Heparin-based coacervate of bFGF facilitates peripheral nerve regeneration by inhibiting endoplasmic reticulum stress following sciatic nerve injury.
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ABSTRACT:
SUBMITTER: Li R
PROVIDER: S-EPMC5564628 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:Peripheral nerve injury (PNI) is a major burden to society with limited therapeutic options, and novel biomaterials have great potential for shifting the current paradigm of treatment. With a rising prevalence of chronic illnesses such as diabetes mellitus (DM), treatment of PNI is further complicated, and only few studies have proposed therapies suitable for peripheral nerve regeneration in DM. To provide a supportive environment to restore structure and/or function of nerves in DM, we developed a novel thermo-sensitive heparin-poloxamer (HP) hydrogel co-delivered with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) in diabetic rats with sciatic nerve crush injury. The delivery vehicle not only had a good affinity for large amounts of growth factors (GFs), but also controlled their release in a steady fashion, preventing degradation in vitro. In vivo, compared with HP hydrogel alone or direct GFs administration, GFs-HP hydrogel treatment is more effective at facilitating Schwann cell (SC) proliferation, leading to an increased expression of nerve associated structural proteins, enhanced axonal regeneration and remyelination, and improved recovery of motor function (all p?<?0.05). Our mechanistic investigation also revealed that these neuroprotective and neuroregenerative effects of the GFs-HP hydrogel may be associated with activations of phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt), janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. Our work provides a promising therapy option for peripheral nerve regeneration in patients with DM.
| S-EPMC5935004 | biostudies-literature
Project description:The use of autologous nerve grafts remains the gold standard for treating nerve defects, but current nerve repair techniques are limited by donor tissue availability and morbidity associated with tissue loss. Recently, the use of conduits in nerve injury repair, made possible by tissue engineering, has shown therapeutic potential. We manufactured a biodegradable, collagen-based nerve conduit containing decellularized sciatic nerve matrix and compared this with a silicone conduit for peripheral nerve regeneration using a rat model. The collagen-based conduit contains nerve growth factor, brain-derived neurotrophic factor, and laminin, as demonstrated by enzyme-linked immunosorbent assay. Scanning electron microscopy images showed that the collagen-based conduit had an outer wall to prevent scar tissue infiltration and a porous inner structure to allow axonal growth. Rats that were implanted with the collagen-based conduit to bridge a sciatic nerve defect experienced significantly improved motor and sensory nerve functions and greatly enhanced nerve regeneration compared with rats in the sham control group and the silicone conduit group. Our results suggest that the biodegradable collagen-based nerve conduit is more effective for peripheral nerve regeneration than the silicone conduit.
| S-EPMC6128056 | biostudies-literature
Project description:Peripheral nervous system owns the ability of self-regeneration, mainly in its regenerative microenvironment including vascular network reconstruction. More recently, more attentions have been given to the close relationship between tissue regeneration and angiogenesis. To explore the overlap of molecular mechanisms and key regulation molecules between peripheral nerve regeneration and angiogenesis post peripheral nerve injury, integrative and bioinformatic analysis was carried out for microarray data of proximal stumps after sciatic nerve transection in SD rats. Nerve regeneration and angiogenesis were activated at 1 day immediately after sciatic nerve transection simultaneously. The more obvious changes of transcription regulators and canonical pathways suggested a phase transition between 1 and 4 days of both nerve regeneration and angiogenesis after sciatic nerve transection. Furthermore, 16 differentially expressed genes participated in significant biological processes of both nerve regeneration and angiogenesis, a few of which were validated by qPCR and immunofluorescent staining. It was demonstrated that STAT3, EPHB3, and Cdc42 co-expressed in Schwann cells and vascular endothelial cells to play a key role in regulation of nerve regeneration and angiogenesis simultaneously response to sciatic nerve transection. We provide a framework for understanding biological processes and precise molecular correlations between peripheral nerve regeneration and angiogenesis after peripheral nerve transection. Our work serves as an experimental basis and a valuable resource to further understand molecular mechanisms that define nerve injury-induced micro-environmental variation for achieving desired peripheral nerve regeneration.
| S-EPMC5649188 | biostudies-literature
Project description:BackgroundRecent experimental studies using herbal extracts have shown the possibility of peripheral nerve regeneration. This study aimed to investigate the effects of herbal extracts on peripheral nerve regeneration in a rat sciatic nerve injury model.MethodsA total of 53 rats were randomly assigned to a control group or one of four experimental groups. In all rats, the sciatic nerve was completely severed and microscopic epineural end-to-end neurorrhaphy was performed. Normal saline (2 mL) was topically applied to the site of nerve repair in the control group, whereas four different herbal extracts - 2 mL each of Astragalus mongholicus Bunge, Coptis japonica (Thunb.) Makino, Aconitum carmichaelii Debeaux, or Paeonia lactiflora Pall. - were topically applied to the site of nerve repair in each experimental group. Nerve conduction studies were performed at an average of 11.9 weeks after the operation, and conduction velocity and proximal and distal amplitudes were measured. Biopsies were performed at an average of 13.2 weeks after the initial neurorrhaphy. The quality of nerve anastomosis and perineural adhesion to the surrounding soft tissues was macroscopically evaluated. The neuroma size at the site of the neurorrhaphy was microscopically measured, whereas the size of the scar tissue was evaluated relative to the diameter of the repaired nerve.ResultsThe nerve conduction study results showed the highest nerve conduction velocity in the experimental group that used the Coptis japonica (Thunb.) Makino extract and the highest proximal and distal amplitudes in the experimental group that used the Aconitum carmichaelii Debeaux extract. Macroscopic evaluations after the second operation showed that grade 2 perineural adhesion was found in 70.8% of rats. The mean neuroma size in the Coptis japonica (Thunb.) Makino, Aconitum carmichaelii Debeaux, and Paeonia lactiflora Pall. groups showed statistically significant decreases relative to the control group. The mean scar tissue formation index in the Paeonia lactiflora Pall. group showed a statistically significant decrease relative to the control group.ConclusionsThe peripheral nerve regeneration effect of the herbal extracts was confirmed through decreased neuroma and scar tissue formation.
| S-EPMC8178854 | biostudies-literature
Project description:BackgroundExcessive inflammation within damaged tissue usually leads to delayed or insufficient regeneration, and nerves in the peripheral nervous system (PNS) generally do not recover fully following damage. Consequently, there is growing interest in whether modulation of the inflammatory response could help to promote nerve regeneration in the PNS. However, to date, there are no practical therapeutic strategies for manipulating inflammation after nerve injury. Thrombomodulin (TM) is a transmembrane glycoprotein containing five domains. The lectin-like domain of TM has the ability to suppress the inflammatory response. However, whether TM can modulate inflammation in the PNS during nerve regeneration has yet to be elucidated.MethodsWe investigated the role of TM in switching proinflammatory type 1 macrophages (M1) to anti-inflammatory type 2 macrophages (M2) in a human monocytic cell line (THP-1) and evaluated the therapeutic application of TM in transected sciatic nerve injury in rats.ResultsThe administration of TM during M1 induction significantly reduced the expression levels of inflammatory cytokines, including TNF-a (p < 0.05), IL-6 (p < 0.05), and CD86 (p < 0.05), in THP-1 cells. Simultaneously, the expression levels of M2 markers, including IL-10 (p < 0.05) and CD206 (p < 0.05), were significantly increased in TM-treated THP-1 cells. Inhibition of IL-4R-c-Myc-pSTAT6-PPARγ signaling abolished the expression levels of IL-10 (p < 0.05) and CD206 (p < 0.05). The conditioned medium (CM) collected from M1 cells triggered an inflammatory response in primary Schwann cells, while CM collected from M1 cells treated with TM resulted in a dose-dependent reduction in inflammation. TM treatment led to better nerve regeneration when tested 6 weeks after injury and preserved effector muscle function. In addition, TM treatment reduced macrophage infiltration at the site of injury and led to potent M1 to M2 transition, thus indicating the anti-inflammatory capacity of TM.ConclusionsCollectively, our findings demonstrate the anti-inflammatory role of TM during nerve regeneration. Therefore, TM represents a potential drug for the promotion and modulation of functional recovery in peripheral nerves that acts by regulating the M1/M2 ratio.
| S-EPMC7477856 | biostudies-literature
Project description:In contrast to neurons in the CNS, damaged neurons from the peripheral nervous system (PNS) regenerate, but this process can be slow and imperfect. Successful regeneration is orchestrated by cytoskeletal reorganization at the tip of the proximal axon segment and cytoskeletal disassembly of the distal segment. Collapsin response mediator protein 4 (CRMP4) is a cytosolic phospho-protein that regulates the actin and microtubule cytoskeleton. During development, CRMP4 promotes growth cone formation and dendrite development. Paradoxically, in the adult CNS, CRMP4 impedes axon regeneration. Here, we investigated the involvement of CRMP4 in peripheral nerve injury in male and female Crmp4-/- mice following sciatic nerve injury. We find that sensory axon regeneration and Wallerian degeneration are impaired in Crmp4-/- mice following sciatic nerve injury. In vitro analysis of dissociated dorsal root ganglion (DRG) neurons from Crmp4-/- mice revealed that CRMP4 functions in the proximal axon segment to promote the regrowth of severed DRG neurons and in the distal axon segment where it facilitates Wallerian degeneration through calpain-dependent formation of harmful CRMP4 fragments. These findings reveal an interesting dual role for CRMP4 in proximal and distal axon segments of injured sensory neurons that coordinately facilitate PNS axon regeneration.
| S-EPMC7053045 | biostudies-literature
Project description:Peripheral nerve injury (PNI), resulting in the impairment of myelin sheaths and axons, seriously affects the transmission of sensory or motor nerves. Growth factors (GFs) provide a biological microenvironment for supporting nerve regrowth and have become a promising alternative for repairing PNI. As one number of intracellular growth factor family, fibroblast growth factor 13 (FGF13) was regard as a microtubule-stabilizing protein for regulating cytoskeletal plasticity and neuronal polarization. However, the therapeutic efficiency and underlying mechanism of FGF13 for treating PNI remained unknown. Here, the application of lentivirus that overexpressed FGF13 was delivered directly to the lesion site of transverse sciatic nerve for promoting peripheral nerve regeneration. Through behavioral analysis and histological and ultrastructure examinations, we found that FGF13 not only facilitated motor and sense functional recovery but also enhanced axon elongation and remyelination. Furthermore, pretreatment with FGF13 also promoted Schwann cell (SC) viability and upregulated the expression cellular microtubule-associated proteins in vitro PNI model. These data indicated FGF13 therapeutic effect was closely related to maintain cellular microtubule stability. Thus, this work provides the evident that FGF13-medicated microtubule stability is necessary for promoting peripheral nerve repair following PNI, highlighting the potential therapeutic value of FGF13 on ameliorating injured nerve recovery.
| S-EPMC8397546 | biostudies-literature
Project description:Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous null mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush.
| S-EPMC4292924 | biostudies-literature
Project description:Several studies have shown that dexmedetomidine (DXM), a selective ?2-adrenoceptor agonist, also has neuroprotective effects. However, its effect on impaired peripheral nerve regeneration has not been studied.Forty-five Sprague-Dawley rats were randomly assigned to three groups: group 1 (control SHAM), group 2 (sciatic nerve injury?+?normal saline), and group 3 (sciatic nerve injury?+?DXM). The rats of group 3 were subdivided into the following three groups: DXM 0.5, 6, and 20??g·kg-1 (groups 3A, 3B, and 3C, resp.). The sciatic nerve injury was assessed for nerve regeneration at 2 and 6 weeks.There were no differences between groups 2 and 3 in their sciatic functional index (SFI) values or histological findings at 2 weeks postinjury. However, SFI differences were statistically significant at 6 weeks postinjury in group 3. The gross findings with H&E staining showed that the number of axons was higher in group 3 than in group 2. There was no histological difference according to the DXM concentration.The coincidental functional and histological assessment results of this study suggest that DXM for 6 weeks positively affects damaged peripheral nerves.
| S-EPMC5745707 | biostudies-literature
Project description:The search for drugs that can facilitate axonal regeneration and elongation following peripheral nerve injury has been an area of increasing interest in recent years. Epothilone B (EpoB) is an FDA-approved antineoplastic agent, which shows the capacity to induce ?-tubulin polymerization and to improve the stability of microtubules. Recently, it has been increasingly recognized that EpoB has a regenerative effect in the central nervous system. However, the information currently available regarding the potential therapeutic effect of EpoB on peripheral nerve regeneration is limited. Here, we used a rat sciatic crush injury model system to determine that EpoB strikingly improved axonal regeneration and recovery of function. Also, EpoB (1 nM) did not result in significant apoptosis in Schwann cells (SCs) and showed little effect on their viability either. Interestingly, EpoB (1 nM) significantly enhanced migration in SCs, which was inhibited by autophagy inhibitors 3-methyladenine (3-MA). Since PI3K/Akt signaling has been implicated in regulating autophagy, we further examined the involvement of PI3K/Akt in the process of EpoB-induced SC migration. We found that EpoB (1 nM) significantly inhibited phosphorylation of PI3K and Akt in SCs. Further studies showed that both EpoB-enhanced migration and autophagy were increased/inhibited by inhibition/activation of PI3K/Akt signaling with LY294002 or IGF-1. In conclusion, EpoB can promote axonal regeneration following peripheral nerve injury by enhancing the migration of SCs, with this activity being controlled by PI3K/Akt signaling-mediated autophagy in SCs. This underscores the potential therapeutic value of EpoB in enhancing regeneration and functional recovery in cases of peripheral nerve injury.
| S-EPMC7264101 | biostudies-literature