Stimulate Nerve Regeneration Research Articles

The use low laser therapy on oral nerve injuries in dental specialities: Literature review

Objective: The objective of this study was to carry out a literature review that addresses the use of low-level laser applied to oral lesions. Methodology: The searches were carried out on the websites: Web of Science, LILACS, MEDLINE, PUBMED, BBO databases and Google scholar using the DeCS. To produce this literature review, we used the perspective of Mattos (2015), who has a study on the different types of reviews, which served as the basis for structuring this article and which provided guidance for the methodology used. Results: Low-level laser has great potential to stimulate nerve regeneration and alleviate symptoms in patients with oral neural injury, however it is a therapy that needs urgent research in order to provide solid scientific bases to establish clearer guidelines on its use in dentistry.

Repeated epidural delivery of Shinbaro2: effects on neural recovery, inflammation, and pain modulation in a rat model of lumbar spinal stenosis.

The choice of treatment for lumbar spinal stenosis (LSS) depends on symptom severity. When severe motor issues with urinary dysfunction are not present, conservative treatment is often considered to be the priority. One such conservative treatment is epidural injection, which is effective in alleviating inflammation and the pain caused by LSS-affected nerves. In this study, Shinbaro2 (Sh2), pharmacopuncture using natural herbal medicines for patients with disc diseases, is introduced as an epidural to treat LSS in a rat model. The treatment of primary sensory neurons from the rats' dorsal root ganglion (DRG) neurons with Sh2 at various concentrations (0.5, 1, and 2mg/mL) was found to be safe and non-toxic. Furthermore, it remarkably stimulated axonal outgrowth even under H2O2-treated conditions, indicating its potential for stimulating nerve regeneration. When LSS rats received epidural injections of two different concentrations of Sh2 (1 and 2mg/kg) once daily for 4 weeks, a significant reduction was seen in ED1+ macrophages surrounding the silicone block used for LSS induction. Moreover, epidural injection of Sh2 in the DRG led to a significant suppression of pain-related factors. Notably, Sh2 treatment resulted in improved locomotor recovery, as evaluated by the Basso, Beattie, and Bresnahan scale and the horizontal ladder test. Additionally, hind paw hypersensitivity, assessed using the Von Frey test, was reduced, and normal gait was restored. Our findings demonstrate that epidural Sh2 injection not only reduced inflammation but also improved locomotor function and pain in LSS model rats. Thus, Sh2 delivery via epidural injection has potential as an effective treatment option for LSS.

Salidroside promotes the repair of spinal cord injury by inhibiting astrocyte polarization, promoting neural stem cell proliferation and neuronal differentiation

Spinal cord injury (SCI) remains a formidable challenge, lacking effective treatments. Following SCI, neural stem cells (NSCs) migrate to SCI sites, offering a potential avenue for nerve regeneration, but the effectiveness of this intrinsic repair mechanism remains suboptimal. Salidroside has demonstrated pro-repair attributes in various pathological conditions, including arthritis and cerebral ischemia, and the ability to curtail early-stage inflammation following SCI. However, the specific role of salidroside in the late-stage repair processes of SCI remains less defined. In this investigation, we observed that continuous salidroside treatment in SCI mice improved motor function recovery. Immunofluorescence-staining corroborated salidroside’s capacity to stimulate nerve regeneration and remyelination, suppress glial scar hyperplasia, reduce the activation of neurotoxic A1 astrocytes, and facilitate NSCs migration towards the injured region. Mechanistically, in vitro experiments elucidated salidroside’s significant role in restraining astrocyte proliferation and A1 polarization. It was further established that A1 astrocytes hinder NSCs proliferation while inducing their differentiation into astrocytes. Salidroside effectively ameliorated this inhibition of NSCs proliferation through diminishing c-Jun N-terminal kinase (JNK) pathway phosphorylation and restored their differentiation into neurons by suppressing the signal transducer and activator of transcription 3 (STAT3) pathway. In summary, our findings suggest that salidroside holds promise as a therapeutic agent for traumatic SCI treatment.

Role of Regenerative Therapeutics in Diabetic Peripheral Neuropathy: Current Advances and Future Prospects

Diabetes is a chronic metabolic condition that has far-reaching consequences for human health. If there is no appropriate therapeutic treatment, diabetic peripheral neuropathy might lead to foot ulceration and limb amputation. Conventional pharmacological therapy have weak anti-DPN activity. By stimulating nerve regeneration, addressing underlying causes of the disorder, and alleviating symptoms, stem cell therapy for diabetic peripheral neuropathy has the potential to alter the management of this debilitating illness. One of its most significant advantages is its ability to regenerate damaged nerves, as stem cells may differentiate into a variety of cell types, including neurons and supporting cells. Preclinical and early-phase clinical research has resulted in improvements in nerve conduction, pain alleviation, and sensory function in patients with diabetic peripheral neuropathy. Stem cell therapy can be tailored to each patient's specific ailment, ensuring personalized care that improves therapeutic outcomes. Future research may uncover further benefits and applications for stem cell treatment, such as refining stem cell source selection, experimenting with novel delivery systems, and capitalizing on tissue engineering advances. Combining stem cell therapy with gene editing or bioengineering procedures may improve regenerative potential in the treatment of diabetic peripheral neuropathy. To completely reap the benefits of stem cell therapy in diabetic peripheral neuropathy, obstacles must be overcome and treatment procedures must be improved. Stem cell therapy has the potential to revolutionize the treatment of diabetic peripheral neuropathy by encouraging nerve regeneration, and symptom relief. The present review discusses the noteworthy developments in various regenerative therapies for diabetic peripheral neuropathy.

Exosomes-loaded electroconductive nerve dressing for nerve regeneration and pain relief against diabetic peripheral nerve injury.

Over the years, electroconductive hydrogels (ECHs) have been extensively applied for stimulating nerve regeneration and restoring locomotor function after peripheral nerve injury (PNI) with diabetes, given their favorable mechanical and electrical properties identical to endogenous nerve tissue. Nevertheless, PNI causes the loss of locomotor function and inflammatory pain, especially in diabetic patients. It has been established that bone marrow stem cells-derived exosomes (BMSCs-Exos) have analgesic, anti-inflammatory and tissue regeneration properties. Herein, we designed an ECH loaded with BMSCs-Exos (ECH-Exos) electroconductive nerve dressing to treat diabetic PNI to achieve functional recovery and pain relief. Given its potent adhesive and self-healing properties, this laminar dressing is convenient for the treatment of damaged nerve fibers by automatically wrapping around them to form a size-matched tube-like structure, avoiding the cumbersome implantation process. Our in vitro studies showed that ECH-Exos could facilitate the attachment and migration of Schwann cells. Meanwhile, Exos in this system could modulate M2 macrophage polarization via the NF-κB pathway, thereby attenuating inflammatory pain in diabetic PNI. Additionally, ECH-Exos enhanced myelinated axonal regeneration via the MEK/ERK pathway in vitro and in vivo, consequently ameliorating muscle denervation atrophy and further promoting functional restoration. Our findings suggest that the ECH-Exos system has huge prospects for nerve regeneration, functional restoration and pain relief in patients with diabetic PNI.

Biased Random Walk Model of Neuronal Dynamics on Substrates with Periodic Geometrical Patterns

Neuronal networks are complex systems of interconnected neurons responsible for transmitting and processing information throughout the nervous system. The building blocks of neuronal networks consist of individual neurons, specialized cells that receive, process, and transmit electrical and chemical signals throughout the body. The formation of neuronal networks in the developing nervous system is a process of fundamental importance for understanding brain activity, including perception, memory, and cognition. To form networks, neuronal cells extend long processes called axons, which navigate toward other target neurons guided by both intrinsic and extrinsic factors, including genetic programming, chemical signaling, intercellular interactions, and mechanical and geometrical cues. Despite important recent advances, the basic mechanisms underlying collective neuron behavior and the formation of functional neuronal networks are not entirely understood. In this paper, we present a combined experimental and theoretical analysis of neuronal growth on surfaces with micropatterned periodic geometrical features. We demonstrate that the extension of axons on these surfaces is described by a biased random walk model, in which the surface geometry imparts a constant drift term to the axon, and the stochastic cues produce a random walk around the average growth direction. We show that the model predicts key parameters that describe axonal dynamics: diffusion (cell motility) coefficient, average growth velocity, and axonal mean squared length, and we compare these parameters with the results of experimental measurements. Our findings indicate that neuronal growth is governed by a contact-guidance mechanism, in which the axons respond to external geometrical cues by aligning their motion along the surface micropatterns. These results have a significant impact on developing novel neural network models, as well as biomimetic substrates, to stimulate nerve regeneration and repair after injury.

Differentiation of Human Induced Pluripotent Stem Cells into Mature and Myelinating Schwann Cells.

In the peripheral nervous system, Schwann cells (SCs) play a crucial role in axonal growth, metabolic support of neurons, and the production of myelin sheaths. Expansion of SCs after extraction from human or animal nerves is a long and often low-yielding process. We established a rapid cell culture method using a defined serum-free medium to differentiate human induced pluripotent stem cells (iPSCs) into SCs in only 21 days. The SC identity was characterized by expression of SRY-Box Transcription factor 10 (SOX10), S100b, glial fibrillary acidic protein (GFAP), P75, growth-associated protein 43 (GAP43), and early growth response 2 (EGR2) markers. The SC purity reached 87% as assessed by flow cytometry using the specific SOX10 marker, and 69% based on S100b expression. When SCs were cocultured with iPSC-derived motor neurons two-dimensionally or three-dimensionally (3D), they also expressed the markers of myelin MBP, MPZ, and gliomedin. Likewise, when they were seeded on the opposite side of a porous collagen sponge from motor neurons in the 3D model, they were able to migrate through it and colocalize with motor axons after 8 weeks of maturation. Moreover, they were shown by transmission electron microscopy to form myelin sheaths around motor axons. These results suggest that the use of autologous iPSC-derived SCs for clinical applications such as the repair of peripheral nerve damage, the treatment of spinal cord injuries, or for demyelinating diseases could be a valuable option. Impact Statement Peripheral nerve injuries can cause the complete paralysis of the upper or lower limbs, which considerably reduces the quality of life of patients. To repair this injury, many approaches have been developed by tissue engineering. Combining biomaterials with Schwann cells (SCs) has been shown to be an effective solution for stimulating nerve regeneration. However, the challenge faced concerns the strategy for obtaining autologous SCs to treat patients. A promising approach is to differentiate them from the patient's own cells, previously induced into pluripotent stem cells. We propose a fast culture method to generate functional SCs differentiated from induced pluripotent stem cells.

Ti3C2Tx MXene-Coated Electrospun PCL Conduits for Enhancing Neurite Regeneration and Angiogenesis.

An electrical signal is the key basis of normal physiological function of the nerve, and the stimulation of the electric signal also plays a very special role in the repair process of nerve injury. Electric stimulation is shown to be effective in promoting axonal regeneration and myelination, thereby promoting nerve injury repair. At present, it is considered that electric conduction recovery is a key aspect of regeneration and repair of long nerve defects. Conductive neural scaffolds have attracted more and more attention due to their similar electrical properties and good biocompatibility with normal nerves. Herein, PCL and MXene-PCL nerve guidance conduits (NGCs) were prepared; their effect on nerve regeneration was evaluated in vitro and in vivo. The results show that the NGCs have good biocompatibility in vitro. Furthermore, a sciatic nerve defect model (15 mm) of SD rats was made, and then the fabricated NGCs were implanted. MXene-PCL NGCs show similar results with the autograft in the sciatic function index, electrophysiological examination, angiogenesis, and morphological nerve regeneration. It is possible that the conductive MXene-PCL NGC could transmit physiological neural electric signals, induce angiogenesis, and stimulate nerve regeneration. This paper presents a novel design of MXene-PCL NGC that could transmit self-originated electric stimulation. In the future, it can be combined with other features to promote nerve regeneration.

Photodynamic Activity of Protoporphyrin IX-Immobilized Cellulose Monolith for Nerve Tissue Regeneration.

The development of nerve conduits with a three-dimensional porous structure has attracted great attention as they closely mimic the major features of the natural extracellular matrix of the nerve tissue. As low levels of reactive oxygen species (ROS) function as signaling molecules to promote cell proliferation and growth, this study aimed to fabricate protoporphyrin IX (PpIX)-immobilized cellulose (CEPP) monoliths as a means to both guide and stimulate nerve regeneration. CEPP monoliths can be fabricated via a simple thermally induced phase separation method and surface modification. The improved nerve tissue regeneration of CEPP monoliths was achieved by the activation of mitogen-activated protein kinases, such as extracellular signal-regulated kinases (ERKs). The resulting CEPP monoliths exhibited interconnected microporous structures and uniform morphology. The results of in vitro bioactivity assays demonstrated that the CEPP monoliths with under 0.54 ± 0.07 μmol/g PpIX exhibited enhanced photodynamic activity on Schwann cells via the generation of low levels of ROS. This photodynamic activation of the CEPP monoliths is a cell-safe process to stimulate cell proliferation without cytotoxic side effects. In addition, the protein expression of phospho-ERK increased considerably after the laser irradiation on the CEPP monoliths with low content of PpIX. Therefore, the CEPP monoliths have a potential application in nerve tissue regeneration as new nerve conduits.

Influence of electrical stimulation on peripheral nerve regeneration: Protocol for a systematic review

This is a protocol for a systematic review (intervention). Electrical stimulation (ES) is a therapeutic strategy used to improve peripheral nerve regeneration that involves the application of electrical fields of constant or varying frequency. We are going to lead a literature search to identify all published and unpublished randomized controlled trials that describe the use of ES in patients with peripheral nerve injury. We will compare: Electrical stimulation (application of electrical fields of constant or varying frequency) versus sham in patients with peripheral nerve injury; Electrical stimulation versus standard treatment (physiotherapy) in patients with peripheral nerve injury; Electrical stimulation versus no treatment in patients with peripheral nerve injury. Considering the scenario of very numerous strategies and different techniques of ES to stimulate nerve regeneration, decisions to recommend them should consider these uncertainties and should be summarized intended its application in clinical practice. The objective of this review is to assess the influence of electrical stimulation (ES) on nerve regeneration in individuals with peripheral nerve injury.

Exosome Released From Schwann Cells May Be Involved in Microenergy Acoustic Pulse–Associated Cavernous Nerve Regeneration

BackgroundNeurogenic erectile dysfunction (ED) is often refractory to treatment because of insufficient functional nerve recovery after injury or insult. Noninvasive mechano-biological intervention, such as microenergy acoustic pulse (MAP), low-intensity pulsed ultrasound, and low-intensity extracorporeal shockwave treatment, is an optimal approach to stimulate nerve regeneration. AimTo establish a new model in vitro to simulate nerve injury in neurogenic ED and to explore the mechanisms of MAP in vitro. MethodsSprague-Dawley rats were used to isolate Schwann cells (SCs), major pelvic ganglion (MPG), and cavernous nerve with MPG (CN/MPG). SCs were then treated with MAP (0.033 mJ/mm2, 1 Hz, 100 pulses), and SC exosomes were isolated. The MPG and CN/MPG were treated with MAP (0.033 mJ/mm2, 1 Hz) at different dosages (25, 50, 100, 200, or 300 pulses) or exosomes derived from MAP-treated SCs in vitro. OutcomesNeurite growth from the MPG fragments and CN was photographed and measured. Expression of neurotropic factors (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) was checked. ResultsNeurite outgrowth from MPG and CN/MPG was enhanced by MAP in a dosage response manner, peaking at 100 pulses. MAP promoted SC proliferation, neurotropic factor (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) expression, and exosome secretion. SC-derived exosomes significantly enhanced neurite outgrowth from MPG in vitro. Clinical ImplicationsMAP may have utility in the treatment of neurogenic ED by SC-derived exosomes. Strength & LimitationsWe confirmed that MAP enhances penile nerve regeneration through exsomes. Limitations of this study include that our study did not explore the exact mechanisms of how MAP increases SC exosome secretion nor whether MAP modulates the content of exosomes. ConclusionThis study revealed that neurite outgrowth from MPG was enhanced by MAP and by SC-derived exosomes which were isolated after MAP treatment. Our findings indicate that one mechanism by which MAP induces nerve regeneration is by stimulation of SCs to secrete exosomes.Peng D, Reed-Maldonado AB, Zhou F, et al. Exosome Released From Schwann Cells May Be Involved in Microenergy Acoustic Pulse–Associated Cavernous Nerve Regeneration. J Sex Med 2020;17:1618–1628.

Interference with SRF expression in skeletal muscles reduces peripheral nerve regeneration in mice

Traumatic injury of peripheral nerves typically also damages nerve surrounding tissue including muscles. Hence, molecular and cellular interactions of neighboring damaged tissues might be decisive for successful axonal regeneration of injured nerves. So far, the contribution of muscles and muscle-derived molecules to peripheral nerve regeneration has only poorly been studied. Herein, we conditionally ablated SRF (serum response factor), an important myofiber transcription factor, in skeletal muscles of mice. Subsequently, the impact of this myofiber-restricted SRF deletion on peripheral nerve regeneration, i.e. facial nerve injury was analyzed. Quantification of facial nerve regeneration by retrograde tracer transport, inspection of neuromuscular junctions (NMJs) and recovery of whisker movement revealed reduced axonal regeneration upon muscle specific Srf deletion. In contrast, responses in brainstem facial motor neuron cell bodies such as regeneration-associated gene (RAG) induction of Atf3, synaptic stripping and neuroinflammation were not overly affected by SRF deficiency. Mechanistically, SRF in myofibers appears to stimulate nerve regeneration through regulation of muscular satellite cell (SC) proliferation. In summary, our data suggest a role of muscle cells and SRF expression within muscles for regeneration of injured peripheral nerves.

Insights into the Effects of the Dental Stem Cell Secretome on Nerve Regeneration: Towards Cell-Free Treatment.

Cell-free treatment is emerging as an alternative to cell delivery to promote endogenous regeneration using cell-derived factors. The purpose of this article was to systematically review studies of the effects of the dental stem cell secretome on nerve regeneration. PubMed and Scopus databases were used where searched and related studies were selected. The primary search identified 36 articles with the utilized keywords; however, only 13 articles met the defined inclusion criteria. Eight out of thirteen articles included in vivo and in vitro studies. We classified the dental stem cell-derived secretome with its nerve regeneration potential. All studies demonstrated that dental stem cell-derived factors promote neurotrophic effects that can mechanistically stimulate nerve regeneration in neurodegenerative diseases and nerve injury. This data collection will enable researchers to gather information to create a precise formulation for future prescribed treatments.

Augmentation of regeneration in peripheral nervous system surgery

The peripheral nervous system exhibits a much larger capacity for regeneration than the central. Numerous non-surgical approaches that complement surgical treatment and support nerve regeneration have been developed to improve the outcome of nerve repair. For some of these methods, a positive effect on the regeneration of peripheral nervous system elements has been demonstrated, while others are still under the pinnacle of science in order to clarify their impact. Laser phototherapy is a supportive factor for accelerating and enhancing axonal regeneration. Results of the experimental study on denervated muscles suggest that laser treatment can restore its function to a substantial degree when initiated at the earliest possible postinjury stage. Low intensity ultrasound stimulates nerve regeneration through a thicker myelin coating, and improves functional recovery with better conductivity. Low-intensity electrical stimulation improves nerve regeneration, substantially accelerating axon outgrowth from the proximal to the distal nerve stumps, so that muscle reinnervation occurs significantly earlier. These methods may be complemented with specific physical treatment for further improvement. Cholecalciferol induces significant locomotor and electrophysiological recovery by increasing: number of preserved or newly formed axons at the proximal end; mean diameter of the axon at the distal end; myelination at distal and proximal ends. Magnesium improves regeneration of the nerves probably through Schwan's cells peservation from apoptosis by suppressing the inflammatory response. Multidisciplinary approach is of the utmost importance. The best results in nerve surgery may only be achieved when an adequate physical treatment, stimulation and supplementation is engaged in the recovery of a compliant patint.

Seeding decellularized nerve allografts with adipose-derived mesenchymal stromal cells: An in vitro analysis of the gene expression and growth factors produced

Mesenchymal stromal cells (MSCs) secrete many soluble growth factors and have previously been shown to stimulate nerve regeneration. MSC-seeded processed nerve allografts could potentially be a promising method for large segmental motor nerve injuries. Further progress in our understanding of how the functions of MSCs can be leveraged for peripheral nerve repair is required before making clinical translation. The present study, therefore, investigated whether interactions of adipose-derived MSCs with decellularized nerve allografts can improve gene and protein expression of growth factors that may support nerve regeneration. Human nerve allografts (n = 30) were decellularized and seeded with undifferentiated human adipose-derived MSCs. Subsequently, the MSCs and MSC-seeded grafts were isolated on days 3, 7, 14, and 21 in culture for RNA expression analysis by qRT-PCR. Evaluated genes included NGF, BDNF, PTN, GAP43, MBP, PMP22, VEGF, and CD31. Growth factor production was evaluated and quantified using enzyme-linked immunosorbent assay (ELISA). On day 21, semi-quantitative RT-PCR analysis showed that adherence of MSCs to nerve allografts significantly enhances mRNA expression of neurotrophic, angiogenic, endothelial, and myelination markers (e.g., BDNF, VEGF, CD31, and MBP). ELISA results revealed an upregulation of BDNF and reduction of both VEGF and NGF protein levels. This study demonstrates that seeding of undifferentiated adipose-derived MSCs onto processed nerve allografts permits the secretion of neurotrophic and angiogenic factors that can stimulate nerve regeneration. These favorable molecular changes suggest that MSC supplementation of nerve allografts may have potential in improving nerve regeneration.

Improved cellular response on functionalized polypyrrole interfaces.

Neuroregeneration strategies involve multiple factors to stimulate nerve regeneration. Neural support with chemical and physical cues to optimize neural growth and replacing the lesion neuron and axons are crucial for designing neural scaffolds, which is a promising treatment approach. In this study, polypyrrole polymerization and its functionalization at the interface developed by glycine and gelatin for further optimization of cellular response. Nanofibrous scaffolds were fabricated by electrospinning of polyvinyl alcohol and chitosan solutions. The electrospun scaffolds were polymerized on the surface by pyrrole monomers to form an electroactive interface for further applications in neural tissue engineering. The polymerized polypyrrole showed a positive zeta potential value of 57.5 ± 5.46 mV. The in vitro and in vivo biocompatibility of the glycine and gelatin-functionalized polypyrrole-coated scaffolds were evaluated. No inflammatory cells were observed for the implanted scaffolds. Further, DAPI nucleus staining showed a superior cell attachment on the gelatin-functionalized polypyrrole-coated scaffolds. The topography and tuned positively charged polypyrrole interface with gelatin functionalization is expected to be particularly efficient physical and chemical simultaneous factors for promoting neural cell adhesion.

Effect of long-term electroacupuncture stimulation on recovery of sensorimotor function after peripheral nerve anastomosis.

BackgroundRecently, application of electroacupuncture (EA) to stimulate nerve regeneration has become a mainstream treatment in clinical rehabilitation and related basic research, but the efficacy of long-term stimulation has not been confirmed.ObjectiveTo evaluate the influence of long term EA on peripheral nerve injury (PNI) from multiple angles.MethodTwenty-four rats were divided into three groups: control, PNI and PNI+EA. In the latter two groups, PNI was modelled by transection followed by re-anastomosis of thesciatic nerve. In the PNI+EA group only, EA was delivered using a discontinuous wave with frequency 5 Hz, pulse width 2 ms, and intensity approximately 2 mA, until the affected limb was observed to twitch slightly. The treatment was given for 15 min each time, six times a week (continuously for 6 days followed by a 1-day break) for a total of 8 weeks. The effects of EA on anastomotic sciatic nerve regeneration were evaluated using the sciatic function index (SFI), mechanical withdrawal thresholds, thermo-nociceptive thresholds, conduction velocity of the sciatic nerve and bilateral gastrocnemius wet weight.ResultsFrom weeks 2 to 4 after modelling, the SFI recovery rate in the PNI+EA group was faster than that in the PNI group. In week 4, the SFI of the PNI+EA group was significantly higher than that of the PNI group (p<0.05). However, a significant effect of EA was no longer evident from weeks 5 to 8. There was no effect of acupuncture on anti-amyotrophy and conduction velocity of the sciatic nerve at 8 weeks after modelling. EA did not shorten the paw withdrawal threshold time, but appeared to alleviate thermo-nociceptive sensitivity.ConclusionLong term repeated stimulation of the same site with EA does not appear to be conducive to the functional recovery of an injured sciatic nerve in rats.

Allogeneic bone marrow mesenchymal stem cells in the epineurium and perineurium of the recipient rat

Achievements in regenerative medicine have demonstrated that using different kinds of stem cells can have some stimulating effect on the reparative regeneration processes of the nervous system. To stimulate nerve regeneration, the experimental elaboration of mesenchymal stem cell (MSC) transplantation is carried out actively. There is evidence that MSCs promote growth of the recipient regenerating axons after transplantation into the damaged nerve or the conduit. However, processes that happen in transplanted cells and these cells’ differentiation are poorly studied. The aim of the present study is to describe the localization and morphologically peculiar properties of bone marrow-derived mesenchymal stem cells after their allotransplantation into the injured nerve of a rat. MSCs from Wistar—Kyoto rats were cultivated for seven days and labeled with BrdU three days before using. The sciatic nerves of adult Wistar—Kyoto rats were damaged, and suspensions of BrdU-labeled cultured MSCs were immediately transplanted into the damaged sciatic nerves. Five to seven days after transplantation, the surviving MSCs were found. Using fluorescent microscopy, we found that some of the transplanted cells were localized in the epineurium and in the perineurium. Some of the transplanted MSCs differentiated into adipocytes and cells of the perineurium.

PEDF plus DHA modulate inflammation and stimulate nerve regeneration after HSV-1 infection

Herpes simplex virus type-1 (HSV-1) infection leads to impaired corneal sensation and, in severe cases, to corneal ulceration, melting and perforation. Here, we explore the potential therapeutic action of pigment epithelial-derived factor (PEDF) plus docosahexaenoic acid (DHA) on corneal inflammation and nerve regeneration following HSV-1 infection. Rabbits inoculated with 100,000 PFU/eye of HSV-1 strain 17Syn+ were treated with PEDF + DHA or vehicle. PEDF + DHA treatment resulted in a biphasic immune response with stronger infiltration of CD4+T cells, neutrophils and macrophages at 7-days post-treatment (p.t.) that was significantly decreased by 14 days, compared to the vehicle-treated group. Screening of 14 immune-related genes by q-PCR showed that treatment induced higher expression of IFN-γ and CCL20 and inhibition of IL-18 by 7 days in the cornea. PEDF + DHA-treated animals developed less dendritic corneal lesions, opacity and neovascularization. Corneal nerve density increased at 12-weeks p.t. with functional recovery of corneal sensation. Treatment with PEDF + DHA that was postponed by 3 weeks also showed increased nerve density when compared to vehicle. Our data demonstrate that PEDF + DHA promotes resolution of the inflammatory response to the virus and, most importantly, induces regeneration of damaged corneal nerves vital for maintaining ocular surface homeostasis.

Recombinant hNeuritin Promotes Structural and Functional Recovery of Sciatic Nerve Injury in Rats.

Neuritin is a new neurotropic factor implicated in nervous system development and plasticity. Studies have shown that Neuritin is upregulated in injured nerves, suggesting that it is involved in nerve repair. To test this hypothesis, we investigated whether recombinant human Neuritin could restore nerve structure and function in a rat model of sciatic nerve injury. Neuritin treatment had a dose-dependent effect on functional recovery 4 weeks after injury, as determined by the walking-track test. Similar trends were observed for gastrocnemius muscular strength and nerve conduction velocity. Additionally, sciatic nerve fiber density and organization as well as degree of remyelination were increased, while growth-associated protein 43 and neurofilament 200 expression was upregulated upon treatment with Neuritin. These findings demonstrate that Neuritin stimulates nerve regeneration and functional recovery and thus promotes the repair of injured sciatic nerves.