• Brain-derived neurotrophic factor (BDNF)
• Insulin growth factor −1 (IGF1)
• Neurite outgrowth
• Obesity
• Spatial memory

• Animals
• Insulin Resistance/physiology
• Insulin-Like Growth Factor I/pharmacology
• Proto-Oncogene Proteins c-akt/metabolism
• Obesity/drug therapy
• Obesity/psychology
• Obesity/physiopathology
• Obesity/metabolism
• Signal Transduction/drug effects
• Glycogen Synthase Kinase 3 beta/metabolism
• Mice
• Male
• Brain-Derived Neurotrophic Factor/metabolism
• Diet, High-Fat
• Neurons/drug effects
• Neurons/metabolism
• Mice, Obese
• Mice, Inbred C57BL
• Neuronal Plasticity/drug effects
• Spatial Memory/drug effects
• Disease Models, Animal
• Memory/drug effects
• Neuroprotective Agents/pharmacology

• neural stem cells
• regeneration
• spinal cord injury
• translational
• transplantation

• Humans
• Neural Stem Cells
• Spinal Cord Injuries/therapy
• Neurosurgical Procedures
• Neurons

• Canadian Institute of Health Research
• Wings for Life, University of Manitoba Graduate Fellowship
• Will-to-Win/Manitoba Paraplegic Foundation
• Medical Student Research Program
• University of Manitoba

• BDNF
• TrkB
• glial cells
• myelination
• p75
• remyelination

• Mason2210 Judith Jane Mason and Harold Stannett Williams Memorial Foundation

Injuries to the spinal cord result in permanent disabilities that limit daily life activities. The main reasons for these poor outcomes are the limited regenerative capacity of central neurons and the inhibitory milieu that is established upon traumatic injuries. Despite decades of research, there is still no efficient treatment for spinal cord injury. Many strategies are tested in preclinical studies that focus on ameliorating the functional outcomes after spinal cord injury. Among these, molecular compounds are currently being used for neurological recovery, with promising results. These molecules target the axon collapsed growth cone, the inhibitory microenvironment, the survival of neurons and glial cells, and the re-establishment of lost connections. In this review we focused on molecules that are being used, either in preclinical or clinical studies, to treat spinal cord injuries, such as drugs, growth and neurotrophic factors, enzymes, and purines. The mechanisms of action of these molecules are discussed, considering traumatic spinal cord injury in rodents and humans.

• Bone morphogenetic proteins
• Cell differentiation
• Neural stem cells
• Neurogenesis
• Neurotrophins, Notch
• Sonic hedgehog
• Wnt wingless-related

• Animals
• Brain Injuries, Traumatic/metabolism
• Brain-Derived Neurotrophic Factor/therapeutic use
• Humans
• Nerve Growth Factor/therapeutic use
• Recovery of Function

• R25 GM072643 NIGMS NIH HHS
• K00 NS105220 NINDS NIH HHS
• R01 NS099595 NINDS NIH HHS
• T32 HL007260 NHLBI NIH HHS
• P20 GM109040 NIGMS NIH HHS

• Alzheimer’s disease
• BDNF
• BECN1
• GABP
• HSV-1
• Latency
• Microcompetition
• Mitochondria
• NMDA
• Neurogenesis

• Alzheimer Disease/genetics
• DNA Copy Number Variations/genetics
• Herpes Simplex/genetics
• Herpesvirus 1, Human/genetics
• Humans
• Neurons

• LOTUS
• Nogo receptor
• axonal regrowth
• ex vivo gene therapy
• iPSC
• motor function
• regenerative medicine
• spinal cord injury
• transplantation

• Animals
• Calcium-Binding Proteins/genetics
• Calcium-Binding Proteins/metabolism
• Cells, Cultured
• Disease Models, Animal
• Female
• Gene Expression
• Humans
• Induced Pluripotent Stem Cells/metabolism
• Mice, Inbred NOD
• Mice, SCID
• Motor Activity/physiology
• Neural Stem Cells/metabolism
• Recovery of Function/physiology
• Spinal Cord/physiopathology
• Spinal Cord Injuries/physiopathology
• Spinal Cord Injuries/therapy
• Stem Cell Transplantation/methods
• Transduction, Genetic
• Transplantation, Heterologous
• Mice

Recent studies have shown that 3D printed scaffolds integrated with growth factors can guide the growth of neurites and promote axon regeneration at the injury site. However, heat, organic solvents or cross-linking agents used in conventional 3D printing reduce the biological activity of growth factors. Low temperature 3D printing can incorporate growth factors into the scaffold and maintain their biological activity. In this study, we developed a collagen/chitosan scaffold integrated with brain-derived neurotrophic factor (3D-CC-BDNF) by low temperature extrusion 3D printing as a new type of artificial controlled release system, which could prolong the release of BDNF for the treatment of spinal cord injury (SCI). Eight weeks after the implantation of scaffolds in the transected lesion of T10 of the spinal cord, 3D-CC-BDNF significantly ameliorate locomotor function of the rats. Consistent with the recovery of locomotor function, 3D-CC-BDNF treatment could fill the gap, facilitate nerve fiber regeneration, accelerate the establishment of synaptic connections and enhance remyelination at the injury site.

• brain-derived neurotrophic factor
• chitosan
• collagen
• diffusion tensor imaging
• low temperature extrusion 3D printing
• spinal cord injury

• Alzheimer’s disease (AD)
• Brain
• Delivery
• Methods
• Nerve growth factor (NGF)
• Techniques

Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD.

• Alzheimer’s disease
• amyloid-beta
• clinical symptoms
• inflammation
• stem cells
• tau
• therapy

• Alzheimer Disease/therapy
• Amyloid beta-Peptides/metabolism
• Animals
• Animals, Genetically Modified
• Disease Models, Animal
• Encephalitis/therapy
• Hippocampus/cytology
• Induced Pluripotent Stem Cells/cytology
• Mice
• Neuronal Plasticity/physiology

• Zenith award Alzheimer's Association

• Long non-coding RNA H19
• Neonatal hypoxia-ischemia
• PI3K/AKT pathway
• Wnt/β-catenin pathway
• microRNA-107

Studying how the fetal spinal cord regenerates in an ex vivo model of spina bifida repair may provide insights into the development of new tissue engineering treatment strategies to better optimize neurologic function in affected patients. Here, we developed hydrogel surgical patches designed for prenatal repair of myelomeningocele defects and demonstrated viability of both human and rat neural progenitor donor cells within this three-dimensional scaffold microenvironment. We then established an organotypic slice culture model using transverse lumbar spinal cord slices harvested from retinoic acid–exposed fetal rats to study the effect of fibrin hydrogel patches ex vivo. Based on histology, immunohistochemistry, gene expression, and enzyme-linked immunoabsorbent assays, these experiments demonstrate the biocompatibility of fibrin hydrogel patches on the fetal spinal cord and suggest this organotypic slice culture system as a useful platform for evaluating mechanisms of damage and repair in children with neural tube defects.

• Myelomeningocele
• fetal surgery
• hydrogels
• neural tube defects
• organotypic
• slice culture
• spina bifida

• Alzheimer’s disease
• Amyloid precursor protein
• Brain development
• Dementia
• Learning and memory
• Neurodegeneration
• Neurogenesis
• Neurogenic niche
• sAPPα

• Alzheimer Disease/metabolism
• Amyloid beta-Protein Precursor/metabolism
• Animals
• Brain/metabolism
• Humans
• Neurons/metabolism
• Neuroprotection/physiology
• Neuroprotective Agents/metabolism

• SBHF-7069 St. Boniface Hospital Research Foundation

• cell therapy
• neural subpopulation
• neurodegenerative disease
• neuronal stem cells

• Animals
• Humans
• Immunomodulation
• Nerve Growth Factors/metabolism
• Neural Stem Cells/metabolism
• Neural Stem Cells/transplantation
• Neurodegenerative Diseases/immunology
• Neurodegenerative Diseases/therapy
• Stem Cell Transplantation

• RF-2016-02362317 Italian Ministry of Health
• Ricerca Corrente 2019 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

• auditory
• brainstem slice (ABS)
• deciduous teeth (SHED)
• human dental pulp stem cell (DPSC)
• spiral ganglion neuron (SGN)
• stem cell from human exfoliated

Brain regenerative strategies through the transplantation of stem cells hold the potential to promote functional rescue of brain lesions caused either by trauma or neurodegenerative diseases. Most of the positive modulations fostered by stem cells are fueled by bystander effects, namely increase of neurotrophic factors levels and reduction of neuroinflammation. Nevertheless, the ultimate goal of cell therapies is to promote cell replacement. Therefore, the ability of stem cells to migrate and differentiate into neurons that later become integrated into the host neuronal network replacing the lost neurons has also been largely explored. However, as most of the preclinical studies demonstrate, there is a small functional integration of graft-derived neurons into host neuronal circuits. Thus, it is mandatory to better study the whole brain cell therapy approach in order to understand what should be better comprehended concerning graft-derived neuronal and glial cells migration and integration before we can expect these therapies to be ready as a viable solution for brain disorder treatment. Therefore, this review discusses the positive mechanisms triggered by cell transplantation into the brain, the limitations of adult brain plasticity that might interfere with the neuroregeneration process, as well as some strategies tested to overcome some of these limitations. It also considers the efforts that have been made by the regulatory authorities to lead to better standardization of preclinical and clinical studies in this field in order to reduce the heterogeneity of the obtained results.

• adult brain plasticity
• brain
• neuronal integration and survival
• regulatory framework
• stem cells transplantation

In spinal cord injured adult mammals, neutralizing the neurite growth inhibitor Nogo‐A with antibodies promotes axonal regeneration and functional recovery, although axonal regeneration is limited in length. Neurotrophic factors such as BDNF stimulate neurite outgrowth and protect axotomized neurons. Can the effects obtained by neutralizing Nogo‐A, inducing an environment favorable for axonal sprouting, be strengthened by adding BDNF? A unilateral incomplete hemicord lesion at C7 level interrupted the main corticospinal component in three groups of adult macaque monkeys: control monkeys (n = 6), anti‐Nogo‐A antibody‐treated monkeys (n = 7), and anti‐Nogo‐A antibody and BDNF‐treated monkeys (n = 5). The functional recovery of manual dexterity was significantly different between the 3 groups of monkeys, the lowest in the control group. Whereas the anti‐Nogo‐A antibody‐treated animals returned to manual dexterity performances close to prelesion ones, irrespective of lesion size, both the control and the anti‐Nogo‐A/BDNF animals presented a limited functional recovery. In the control group, the limited spontaneous functional recovery depended on lesion size, a dependence absent in the combined treatment group (anti‐Nogo‐A antibody and BDNF). The functional recovery in the latter group was significantly lower than in anti‐Nogo‐A antibody‐treated monkeys, although the lesion was larger in three out of the five monkeys in the combined treatment group.

• Nogo-A antibody therapy
• brain-derived neurotrophic factor
• hand
• manual dexterity
• motor control
• nonhuman primates
• spinal cord injury

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with abnormal protein modification, inflammation and memory impairment. Aggregated amyloid beta (Aβ) and phosphorylated tau proteins are medical diagnostic features. Loss of memory in AD has been associated with central cholinergic dysfunction in basal forebrain, from where the cholinergic circuitry projects to cerebral cortex and hippocampus. Various reports link AD progression with declining activity of cholinergic neurons in basal forebrain. The neurotrophic molecule, nerve growth factor (NGF), plays a major role in the maintenance of cholinergic neurons integrity and function, both during development and adulthood. Numerous studies have also shown that NGF contributes to the survival and regeneration of neurons during aging and in age-related diseases such as AD. Changes in neurotrophic signaling pathways are involved in the aging process and contribute to cholinergic and cognitive decline as observed in AD. Further, gradual dysregulation of neurotrophic factors like NGF and brain derived neurotrophic factor (BDNF) have been reported during AD development thus intensifying further research in targeting these factors as disease modifying therapies against AD. Today, there is no cure available for AD and the effects of the symptomatic treatment like cholinesterase inhibitors (ChEIs) and memantine are transient and moderate. Although many AD treatment studies are being carried out, there has not been any breakthrough and new therapies are thus highly needed. Long-term effective therapy for alleviating cognitive impairment is a major unmet need. Discussion and summarizing the new advancements of using NGF as a potential therapeutic implication in AD are important. In summary, the intent of this review is describing available experimental and clinical data related to AD therapy, priming to gain additional facts associated with the importance of NGF for AD treatment, and encapsulated cell biodelivery (ECB) as an efficient tool for NGF delivery.

• Alzheimer disease
• NGF
• cholinergic
• encapsulated cell biodelivery
• neurotrophins

The regeneration of peripheral nerves comprises complicated steps involving a set of cellular and molecular events in distal nerve stumps with axonal sprouting and remyelination. Stem cell isolation and expansion for peripheral nerve repair (PNR) can be achieved using a wide diversity of prenatal and adult tissues, such as bone marrow or brain tissues. The ability to obtain stem cells for cell-based therapy (CBT) is limited due to donor site morbidity and the invasive nature of the harvesting process. Dental pulp stem cells (DPSCs) can be relatively and simply isolated from the dental pulps of permanent teeth, extracted for surgical or orthodontic reasons. DPSCs are of neural crest origin with an outstanding ability to differentiate into multiple cell lineages. They have better potential to differentiate into neural and glial cells than other stem cell sources through the expression and secretion of certain markers and a range of neurotropic factors; thus, they should be considered a good choice for PNR using CBT. In addition, these cells have paracrine effects through the secretion of neurotrophic growth factors and extracellular vesicles, which can enhance axonal growth and remyelination by decreasing the number of dying cells and activating local inhabitant stem cell populations, thereby revitalizing dormant or blocked cells, modulating the immune system and regulating inflammatory responses. The use of DPSC-derived secretomes holds great promise for controllable and manageable therapy for peripheral nerve injury. In this review, up-to-date information about the neurotrophic and neurogenic properties of DPSCs and their secretomes is provided.

• Dental pulp stem cells
• Secretomes
• Cell-based therapy
• Cell-free therapy
• Peripheral nerve injury

Magnetic targeting is a cell delivery system using the magnetic labeling of cells and the magnetic field; it has been developed for minimally invasive cell transplantation. Cell transplantation with both minimal invasiveness and high efficacy on tissue repair can be achieved by this system. Magnetic targeting has been applied for the transplantation of bone marrow mesenchymal stem cells, blood CD133-positive cells, neural progenitor cells, and induced pluripotent stem cells, and for the regeneration of bone, cartilage, skeletal muscles, and the spinal cord. It enhances the accumulation and adhesion of locally injected cells, resulting in the improvement of tissue regeneration. It is a promising technique for minimally invasive and effective cell transplantation therapy.

• Cell delivery
• IKDC, International Knee Documentation Committee
• KOOS, Knee Injury and Osteoarthritis Outcome Score
• MRI, Magnetic resonance imaging
• MSC, mesenchymal stem cell
• Magnet
• Regeneration
• SPIO, superparamagnetic iron oxide
• Stem cell
• T, tesla
• iPS, induced pluripotent stem

• axon elongation
• biomaterial
• spinal cord injury
• spinal progenitor cells

• allodynia
• exercise
• neuropathic pain
• regenerative medicine
• rehabilitation
• sensory function

• Cholinergic system
• Muscarinic receptors
• NGF
• Nervous system
• Neuronal survival
• Phorbol ester

The aim of the present study was to determine the effect of implanted neural stem cells (NSCs) on the functional recovery of tree shrews (TSs) subjected to hemi-sectioned spinal cord injury (hSCI), and to investigate the possible mechanism involved. NSCs (passage 2), derived from the hippocampus of TSs (embryonic day 20), were labeled with Hoechst 33342 and transplanted intraspinally into the hSC of TSs at thoracic level 10 in the acute (immediately after injury) and chronic (day 9 post-injury) stages. The Basso-Beattie-Bresnahan (BBB) score was recorded from days 1 to 16 post-injury, and the survival, migration, differentiation and neurotrophic factor (NTF) expression in vivo were detected. In vitro and in vivo, the expanded NSCs were able to differentiate into neurons and astrocytes, and secreted a variety of NTFs, including ciliary NTF, transforming growth factor-β1, glial cell line-derived NTF, nerve growth factor (NGF), brain-derived NTF and insulin-like growth factor. Following transplantation, the BBB score in the TSs with chronic-stage transplantation exhibited a statistically significant increase, while there was no significant difference in the acute group, compared with the control group. This corresponded with the marked upregulation of NGF indicated by reverse transcription-quantitative polymerase chain reaction. In conclusion, the transplantation of NSCs into the hSC in the chronic phase, but not the acute stage, of hSCI in non-human primate TSs is effective and associated with upregulated NGF expression. These findings may provide novel strategies for the treatment of SCI in clinical patients.

Stroke represents a severe medical condition that causes stroke survivors to suffer from long-term and even lifelong disability. Over the past several decades, a vast majority of stroke research targets neuroprotection in the acute phase, while little work has been done to enhance stroke recovery at the later stage. Through reviewing current understanding of brain plasticity, stroke pathology, and emerging preclinical and clinical restorative approaches, this review aims to provide new insights to advance the research field for stroke recovery. Lifelong brain plasticity offers the long-lasting possibility to repair a stroke-damaged brain. Stroke impairs the structural and functional integrity of entire brain networks; the restorative approaches containing multi-components have great potential to maximize stroke recovery by rebuilding and normalizing the stroke-disrupted entire brain networks and brain functioning. The restorative window for stroke recovery is much longer than previously thought. The optimal time for brain repair appears to be at later stage of stroke rather than the earlier stage. It is expected that these new insights will advance our understanding of stroke recovery and assist in developing the next generation of restorative approaches for enhancing brain repair after stroke.

• Brain plasticity
• Brain repair
• Restorative timing
• Stroke recovery

• axonal regeneration
• bone marrow stromal cell
• conditioned culture medium
• locomotor function
• spinal cord injury

• brain
• innovative intervention measures
• neurodegenerative pathologies
• neuronal stem cells
• self-repair/regenerative process
• stem cell therapy

Cell-cell interaction as one of the niche signals plays an important role in the balance of stem cell quiescence and proliferation or differentiation. In order to address the effect and the possible mechanisms of cell-cell connection on neural stem/progenitor cells (NSCs/NPCs) proliferation and differentiation, upon passaging, NSCs/NPCs were either dissociated into single cell as usual (named Group I) or mechanically triturated into a mixture of single cell and small cell clusters containing direct cell-cell connections (named Group II). Then the biological behaviors including proliferation and differentiation of NSCs/NPCs were observed. Moreover, the expression of gap junction channel, neurotrophic factors and the phosphorylation status of MAPK signals were compared to investigate the possible mechanisms. Our results showed that, in comparison to the counterparts in Group I, NSCs/NPCs in Group II survived well with preferable neuronal differentiation. In coincidence with this, the expression of connexin 45 (Cx45), as well as brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in Group II were significantly higher than those in Group I. Phosphorylation of ERK1/2 and JNK2 were significantly upregulated in Group II too, while no change was found about p38. Furthermore, the differences of NSCs/NPCs biological behaviors between Group I and II completely disappeared when ERK and JNK phosphorylation were inhibited. These results indicated that cell-cell connection in Group II enhanced NSCs/NPCs survival, proliferation and neuronal differentiation through upregulating the expression of gap junction and neurotrophic factors. MAPK signals- ERK and JNK might contribute to the enhancement. Efforts for maintaining the direct cell-cell connection are worth making to provide more favorable niches for NSCs/NPCs survival, proliferation and neuronal differentiation.

• MAPK
• NSCs/NPCs
• cell-cell connection
• neuronal differentiation
• proliferation

• Alzheimer's disease
• BDNF
• GDNF
• Neural stem cells
• Parkinson's disease
• Transplantation

• Animals
• Brain-Derived Neurotrophic Factor/physiology
• Cell Survival/physiology
• Glial Cell Line-Derived Neurotrophic Factor/physiology
• Humans
• Nerve Growth Factors/physiology
• Neural Stem Cells/physiology
• Neural Stem Cells/transplantation
• Neurodegenerative Diseases/metabolism
• Neurodegenerative Diseases/therapy
• Stem Cell Transplantation/methods
• Stem Cell Transplantation/trends

• P50 AG016573 NIA NIH HHS
• RF1 AG048099 NIA NIH HHS
• T32 AG000096 NIA NIH HHS
• T32 NS082174 NINDS NIH HHS

• biomimetics
• neural stem cells
• spinal cord regeneration
• stem cell transplantation

Endothelial progenitor cells (EPCs) derived from bone marrow and blood can differentiate into endothelial cells and promote neovascularization. In addition, EPCs are a promising cell source for the repair of various types of vascularized tissues and have been used in animal experiments and clinical trials for tissue repair. In this review, we focused on the kinetics of endogenous EPCs during tissue repair and the application of EPCs or stem cell populations containing EPCs for tissue regeneration in musculoskeletal and neural tissues including the bone, skeletal muscle, ligaments, spinal cord, and peripheral nerves. EPCs can be mobilized from bone marrow and recruited to injured tissue to contribute to neovascularization and tissue repair. In addition, EPCs or stem cell populations containing EPCs promote neovascularization and tissue repair through their differentiation to endothelial cells or tissue-specific cells, the upregulation of growth factors, and the induction and activation of endogenous stem cells. Human peripheral blood CD34(+) cells containing EPCs have been used in clinical trials of bone repair. Thus, EPCs are a promising cell source for the treatment of musculoskeletal and neural tissue injury.

• Axonal injury
• Cj-LPS
• NT-3/TrkC
• NogoA/NgR

To investigate the permeability of β-NGF through blood–brain-barrier (BBB) in neonatal and adult rats, and the spatial distribution of β-NGF in different brain regions in hypoxic-ischemic (HI) and normal neonatal rats.

To investigate the overall permeability of β-NGF through BBB, β-NGF labeled with I¹²⁵ was injected into adult rats, neonatal rats and HI neonatal rats via tail vein. The radioactivity of brain tissue and blood was examined and analyzed 30 min after injection. Also, brain regions including the basal forebrain, frontal cortex, hippocampus, hypothalamus, cerebellum, bulbus olfactorius and hypophysis, of all the rats were dissected and radioactivity was examined to investigate the spatial specificity of NGF permeation through BBB.

Statistically significant results were observed in I¹²⁵-β-NGF contents in brain tissues of adult rats group, neonatal rats group and HI neonatal rats group (P < 0.05). Compared to the HI neonatal rats’ brain with the highest I¹²⁵-β-NGF contents, normal neonatal rats ranks the second while the adult rats were the lowest. While for the spatial specificity examination part, I¹²⁵-β-NGF in both HI group and control group were widely distributed in basal forebrain, frontal cortex, hippocampus, cerebellum and bulbus olfactorius. But the radioactivity in frontal cortex, hippocampus and cerebellum of HI groups are statistically higher than control groups (P < 0.05).

β-NGF can more easily penetrate the BBB of newborn rats than adult rats via peripheral venous administration and this effect can be enhanced by HI insult. Also, this HI-induced permeation of β-NGF through BBB is more obvious in frontal cortex, hippocampus and cerebellum.

• Blood–brain barrier
• Hypoxic
• Ischemic
• Nerve growth factor

• differentiation
• immunocytochemical and immunohistochemical analysis
• neocortex
• neural stem cells
• regenerative medicine

Injectable hydrogel allows for sustained delivery of growth factor resulting in spinal mediated learning after injury.

• cell therapy
• nervous system lesions
• neural progenitor cells
• neurodegenerative disease
• stem cells
• transplantation

• BDNF
• BIO
• GSK-3β
• Human neuron
• Wnt/β-catenin signaling

• Brain-Derived Neurotrophic Factor/metabolism
• Cell Survival/drug effects
• Cells, Cultured
• Fetus/cytology
• Fetus/metabolism
• Glycogen Synthase Kinase 3/antagonists & inhibitors
• Glycogen Synthase Kinase 3/metabolism
• Glycogen Synthase Kinase 3 beta
• Humans
• Indoles/pharmacology
• Neurons/cytology
• Neurons/metabolism
• Oximes/pharmacology
• RNA, Messenger/metabolism
• Spinal Cord/cytology
• Spinal Cord/metabolism
• Wnt Signaling Pathway

A variety of neurotrophic factors have been shown to repair the damaged peripheral nerve. However, in clinical practice, nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor are all peptides or proteins that may be rapidly deactivated at the focal injury site; their local effective concentration time following a single medication cannot meet the required time for spinal axons to regenerate and cross the glial scar. In this study, we produced polymer sustained-release microspheres based on the polylactic-co-glycolic acid copolymer; the microspheres at 300-μm diameter contained nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor. Six microspheres were longitudinally implanted into the sciatic nerve at the anastomosis site, serving as the experimental group; while the sciatic nerve in the control group was subjected to the end-to-end anastomosis using 10/0 suture thread. At 6 weeks after implantation, the lower limb activity, weight of triceps surae muscle, sciatic nerve conduction velocity and the maximum amplitude were obviously better in the experimental group than in the control group. Compared with the control group, more regenerating nerve fibers were observed and distributed in a dense and ordered manner with thicker myelin sheaths in the experimental group. More angiogenesis was also visible. Experimental findings indicate that polylactic-co-glycolic acid composite microspheres containing nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor can promote the restoration of sciatic nerve in rats after injury.

• biological compatibility
• brain-derived neurotrophic factor
• microspheres
• nerve growth factor
• nerve injury
• nerve regeneration
• nerve repair
• neurotrophin-3
• polylactic-co-glycolic acid copolymer

Despite advances in our understanding of spinal cord injury (SCI) mechanisms, there are still no effective treatment approaches to restore functionality. Although many studies have demonstrated that transplanting NT3 gene-transfected bone marrow-derived mesenchymal stem cells (BMSCs) is an effective approach to treat SCI, the approach is often low efficient in the delivery of engrafted BMSCs to the site of injury. In this study, we investigated the therapeutic effects of magnetic targeting of NT3 gene-transfected BMSCs via lumbar puncture in a rat model of SCI. With the aid of a magnetic targeting cells delivery system, we can not only deliver the engrafted BMSCs to the site of injury more efficiently, but also perform cells imaging in vivo using MR. In addition, we also found that this composite strategy could significantly improve functional recovery and nerve regeneration compared to transplanting NT3 gene-transfected BMSCs without magnetic targeting system. Our results suggest that this composite strategy could be promising for clinical applications.

• Ex vivo
• Experimental model
• Organotypic culture
• Spinal cord

Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system.