• Bone marrow mesenchymal stem cells
• Myelin sheath
• Peripheral nerve injury
• Schwann cells
• Tissue engineering

• Cell therapy
• Clinical transformation
• Peripheral nerve regeneration
• Schwann cells
• Signaling pathways

• Schwann Cells/physiology
• Humans
• Animals
• Nerve Regeneration/physiology
• Peripheral Nerve Injuries/therapy
• Cell- and Tissue-Based Therapy/methods
• Peripheral Nerves/physiology

• Animals
• Female
• Fibrosis
• Inflammation
• Nerve Regeneration
• Peripheral Nerves/surgery
• Rats
• Rats, Wistar
• Sciatic Nerve/physiology
• Sciatic Nerve/surgery

Nerve injuries are debilitating, leading to long-term motor deficits. Remyelination and axonal growth are supported and enhanced by growth factor and cytokines. Combination of nerve guidance conduits (NGCs) with adipose-tissue-derived multipotent mesenchymal stromal cells (AdMSCs) has been performing promising strategy for nerve regeneration.

3D-printed polycaprolactone (PCL)-NGCs were fabricated. Wistar rats subjected to critical sciatic nerve damage (12-mm gap) were divided into sham, autograft, PCL (empty NGC), and PCL + MSCs (NGC multi-functionalized with 10⁶ canine AdMSCs embedded in heterologous fibrin biopolymer) groups. In vitro, the cells were characterized and directly stimulated with interferon-gamma to evaluate their neuroregeneration potential. In vivo, the sciatic and tibial functional indices were evaluated for 12 weeks. Gait analysis and nerve conduction velocity were analyzed after 8 and 12 weeks. Morphometric analysis was performed after 8 and 12 weeks following lesion development. Real-time PCR was performed to evaluate the neurotrophic factors BDNF, GDNF, and HGF, and the cytokine and IL-10. Immunohistochemical analysis for the p75^NTR neurotrophic receptor, S100, and neurofilament was performed with the sciatic nerve.

The inflammatory environment in vitro have increased the expression of neurotrophins BDNF, GDNF, HGF, and IL-10 in canine AdMSCs. Nerve guidance conduits multi-functionalized with canine AdMSCs embedded in HFB improved functional motor and electrophysiological recovery compared with PCL group after 12 weeks. However, the results were not significantly different than those obtained using autografts. These findings were associated with a shift in the regeneration process towards the formation of myelinated fibers. Increased immunostaining of BDNF, GDNF, and growth factor receptor p75^NTR was associated with the upregulation of BDNF, GDNF, and HGF in the spinal cord of the PCL + MSCs group. A trend demonstrating higher reactivity of Schwann cells and axonal branching in the sciatic nerve was observed, and canine AdMSCs were engrafted at 30 days following repair.

3D-printed NGCs multi-functionalized with canine AdMSCs embedded in heterologous fibrin biopolymer as cell scaffold exerted neuroregenerative effects. Our multimodal approach supports the trophic microenvironment, resulting in a pro-regenerative state after critical sciatic nerve injury in rats.

• 3D printing
• Canine mesenchymal stem cells
• Cell-based therapy
• Fibrin
• Nerve guidance conduits
• Nerve regeneration
• Scaffold
• Sciatic nerve injury
• Tissue engineering

The successful introduction of innovative treatment strategies into clinical practise strongly depends on the availability of effective experimental models and their reliable pre-clinical assessment. Considering pre-clinical research for peripheral nerve repair and reconstruction, the far most used nerve regeneration model in the last decades is the sciatic nerve injury and repair model. More recently, the use of the median nerve injury and repair model has gained increasing attention due to some significant advantages it provides compared to sciatic nerve injury. Outstanding advantages are the availability of reliable behavioural tests for assessing posttraumatic voluntary motor recovery and a much lower impact on the animal wellbeing. In this article, the potential application of the median nerve injury and repair model in pre-clinical research is reviewed. In addition, we provide a synthetic overview of a variety of methods that can be applied in this model for nerve regeneration assessment. This article is aimed at helping researchers in adequately adopting this in vivo model for pre-clinical evaluation of peripheral nerve reconstruction as well as for interpreting the results in a translational perspective.

• animal experimental model
• injury
• median nerve
• regeneration
• repair
• translational research

Implantable tubular devices known as nerve guidance conduits (NGCs) have drawn considerable interest as an alternative to autografting in the repair of peripheral nerve injuries.

The biology of stem cells is one of the most dynamic and promising fields of the biological sciences, since it is the basis for the development of organisms. Its biological complexity demands efforts from several lines of research aimed mainly at its therapeutic use. Nanotechnology has been emerging as a new field of study, which shows great potential in the treatment of various diseases. This new area of health has been called “Nanomedicine” or “Bionanotechnology”, which can be applied in Medicine by transport and drug delivery systems, robotic tools to be used in diagnostic and surgical processes, nanobiomaterials, gene therapies, nanobiomedical devices, among others. Because stem cells and Nanotechnology are two areas of extremely promising science, a new field of study, called “stem cell Nanotechnology”, has gradually emerged. In this, Nanotechnology is used to help the stem cells apply their therapeutic potential in the treatment, cure, and repair of the damaged tissues, in an effective and safe way. In this way, stem cell Nanotechnology has generated great interest, since it may result in significant contributions to Regenerative Medicine and tissue engineering. The present work aims to present the state-of-the-art regarding its therapeutic use in Human Medicine.

• biomaterials
• electrical cellular stimulation
• nerve conduits
• nerve regeneration
• stem cell differentiation

• Brain-derived neurotrophic factor
• Clinical trials
• Genetic modification
• Mesenchymal stem cells
• Neuroprotection
• Neuroregeneration
• Peripheral nerve regeneration
• Schwann cells
• Transdifferentiation
• Transplantation

• Blast trauma
• Endothelial cells
• Mesenchymal stem cells
• Muscle stem cells
• Neurotrophic factors
• Paracrine mechanism
• Peripheral nerve repair
• VEGF-A

• Adipose-derived mesenchymal stem cells
• Bone marrow mesenchymal stem cells
• Cell-based therapies
• Mesenchymal stem cells
• Peripheral nerve injury
• Stem cells
• Umbilical cord mesenchymal stem cells

• Brain-derived neurotrophic factor
• Cellular area
• High content screening
• Mesenchymal stem cells
• Morphometric analysis
• Neurite outgrowth
• Neuroprotection
• Neuroregeneration
• Peripheral nerve regeneration
• Schwann cells

Maintaining a permissive microenvironment is essential for adequate nerve regeneration. Cell-based therapy has the potential based cell replacement and promotion of axonal growth. The adipose tissue derived mesenchymal stromal cells (Ad-MSC) attract interest because neuroregenerative and anti-inflammatory properties. The aim of this study was to evaluate the effects of canine and murine Ad-MSC transplantation on the sciatic nerve regeneration.

Forty Wistar rats were divided randomly into: control group - CG (n=8); denervated group - DG (n=8); decellularized vein group - VG (n=8); decellularized vein+canine MSC–cMSC (n=8); descellularized vein+murine MSC–mMSC (n=8). After 10-mm nerve gap, the tubulation technique was performed with decellularized vein filled with 10⁶ MSC labeled with quantum dots (Qtracker 665^®). The sciatic nerve functional index (SFI) and electroneuromyography (ENMG) measurements were carried and morphometric and immunohistochemistry analysis of the tissue.

The SFI values were higher in the cMSC and mMSC groups at day 27 (p<0.020) and day 35 (p<0.011). The ENMG analysis also revealed better results in the mMSC group. Density, number, and total area of the fibers were increased in the mMSC and cMSC groups. Brain-derived neurotrophic factor BDNF and S-100 protein positive immunoreactivity showed a higher expression for both in the nerve of the mMSC and cMSC groups. The MSC labeled with quantum dots were detected at day 35, indicating neuronal survival long after the nerve damage.

Murine and canine Ad-MSC associated with decellularized vein scaffold had positive effects on sciatic nerve regeneration in rats.

• Cell-based therapy
• Nerve regeneration
• Regenerative medicine
• Sciatic nerve

• BBG
• Ischiatic nerve
• Mice
• P2 receptor antagonists and crush injury
• PPADS

In the current research, to find if the combination of chitosan nerve conduits seeded with autologous bone marrow mononuclear cells (BM-MNCs) can be used to bridge 30 mm long peroneal nerve defects in goats, 15 animals were separated into BM-MNC group (n = 5), vehicle group (n = 5), and autologous nerve graft group (n = 5). 12 months after the surgery, animals were evaluated by behavioral observation, magnetic resonance imaging tests, histomorphological and electrophysiological analysis. Results revealed that animals in BM-MNC group and autologous nerve graft group achieved fine functional recovery; magnetic resonance imaging tests and histomorphometry analysis showed that the nerve defect was bridged by myelinated nerve axons in those animals. No significant difference was found between the two groups concerning myelinated axon density, axon diameter, myelin sheath thickness and peroneal nerve action potential. Animals in vehicle group failed to achieve significant functional recovery. The results indicated that chitosan nerve conduits seeded with autologous bone marrow mononuclear cells have strong potential in bridging long peripheral nerve defects and could be applied in future clinical trials.

• Cell therapy
• Ensheathing cells
• Nerve conduit
• Nerve regeneration
• Olfactory
• Peripheral nerve trauma

Mesenchymal stem cells are posing as a promising character in the most recent therapeutic strategies and, since their discovery, extensive knowledge on their features and functions has been gained. In recent years, innovative sources have been disclosed in alternative to the bone marrow, conveying their associated ethical concerns and ease of harvest, such as the umbilical cord tissue and the dental pulp. These are also amenable of cryopreservation and thawing for desired purposes, in benefit of the donor itself or other patients in pressing need. These sources present promising possibilities in becoming useful cell sources for therapeutic applications in the forthcoming years. Effective and potential applications of these cellular-based strategies for the regeneration of peripheral nerve are overviewed, documenting recent advances and identified issues for this research area in the near future. Finally, besides the differentiation capacities attributed to mesenchymal stem cells, advances in the recognition of their effective mode of action in the regenerative theatre have led to a new area of interest: the mesenchymal stem cells' secretome. The paracrine modulatory pathway appears to be a major mechanism by which these are beneficial to nerve regeneration and comprehension on the specific growth factors, cytokine, and extracellular molecules secretion profiles is therefore of great interest.

Three-dimensional neural tissue engineering has significantly advanced the development of neural disease models and replacement tissues for patients by leveraging the unique capabilities of stem cells.

• Experimental
• Magnetic resonance imaging
• Mesenchymal stem cells
• Nerve conduit
• Peripheral nerve injury
• Radiation injuries

• Nerve Regeneration
• Peripheral Nerve System/injuries
• Regenerative Medicine

• Ischiatic nerve
• Mice
• Nerve conduits
• Nerve regeneration
• Poly(l-lactic acid)

• Deleted in Colorectal Cancer
• UNC5B
• bone marrow mesenchymal stem cells
• brain-derived neurotrophic factor
• nerve growth factor
• netrin-1

• Animals
• Axons/drug effects
• Bacterial Infections/drug therapy
• Clinical Trials as Topic
• Corneal Injuries/drug therapy
• Drug Evaluation, Preclinical
• Epithelial Cells/drug effects
• Fibroblasts/transplantation
• Fractures, Bone/drug therapy
• Humans
• In Vitro Techniques
• Intercellular Signaling Peptides and Proteins/blood
• Intercellular Signaling Peptides and Proteins/therapeutic use
• Ligaments/injuries
• Mesenchymal Stem Cell Transplantation
• Models, Animal
• Neovascularization, Physiologic/drug effects
• Pain/drug therapy
• Platelet-Rich Plasma/chemistry
• Regeneration/drug effects
• Tendon Injuries/drug therapy
• Wound Healing/drug effects

• Amyotrophic lateral sclerosis
• Mesenchymal stem cells
• Neural differentiation
• Neuroprotection
• Peripheral nerve regeneration
• Wharton's jelly

Peripheral nerve injury is a worldwide clinical problem which could lead to loss of neuronal communication along sensory and motor nerves between the central nervous system (CNS) and the peripheral organs and impairs the quality of life of a patient. The primary requirement for the treatment of complete lesions is a tension-free, end-to-end repair. When end-to-end repair is not possible, peripheral nerve grafts or nerve conduits are used. The limited availability of autografts, and drawbacks of the allografts and xenografts like immunological reactions, forced the researchers to investigate and develop alternative approaches, mainly nerve conduits. In this review, recent information on the various types of conduit materials (made of biological and synthetic polymers) and designs (tubular, fibrous, and matrix type) are being presented.

• natural biomaterials
• peripheral nerve injury
• synthetic biomaterials

We studied the morphology and the cortical representation of the median nerve (MN), 10 weeks after a transection immediately followed by treatment with tubulization using a polycaprolactone (PCL) conduit with or without bone marrow-derived mesenchymal stem cell (MSC) transplant. In order to characterize the cutaneous representation of MN inputs in primary somatosensory cortex (S1), electrophysiological cortical mapping of the somatosensory representation of the forepaw and adjacent body parts was performed after acute lesion of all brachial plexus nerves, except for the MN. This was performed in ten adult male Wistar rats randomly assigned in three groups: MN Intact (n = 4), PCL-Only (n = 3), and PCL+MSC (n = 3). Ten weeks before mapping procedures in animals from PCL-Only and PCL+MSC groups, animal were subjected to MN transection with removal of a 4-mm-long segment, immediately followed by suturing a PCL conduit to the nerve stumps with (PCL+MSC group) or without (PCL-Only group) injection of MSC into the conduit. After mapping the representation of the MN in S1, animals had a segment of the regenerated nerve processed for light and transmission electron microscopy. For histomorphometric analysis of the nerve segment, sample size was increased to five animals per experimental group. The PCL+MSC group presented a higher number of myelinated fibers and a larger cortical representation of MN inputs in S1 (3,383 ± 390 fibers; 2.3 mm², respectively) than the PCL-Only group (2,226 ± 575 fibers; 1.6 mm²). In conclusion, MSC-based therapy associated with PCL conduits can improve MN regeneration. This treatment seems to rescue the nerve representation in S1, thus minimizing the stabilization of new representations of adjacent body parts in regions previously responsive to the MN.

• cortical plasticity
• median nerve lesion
• nerve regeneration
• polycaprolactone conduits
• rat
• stem-cell therapy

Despite the regenerative potential of the peripheral nervous system, severe nerve lesions lead to loss of target-organ innervation, making complete functional recovery a challenge. Few studies have given attention to combining different approaches in order to accelerate the regenerative process.

Test the effectiveness of combining Schwann-cells transplantation into a biodegradable conduit, with treadmill training as a therapeutic strategy to improve the outcome of repair after mouse nerve injury.

Sciatic nerve transection was performed in adult C57BL/6 mice; the proximal and distal stumps of the nerve were sutured into the conduit. Four groups were analyzed: acellular grafts (DMEM group), Schwann cell grafts (3×10⁵/2 µL; SC group), treadmill training (TMT group), and treadmill training and Schwann cell grafts (TMT + SC group). Locomotor function was assessed weekly by Sciatic Function Index and Global Mobility Test. Animals were anesthetized after eight weeks and dissected for morphological analysis.

Combined therapies improved nerve regeneration, and increased the number of myelinated fibers and myelin area compared to the DMEM group. Motor recovery was accelerated in the TMT + SC group, which showed significantly better values in sciatic function index and in global mobility test than in the other groups. The TMT + SC group showed increased levels of trophic-factor expression compared to DMEM, contributing to the better functional outcome observed in the former group. The number of neurons in L4 segments was significantly higher in the SC and TMT + SC groups when compared to DMEM group. Counts of dorsal root ganglion sensory neurons revealed that TMT group had a significant increased number of neurons compared to DMEM group, while the SC and TMT + SC groups had a slight but not significant increase in the total number of motor neurons.

These data provide evidence that this combination of therapeutic strategies can significantly improve functional and morphological recovery after sciatic injury.

Sciatic nerve crush injury in rat animal model is one of the most common experimental models used in regenerative research. However, the availability of transgenic mouse for nerve regeneration studies is constantly increasing and, therefore, the shift from rat model to mouse model is, in some cases, necessary. Moreover, since most of the human nerve lesions occur in the upper limb, it is also advantageous to shift from sciatic nerve to median nerve. In this study we described an experimental model which involves lesions of the median nerve in the mouse. Data showed that the finger flexor muscle contraction strength, assessed to evaluate the motor function recovery, and reached values not different from the control already 20 days after injury. The degree of nerve regeneration evaluated with stereological methods in light microscopy showed that, 25 days after injury, the number of regenerated myelinated fibers was comparable to the control, but they were smaller with a thinner myelin thickness. Stereological analysis made in electron microscopy confirmed these results, although the total number of fibers quantified was significantly higher compared to light microscopy analysis, due to the very small size of some fibers that can be detected only in electron microscopy.

• Bone marrow mesenchymal stem cells
• Cell-based therapy
• Mechanisms
• Nerve regeneration
• Therapeutic strategies

• Clinical trials
• Mesenchymal stem cells
• Neurotrauma
• Pre-clinical studies
• Stem cell therapy

• PHBHHx
• bacterial polyester
• bone marrow stromal cell
• hMSC
• peripheral nerve
• stem cell

We previously established that mesenchymal stem cells originating from mouse embryonic stem (ES) cells (E-MSCs) showed markedly higher potential for differentiation into skeletal muscles in vitro than common mesenchymal stem cells (MSCs). Further, the E-MSCs exhibited a low risk for teratoma formation. Here we evaluate the potential of E-MSCs for differentiation into skeletal muscles in vivo and reveal the regeneration and functional recovery of injured muscle by transplantation. E-MSCs were transplanted into the tibialis anterior (TA) muscle 24 h following direct clamping. After transplantation, the myogenic differentiation of E-MSCs, TA muscle regeneration, and re-innervation were morphologically analyzed. In addition, footprints and gaits of each leg under spontaneous walking were measured by CatWalk XT, and motor functions of injured TA muscles were precisely analyzed. Results indicate that >60% of transplanted E-MSCs differentiated into skeletal muscles. The cross-sectional area of the injured TA muscles of E-MSC–transplanted animals increased earlier than that of control animals. E-MSCs also promotes re-innervation of the peripheral nerves of injured muscles. Concerning function of the TA muscles, we reveal that transplantation of E-MSCs promotes the recovery of muscles. This is the first report to demonstrate by analysis of spontaneous walking that transplanted cells can accelerate the functional recovery of injured muscles. Taken together, the results show that E-MSCs have a high potential for differentiation into skeletal muscles in vivo as well as in vitro. The transplantation of E-MSCs facilitated the functional recovery of injured muscles. Therefore, E-MSCs are an efficient cell source in transplantation.

• CD105
• MSC
• embryonic stem cells
• functional recovery
• regeneration of skeletal muscle

• Allograft
• Nerve conduit
• Peripheral nerve injury
• Peripheral nerve repair