locally injected into the injury site. The mRNA expression of M1 macrophagic markers (IL-10, Arg-1, TGF-β1) and M2 macrophagic markers (IL-6, IL-1β, TNF-α) were detected by qRT-PCR to determine the sub-phenotype of macrophages in the injury site. IF was used to detect the expression of MBP and NF200, reflecting the myelin sheath and axon regeneration, and sciatic nerve function index (SFI) was measured to evaluate function repair. ResultIn vitro, Nor-SC-Exos promoted macrophage M2 polarization, increased anti-inflammation factors secretion, and facilitated axon elongation of DRGns. OGD-SC-Exos promoted M1 polarization, increased pro-inflammation factors secretion, and restrained axon elongation of DRGns. High-throughput sequencing and qRT-PCR results found that compared with Nor-SC-Exos, a shift from anti-inflammatory (pro-M2) to pro-inflammatory (pro-M1) of OGD-SC-Exos was closely related to the down-regulation of miR-146a-5p and its decreasing inhibition on TRAF6/NF-κB pathway after OGD injury. In vivo, we found Nor-SC-Exos and miR-146a-5p mimic promoted regeneration of myelin sheath and axon, and facilitated sciatic function repair via targeting TRAF6, while OGD-SC-Exos and miR-146a-5p inhibitor restrained them. ConclusionOur study confirmed that miR-146a-5p was significantly decreased in SC-Exos under the ischemia-hypoxic microenvironment of the injury site after PNI, which mediated its shift from promoting macrophage M2 polarization (anti-inflammation) to promoting M1 polarization (pro-inflammation), thereby limiting axonal regeneration and functional recovery.

Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43.

Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA-binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures, and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43-deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult central nervous system (CNS) induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.

Electroacupuncture Inhibits Myelin Sheath Injury in the Internal Capsule After Focal Cerebral Infarction in Rats Through the Nogo-A/NgR Signaling Pathway

BackgroundIschemic stroke is usually accompanied by white matter damage. The effect of electroacupuncture (EA) on ameliorating white matter damage is still unclear. The purpose of this study was to explore the precise mechanism of EA in treating ischemic white matter.Material/MethodsIn this study, 40 Sprague-Dawley rats were randomly divided into 4 groups: normal group, the sham-operated group, model group, and EA group. The stroke model was established by right middle cerebral artery occlusion, and EA was performed 24 h after the operation for 30 min per day. After 14 days of treatment, brain tissue samples were collected. Hematoxylin and eosin and Luxol fast blue staining were used to observe the changes of white matter damage in the internal capsule (IC). The expression levels of myelin basic protein (MBP), Nogo-A, and Nogo-A receptor (NgR) were detected by immunohistochemistry and western blot.ResultsCompared with the sham-operated group, the model group had decreased expression of MBP and significantly increased expression of Nogo-A and NgR (P<0.05). Compared with the model group, the IC damage was alleviated in the EA group. Immunohistochemistry and western blot analysis showed that EA significantly increased the expression of MBP in white matter (P<0.05) and downregulated the expression levels of Nogo-A and NgR (P<0.05).ConclusionsThe results of this study indicate that EA can inhibit the expression of Nogo-A/NgR and promote myelin sheath regeneration.

Cortical neurons exhibit diverse myelination patterns that scale between mouse brain regions and regenerate after demyelination

ABSTRACTAxons in the cerebral cortex show a broad range of myelin coverage. Oligodendrocytes establish this pattern by selecting a cohort of axons for myelination; however, the distribution of myelin on distinct neurons and extent of internode replacement after demyelination remain to be defined. Here we show that myelination patterns of seven distinct neuron subtypes in somatosensory cortex are influenced by both axon diameter and neuronal identity. Preference for myelination of parvalbumin interneurons was preserved between cortical areas with varying myelin density, suggesting that regional differences in myelin abundance arises through local control of oligodendrogenesis. By imaging loss and regeneration of myelin sheaths in vivo we show that myelin distribution on individual axons was altered but overall myelin content on distinct neuron subtypes was restored. Our findings suggest that local changes in myelination are tolerated, allowing regenerated oligodendrocytes to restore myelin content on distinct neurons through opportunistic selection of axons.

Exosomes produced by adipose-derived stem cells inhibit schwann cells autophagy and promote the regeneration of the myelin sheath.

Peripheral nerve injury (PNI) is encountered relatively commonly in the clinic and often results in long-term functional deficits. Research to develop methods to improve regeneration following nerve injury is ongoing. Numerous studies have shown that adipose-derived stem cells (ADSCs) promote the regeneration of peripheral nerve injury; however, the mechanism is unclear. Autophagy, a highly conserved intracellular process responsible for maintaining cellular homeostasis, and Schwann cells (SCs), play important roles in regeneration after PNI. In the present study, we explored the effect and mechanism of exosomes produced by adipose-derived stem cells (ADSC-Exos) on autophagy of SCs in PNI, as well as their effect on the regeneration of the nerve myelin sheath. The levels of autophagy and the expression of karyopherin subunit alpha 2 (Kpna2) in SCs increased markedly after the sciatic nerve was injured in SCs (SNI-SCs). The enhanced autophagy and the upregulated Kpna2 in SNI-SCs were inhibited after treatment with ADSC-Exos in vivo and in vitro. The effect of ADSC-Exos on inhibiting SC autophagy was blocked by overexpression of Kpna2 in SNI-SCs. Using quantitative real-time reverse transcription PCR, ADSC-Exos were demonstrated to contain a large amount of miRNA-26b, which was predicted to regulate Kpna2 on the TargetScan website. The effect of ADSC-Exos on inhibiting SCs autophagy was blocked after the silencing of miRNA-26b. Moreover, ADSC-Exos promoted the regeneration of the myelin sheath by inhibiting SC autophagy in rat SNI models. In conclusion, our results indicated that ADSC-Exos promote the regeneration of the myelin sheath by moderately reducing autophagy of injured SCs via miRNA-26b downregulation of Kpna2.

Changes in Type II NRG-1 Expression during Regeneration Following Autologous Nerve Transplantation in Rats.

To investigate the changes in type II neuregulin-1 (NRG-1) during the regeneration process following autologous sciatic nerve transplantation in rats. In total, 40 healthy male Sprague-Dawley (SD) rats of clean grade with body weights between 250 g and 300 g were randomly divided into an experimental and control group, with 20 rats per group. Five time points were set, including the 3 < sup > rd < /sup > , 7 < sup > th < /sup > , 14 < sup > th < /sup > , 21 < sup > st < /sup > and 28 < sup > th < /sup > days after surgery. In the experimental group, reversed autologous transplantation of the sciatic nerve was performed, while in the control group, the sciatic nerve was simply exposed without autologous transplantation. At the different time points, changes in the rat footprints were observed, the sciatic functional index (SFI) was calculated, changes in the regeneration of the myelin sheath at the nerve end after transplantation were observed by transmission electron microscopy, changes in type II NRG-1 protein expression were detected by a western blot analysis, and changes in type II NRG-1 mRNA expression were detected by real-time PCR. The SFI in the experimental group was lower than that in the control group at all time points after surgery, and the SFI in the experimental group gradually increased; these differences were statistically significant (p < 0.05). The expression of type II NRG-1 protein in the experimental group was significantly increased on the 3rd day after nerve transplantation and peaked on the 7 < sup > th < /sup > day, which continued until the 28 < sup > th < /sup > day after surgery, indicating a significant difference from the control group (p < 0.01). NRG-1 mRNA expression was markedly increased on the 7th day after nerve transplantation, further increased, and peaked on the 14 < sup > th < /sup > day (p < 0.01). The area of medullated nerve fibers (?m2) in the experimental group significantly differed from that in the control group on the 7 < sup > th < /sup > , 14 < sup > th < /sup > , 21 < sup > st < /sup > and 28 < sup > th < /sup > days (p < 0.01), and the diameters of the axons in the experimental group notably differed from those in the control group on the 7 < sup > th < /sup > , 14 < sup > th < /sup > and 21 < sup > st < /sup > days (p < 0.01). Type II NRG-1 expression peaked between the 3 < sup > rd < /sup > day and 14 < sup > th < /sup > day after autologous nerve transplantation and is likely involved in the regulation of myelin sheath regeneration during this period.

Effect of hyaluronidase on expression of neuron-glial antigen 2 and myelin basic protein after germinal matrix-intraventricular hemorrhage in premature rabbits

Objective To investigate the neuroprotective effect of hyaluronidase(HAase) on rabbit brain tissue in germinal matrix-intraventricular hemorrhage(GM-IVH) premature rabbits. Methods Eighty premature rabbits of gestation age 29 days were randomly divided into normal group, GM-IVH control group and HAase treatment group.The rabbits in GM-IVH control group and HAase treatment group were given intraperitoneal injection of 50 g/L glycerol to establish GM-IVH animal model, while the premature rabbits in normal group were given the same dose of 9 g/L saline.The GM-IVH was screened by using cranial ultrasound.The premature rabbits in HAase treatment group were given HAase into the lateral forebrain while the rabbits in the GM-IVH control group were given the same dose of 9 g/L saline.In 3 days, 7 days and 14 days after birth, the premature rabbits were killed and brain tissue were separated.The expression of neuron-glial antigen 2(NG2) were detected by adopting immunohistochemical method.The expression of myelin basic protein(MBP) were detected by Western blot method. Results The expression of NG2 in 3 groups of premature rabbits decreased gradually with the increase of age[the values of NG2 in the normal group were(62.65±33.58)×104, (15.61±4.22)×104, and (13.54±4.51)×104 on the 3rd, 7th, and 14th day; those in the GM-IVH control group were (54.58±25.48)×104, (48.91±22.49)×104, (7.18±2.28)×104 on the 3rd, 7th, and 14th day; those in the HAase treatment group were (148.13±27.30)×104, (88.38±14.55)×104, (77.98±18.96)×104 on the 3rd, 7th, and 14th day]. At the same time, the expression of NG2 in the HAase treatment group was higher than that of the GM-IVH control group, and the differences were statistically significant among the 3 groups at any time(all P<0.05). The expression of MBP protein in the 3 groups increased with the increase of day age[MBP protein in the normal group were (0.30±0.22)×103, (1.91±0.43)×103, and (5.67±2.14) ×103 on the 3rd, 7th, and 14th day; those in the GM-IVH control group were (0.87±0.12)×103, (1.15±0.22)×103 and (2.54±0.69) ×103 on the 3rd, 7th, and 14th day; those in the HAase treatment group were (0.91±1.01)×103, (2.25±0.66)×103, (3.40±1.10)×103 on the 3rd, 7th, and 14th day]. The difference was statistically significant between the normal group and the HAase treatment group(P<0.05). Conclusions After HAase treatment, the expression of NG2 and MBP can be improved to a certain extent, promoting the development of oligodendrocytes and regeneration of myelin sheath. Key words: Germinal matrix-intraventricular hemorrhage; Hyaluronidase; Neuron-glial antigen 2; Myelin basic protein

Exosomes Derived from ADSCs Promote the Regeneration of Myelin Sheath by Inhibiting SCs Autophagy via miRNA26b Targeting KPNA2

Background: Peripheral nerve injury is encountered quite commonly in the clinic and often results in long-term functional deficits. Investigation toward the development of methods to improve regeneration following nerve injury is ongoing. Numerous studies proved that adipose-derived stem cells (ADSCs) promote the regeneration of peripheral nerve injury, but the mechanism is not clear. Autophagy, highly conserved intracellular process responsible for maintaining cellular homeostasis, and Schwann cells (SCs) play important roles in the regeneration of peripheral nerve injury. Methods: In this study, we explored the effect of ADSC-derived exosomes (ADSC-Exos) on the SCs autophagy and the regeneration of myelin sheath after sciatic nerve injury. Findings: The enhanced autophagy was inhibited, the up-regulated expression of KPNA2 was decreased, and the down-regulated levels of miRNA-26b was increased in injured SCs after treatment with ADSCs-Exos. Usingreal-time PCR, ADSC-Exos were shown to contained a large number of miRNA-26b. The effect of ADSC-Exos inhibiting SCs autophagy were blocked after the over-expression of KPNA2 or the silence of miRNA-26b. Moreover, ADSC-Exos promoted the regeneration of myelin sheaths of injured sciatic nerves in rats. Interpretation: Our results indicate that ADSC-Exos promote the regeneration of myelin sheath by moderately reducing autophagy of injured SCs via miRNA-26b down-regulating KPNA2. Funding Statement: This study was supported by National Key R&D Program of China (2018YFA0107500), National Natural Science Foundation of China (81572146, 31771511), Shanghai Health System Excellent Discipline Leadership Program(2017BR034)and China Postdoctoral Science Foundation (2017M623362, 2018T111131). Declaration of Interests: The authors report no conflicts of interest in this work. Ethics Approval Statement: All animal experiments met the requirements of the Ethics Committee.

Polyurethane/Gelatin Nanofiber Neural Guidance Conduit in Combination with Resveratrol and Schwann Cells for Sciatic Nerve Regeneration in the Rat Model

Peripheral nerve injury is a serious challenge which influences 2.8 percent of trauma patients. Tissue engineering of peripheral nerves mainly focuses on axonal regeneration via various nerve guides. The aim of this study is to evaluate a novel polyurethane (PU)/gelatin nanofibers (GNFs) conduit’s potential combination with resveratrol (RVT) for sciatic nerve regeneration in the rat. Platelet-rich plasma (PRP) was used as a carrier for RVT. Different tests like contact angle, tensile strength etc. was used to evaluate properties of PU/GNFs conduits. In addition, the electron microscopy, MTT assay, and DAPI staining revealed its compatibility with Schwann cells. 24 male Wistar rats were allocated into four groups (n=6) (1) PU/GNF/PRP/Schwann cell, 2) PU/GNF/Schwann cell/PRP/RVT, 3) Positive control, and 4) Negative control in order to assess sciatic functional index (SFI), hot plate latency, electromyographical (EMG), the percentage of wet weight-loss of gastrocnemius muscle and histopathological studies using hematoxylin-eosin staining. The results represented sciatic functional index (SFI), hot plate latency, electromyographical improved significantly in group 1 and 2 compared to the negative control group. Histopathological findings showed remarkable improvements in myelin sheath regeneration and fibers condition in group 1 and 2 compared to the negative control group. Group 2 showed more resemblance to the normal sciatic nerve, with well-arranged fibers and an intact myelin sheath. This study successfully applied PU/GNFs/PRP/RVT conduits as a potential biocompatible nerve guide with proper mechanical properties, biocompatibility, and biodegradability that enhanced injured sciatic nerve’s recovery rate.

Painful Terminal Neuroma Prevention by Capping PRGD/PDLLA Conduit in Rat Sciatic Nerves.

Neuroma formation after amputation as a long‐term deficiency leads to spontaneous neuropathic pain that reduces quality of life of patients. To prevent neuroma formation, capping techniques are implemented as effective treatments. However, an ideal, biocompatible material covering the nerves is an unmet clinical need. In this study, biocompatible characteristics presented by the poly(D,L‐lactic acid)/arginylglycylaspartic acid (RGD peptide) modification of poly{(lactic acid)‐co‐ [(glycolic acid)‐alt‐(L‐lysine)]} (PRGD/PDLLA) are evaluated as a nerve conduit. After being capped on the rat sciatic nerve stump in vivo, rodent behaviors and tissue structures are compared via autotomy scoring and histological analyses. The PRGD/PDLLA capped group gains lower autotomy score and improves the recovery, where inflammatory infiltrations and excessive collagen deposition are defeated. Transmission electron microscopy images of the regeneration of myelin sheath in both groups show that abnormal myelination is only present in the uncapped rats. Changes in related genes (MPZ, MBP, MAG, and Krox20) are monitored quantitative real‐time polymerase chain reaction (qRT‐PCR) for mechanism investigation. The PRGD/PDLLA capping conduits not only act as physical barriers to inhibit the invasion of inflammatory infiltration in the scar tissue but also provide a suitable microenvironment for promoting nerve repairing and avoiding neuroma formation during nerve recovery.

Insulin-induced upregulation of lipoprotein lipase in Schwann cells during diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is one of the major complications associated with diabetes. It is characterized by the degeneration of the myelin sheath around axons, referred to as demyelination. Such demyelinations are often caused by reduced lipid component of the myelin sheath. Since, lipoprotein lipase (LPL) provides the lipid for myelin sheath by hydrolysing the triglyceride rich lipoproteins, and also helps in the uptake of lipids by the Schwann cells (SCs) for its utilization, LPL is considered as the important factor in the regeneration of myelin sheath during diabetic neuropathy. Earlier reports from our laboratory have provided the insights of insulin and its receptor in SCs during diabetic neuropathy. In order to evaluate the long term effect of insulin on lipid metabolism during diabetic neuropathy, in this study, we analyzed the expression of LPL in SCs under normal, high glucose and insulin treated conditions. A decrease in the expression of LPL was observed in SCs of high glucose condition and it was reversed upon insulin treatment. Histochemical observations of sciatic nerve of insulin treated neuropathy subjects showed the improved nerve morphology, signifying the importance of insulin in restoring the pathophysiology of diabetic neuropathy.

Effects of physical exercise on myelin sheath regeneration: A systematic review and meta-analysis

This study aimed to verify the effects of physical exercise (PE) on myelin sheath regeneration (MSR). The databases searched were MedLine/PubMed, Lilacs, and Scielo. Articles not related to the effects of PE on MSR, concentration of proteins and other factors linked to myelin regeneration, and studies that used medicine concomitantly with PE were defined as exclusion criteria. After removing duplicates, applying exclusion criteria, and checking the reference lists, 21 studies were added to this review and divided in two groups: i) articles assessing the effect of PE on permissiveness of environment in central nervous system to MSR and ii) articles assessing the effect of PE on regeneration of myelin sheath components. The random effect model was used to the meta-analysis of myelin sheath thickness (MST) and G ratio because Cochran's Q test showed high heterogeneity. In the first group, low-intensity physical training was the most common PE adopted among the interventions and resulted in improvement of permissiveness on central nervous system environment. The studies in the second group, low-to-moderate PE was the most prevalent protocol adopted among interventions. Additionally, this type of training enhanced MST and maturation. Regarding to meta-analysis, PE was associated with the MST [0.11 (0.05–0.17) μm, P < 0.001] and G ratio [−0.04 (−0.06 – −0.02), P = 0.009], although the high (I2 = 77.1%) and moderate (I2 = 65.0%) heterogeneity, respectively. The results suggest that moderate continuous exercise could potentially enhance MSR and improve concentration of myelination-related proteins and as a result, its practice is encouraged to both prevent and treat demyelination. Cette étude visait à vérifier les effets de l’exercice physique (PE) sur la régénération de la gaine de myéline (MSR). Les bases de données recherchées étaient MedLine/PubMed, Lilas et Scielo. Les articles non liés aux effets de l’EP sur MSR, la concentration de protéines et d’autres facteurs liés à la régénération de la myéline, et les études qui ont utilisé des médicaments en même temps que les PE ont été définis comme des critères d’exclusion. Après avoir supprimé les doublons, en appliquant les critères d’exclusion et en vérifiant les listes de référence, 21 études ont été ajoutées à cette revue et divisées en deux groupes : i) articles évaluant l’effet de PE sur la permissivité de l’environnement dans le système nerveux central à MSR et ii) évaluation des articles sur l’effet de l’EP sur la régénération des composants de la gaine de myéline. Le modèle d’effet aléatoire a été utilisé pour la méta-analyse de l’épaisseur de la gaine de myéline (MST) et du ratio G car le test Q de Cochrane présentait une hétérogénéité élevée. Dans le premier groupe, la formation physique de faible intensité a été l’adoption de l’EP plus fréquent parmi les interventions et a entraîné une amélioration de la permissivité sur l’environnement du système nerveux central. Les études dans le deuxième groupe, PE à faible à modérée ont été le protocole le plus répandu adopté parmi les interventions. En outre, ce type de formation a amélioré le MST et la maturation. En ce qui concerne la méta-analyse, le PE a été associé au MST [0,11 (0,05–0,17) μm, p < 0,001] et le ratio G [−0,04 (−0,06–−0,02), p = 0,009], bien que le haut (I2 = 77,1 %) et une hétérogénéité modérée (I2 = 65,0 %), respectivement. Les résultats suggèrent que l’exercice continu modéré pourrait améliorer la MSR et améliorer la concentration des protéines liées à la myélinisation et, par conséquent, sa pratique est encouragée à la fois pour prévenir et traiter la démyélinisation.

STEREOLOGICAL EVIDENCE FOR DE/RE-GENERATION OF MYELIN SHEATHS IN AGED BRAIN WHITE MATTER OF FEMALE RATS

Studies have provided qualitative evidence of de-myelination and re-myelination in aged brain white matter. However, there have been no quantitative evidences of degeneration and regeneration of myelin sheaths in white matter. The present study was designed to investigate the quantitative changes in myelin sheaths using unbiased stereological techniques and qualitative changes using electron microscopy in aged brain white matter. Results obtained showed that in brain white matter, the total volume of myelin sheaths of old-age female rats was not significantly different from that of young female rats, but the total length of myelinated fibers in old female rats was significantly decreased by 46.1% when compared with that of young female rats. Myelin sheath volume per unit length of myelinated fibers of old female rats was significantly increased by 43.4% compared with that of young female rats. The mean thickness of myelin sheaths in the white matter of the old rats was significantly increased by 33.3%, when compared with that of young female rats. In age-related loss of myelinated fibers, most fibers had diameters less than 1.4 μm, and myelin sheath thicknesses less than 0.14 μm, but the length of myelinated fibers with diameters more than 0.6 μm and myelin sheath thicknesses more than 0.22 μm increased with age. Myelinated fibers with ratios of myelin sheath thicknesses to myelinated fiber external diameter less than 0.21 were significantly lower in elderly rats than in young rats. However, the total length of myelinated fibers with ratios of myelin sheath thicknesses to myelinated fiber external diameter more than 0.23 was higher in aged rats than in young rats. About 6.58% of myelin sheaths showed degenerative alterations, while 0.88% myelin sheaths showed regenerative alterations. This study provides stereological evidence not only for degeneration but also regeneration of myelin sheaths in aged white matter.

Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord

Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease. The presence of myelin lipid debris was seen only at the peak of EAE in demyelination loci being efficiently removed during the recovery period. Since CYP46A1 is responsible for removal of cholesterol excess, we performed a detailed profiling of CYP46A1 expression and revealed regional and temporal specificities in its distribution. Double immunofluorescence staining demonstrated CYP46A1 localization with neurons, infiltrated macrophages, microglia and astrocytes in the areas of demyelination, suggesting that these cells play a role in cholesterol turnover in EAE. We propose that alterations in the regulation of cholesterol metabolism at the onset and peak of EAE may add to the progression of disease, while during the recovery period may have beneficial effects contributing to the regeneration of myelin sheath and restoration of neuronal function.

Regeneration of myelin sheaths of normal length and thickness in the zebrafish CNS correlates with growth of axons in caliber.

Demyelination is observed in numerous diseases of the central nervous system, including multiple sclerosis (MS). However, the endogenous regenerative process of remyelination can replace myelin lost in disease, and in various animal models. Unfortunately, the process of remyelination often fails, particularly with ageing. Even when remyelination occurs, it is characterised by the regeneration of myelin sheaths that are abnormally thin and short. This imperfect remyelination is likely to have implications for the restoration of normal circuit function and possibly the optimal metabolic support of axons. Here we describe a larval zebrafish model of demyelination and remyelination. We employ a drug-inducible cell ablation system with which we can consistently ablate 2/3rds of oligodendrocytes in the larval zebrafish spinal cord. This leads to a concomitant demyelination of 2/3rds of axons in the spinal cord, and an innate immune response over the same time period. We find restoration of the normal number of oligodendrocytes and robust remyelination approximately two weeks after induction of cell ablation, whereby myelinated axon number is restored to control levels. Remarkably, we find that myelin sheaths of normal length and thickness are regenerated during this time. Interestingly, we find that axons grow significantly in caliber during this period of remyelination. This suggests the possibility that the active growth of axons may stimulate the regeneration of myelin sheaths of normal dimensions.