• gliosis
• inflammation
• spinal cord injury
• stem cell therapy

• 2018/25845-7, 2018/05006-0, and 2021/11936-3 São Paulo Research Foundation - FAPESP
• 303050/2021-7, 303224/2018-5, and 306339/2020-0 CNPq

• Cell therapy
• Dental pulp
• Spheroid
• Spinal cord injury

• Adult
• Animals
• Female
• Humans
• Rats
• Dental Pulp
• Motor Neurons/physiology
• Rats, Inbred Lew
• Spinal Cord
• Spinal Cord Injuries/therapy
• Spinal Nerve Roots/injuries
• Spinal Nerve Roots/physiology
• Stem Cells
• Cell Culture Techniques

• Cell transplantation
• Cellular engineering
• Neural progenitor cells
• Spinal cord injury

• Humans
• Spinal Cord/surgery
• Cell Transplantation

• F32 NS119348 NINDS NIH HHS
• R01 NS104291 NINDS NIH HHS

Human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising candidate for spinal cord injury (SCI) repair owing to their advantages of low immunogenicity and easy accessibility over other MSC sources. However, modest clinical efficacy hampered the progression of these cells to clinical translation. This discrepancy may be due to many variables, such as cell source, timing of implantation, route of administration, and relevant efficacious cell dose, which are critical factors that affect the efficacy of treatment of patients with SCI. Previously, we have evaluated the safety and efficacy of 4 × 10⁶ hUC-MSCs/kg in the treatment of subacute SCI by intrathecal implantation in rat models. To search for a more accurate dose range for clinical translation, we compared the effects of three different doses of hUC-MSCs – low (0.25 × 10⁶ cells/kg), medium (1 × 10⁶ cells/kg) and high (4 × 10⁶ cells/kg) – on subacute SCI repair through an elaborate combination of behavioral analyses, anatomical analyses, magnetic resonance imaging-diffusion tensor imaging (MRI-DTI), biotinylated dextran amine (BDA) tracing, electrophysiology, and quantification of mRNA levels of ion channels and neurotransmitter receptors. Our study demonstrated that the medium dose, but not the low dose, is as efficient as the high dose in producing the desired therapeutic outcomes. Furthermore, partial restoration of the γ-aminobutyric acid type A (GABA_A) receptor expression by the effective doses indicates that GABA_A receptors are possible candidates for therapeutic targeting of dormant relay pathways in injured spinal cord. Overall, this study revealed that intrathecal implantation of 1 × 10⁶ hUC-MSCs/kg is an alternative approach for treating subacute SCI.

• effective dose
• human umbilical cord mesenchymal stem cells
• intrathecal implantation
• ion channels
• neurotransmitter receptors
• spinal cord injury
• subacute spinal cord injury
• γ-aminobutyric acid type A (GABA_A) receptors

A spinal root avulsion is the most severe proximal peripheral nerve lesion possible. Avulsion of ventral root filaments disconnects spinal motoneurons from their target muscles, resulting in complete paralysis. In patients that undergo brachial plexus nerve repair, axonal regeneration is a slow process. It takes months or even years to bridge the distance from the lesion site to the distal targets located in the forearm. Following ventral root avulsion, without additional pharmacological or surgical treatments, progressive death of motoneurons occurs within 2 weeks (Koliatsos et al., 1994). Reimplantation of the avulsed ventral root or peripheral nerve graft can act as a conduit for regenerating axons and increases motoneuron survival (Chai et al., 2000). However, this beneficial effect is transient. Combined with protracted and poor long-distance axonal regeneration, this results in permanent function loss. To overcome motoneuron death and improve functional recovery, several promising intervention strategies are being developed. Here, we focus on GDNF gene-therapy. We first introduce the experimental ventral root avulsion model and discuss its value as a proxy to study clinical neurotmetic nerve lesions. Second, we discuss our recent studies showing that GDNF gene-therapy is a powerful strategy to promote long-term motoneuron survival and improve function when target muscle reinnervation occurs within a critical post-lesion period. Based upon these observations, we discuss the influence of timing of the intervention, and of the duration, concentration and location of GDNF delivery on functional outcome. Finally, we provide a perspective on future research directions to realize functional recovery using gene therapy.

• axonal regeneration
• gene therapy
• nerve regeneration
• peripheral nerve injury
• ventral root avulsion

• clinical study
• early chronic phase
• efficacy
• human umbilical cord mesenchymal stem cell
• multicenter trial
• prospective study
• randomized controlled trial
• safety
• spinal cord injury
• study protocol

• behavior
• central nervous system
• factor
• inflammation
• model
• spinal cord
• stem cells
• transplantation

• Brachial plexus
• GDNF
• Gene therapy
• Nerve injury
• Regeneration
• Root avulsion

Peripheral nerve injuries caused by accidents may lead to paralysis, sensory disturbances, anaesthesia, and lack of autonomic functions. Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors: motoneuronal soma viability, proper axonal sprouting across inhibitory zones and elongation toward specific muscle, effective synapse contact rebuilding, and prevention of muscle atrophy. Therapies, such as adjuvant drugs with pleiotropic effects, that promote functional recovery after peripheral nerve injury are needed. Toward this aim, we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools. Our focus is on boosting intrinsic capabilities of neurons for neuroprotection; this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition. Using our workflow, we discovered neuroheal, a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection, is anti-inflammatory, enhances axonal regeneration after axotomy, and reduces muscle atrophy. This drug discovery workflow has thus yielded a therapy that is close to its clinical application.

• PI3K/AKT
• axonal regeneration
• motoneuron
• motor function recovery
• muscle atrophy
• neurodegeneration
• neuroheal
• sirtuin 1
• systems biology

Human mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) were used for the treatment of the ischemic-compression model of spinal cord injury in rats. To assess the effectivity of the treatment, different dosages (0.5 or 1.5 million cells) and repeated applications were compared. Cells or saline were applied intrathecally by lumbar puncture for one week only, or in three consecutive weeks after injury. Rats were assessed for locomotor skills (BBB, rotarod, flat beam) for 9 weeks. Spinal cord tissue was morphometrically analyzed for axonal sprouting, sparing of gray and white matter and astrogliosis. Endogenous gene expression (Gfap, Casp3, Irf5, Cd86, Mrc1, Cd163) was studied with quantitative Real-time polymerase chain reaction (qRT PCR). Significant recovery of functional outcome was observed in all of the treated groups except for the single application of the lowest number of cells. Histochemical analyses revealed a gradually increasing effect of grafted cells, resulting in a significant increase in the number of GAP43+ fibers, a higher amount of spared gray matter and reduced astrogliosis. mRNA expression of macrophage markers and apoptosis was downregulated after the repeated application of 1.5 million cells. We conclude that the effect of hWJ-MSCs on spinal cord regeneration is dose-dependent and potentiated by repeated application.

• Wharton’s jelly
• astrogliosis
• axonal growth
• human mesenchymal stem cells
• inflammatory response
• neuroregeneration
• spinal cord injury

The “gold standard” treatment of patients with spinal root injuries consists of delayed surgical reconnection of nerves. The sooner, the better, but problems such as injury-induced motor neuronal death and muscle atrophy due to long-term denervation mean that normal movement is not restored. Herein we describe a preclinical model of root avulsion with delayed reimplantation of lumbar roots that was used to establish a new adjuvant pharmacological treatment. Chronic treatment (up to 6 months) with NeuroHeal, a new combination drug therapy identified using a systems biology approach, exerted long-lasting neuroprotection, reduced gliosis and matrix proteoglycan content, accelerated nerve regeneration by activating the AKT pathway, promoted the formation of functional neuromuscular junctions, and reduced denervation-induced muscular atrophy. Thus, NeuroHeal is a promising treatment for spinal nerve root injuries and axonal regeneration after trauma.

Alzheimer’s disease, Parkinson’s disease, traumatic brain and spinal cord injury and neuroinflammatory multiple sclerosis are diverse disorders of the central nervous system. However, they are all characterized by various levels of inappropriate inflammatory/immune response along with tissue destruction. In the gastrointestinal system, inflammatory bowel disease (IBD) is also a consequence of tissue destruction resulting from an uncontrolled inflammation. Interestingly, there are many similarities in the immunopathomechanisms of these CNS disorders and the various forms of IBD. Since it is very hard or impossible to cure them by conventional manner, novel therapeutic approaches such as the use of mesenchymal stem cells, are needed. Mesenchymal stem cells have already been isolated from various tissues including the dental pulp and periodontal ligament. Such cells possess transdifferentiating capabilities for different tissue specific cells to serve as new building blocks for regeneration. But more importantly, they are also potent immunomodulators inhibiting proinflammatory processes and stimulating anti-inflammatory mechanisms.

The present review was prepared to compare the immunopathomechanisms of the above mentioned neurodegenerative, neurotraumatic and neuroinflammatory diseases with IBD. Additionally, we considered the potential use of mesenchymal stem cells, especially those from dental origin to treat such disorders. We conceive that such efforts will yield considerable advance in treatment options for central and peripheral disorders related to inflammatory degeneration.

Spinal cord injury (SCI) is a devastating condition with loss of motor and sensory functions below the injury level. Cell based therapies are experimented in pre-clinical studies around the world. Neural stem cells are located intra-cranially in subventricular zone and hippocampus which are highly invasive sources. The olfactory epithelium is a neurogenic tissue where neurogenesis takes place throughout the adult life by a population of stem/progenitor cells. Easily accessible olfactory neuroepithelial stem/progenitor cells are an attractive cell source for transplantation in SCI. Globose basal cells (GBCs) were isolated from rat olfactory epithelium, characterized by flow cytometry and immunohistochemically. These cells were further studied for neurosphere formation and neuronal induction. T10 laminectomy was done to create drop-weight SCI in rats. On the 9^th day following SCI, 5 × 10⁵ cells were transplanted into injured rat spinal cord. The outcome of transplantation was assessed by the Basso, Beattie and Bresnahan (BBB) locomotor rating scale, motor evoked potential and histological observation. GBCs expressed neural stem cell markers nestin, SOX2, NCAM and also mesenchymal stem cell markers (CD29, CD54, CD90, CD73, CD105). These cells formed neurosphere, a culture characteristics of NSCs and on induction, differentiated cells expressed neuronal markers βIII tubulin, microtubule-associated protein 2, neuronal nuclei, and neurofilament. GBCs transplanted rats exhibited hindlimb motor recovery as confirmed by BBB score and gastrocnemius muscle electromyography amplitude was increased compared to controls. Green fluorescent protein labelled GBCs survived around the injury epicenter and differentiated into βIII tubulin-immunoreactive neuron-like cells. GBCs could be an alternative to NSCs from an accessible source for autologous neurotransplantation after SCI without ethical issues.

• BBB score
• EMG
• globose basal cells
• nerve regeneration
• neural regeneration
• neural stem cell marker
• spinal cord injury
• the Basso Beattie and Bresnahan (BBB) locomotor scale score
• transplantation

Cervical-level injuries account for the majority of presented spinal cord injuries (SCIs) to date. Despite the increase in survival rates due to emergency medicine improvements, overall quality of life remains poor, with patients facing variable deficits in respiratory and motor function. Therapies aiming to ameliorate symptoms and restore function, even partially, are urgently needed. Current therapeutic avenues in SCI seek to increase regenerative capacities through trophic and immunomodulatory factors, provide scaffolding to bridge the lesion site and promote regeneration of native axons, and to replace SCI-lost neurons and glia via intraspinal transplantation. Induced pluripotent stem cells (iPSCs) are a clinically viable means to accomplish this; they have no major ethical barriers, sources can be patient-matched and collected using non-invasive methods. In addition, the patient’s own cells can be used to establish a starter population capable of producing multiple cell types. To date, there is only a limited pool of research examining iPSC-derived transplants in SCI—even less research that is specific to cervical injury. The purpose of the review herein is to explore both preclinical and clinical recent advances in iPSC therapies with a detailed focus on cervical spinal cord injury.

• cervical
• embryonic stem cell
• iPSC
• induced pluripotent stem cell
• intraspinal transplantation
• spinal cord injury

• Animals
• Cervical Cord/injuries
• Disease Models, Animal
• Humans
• Induced Pluripotent Stem Cells/transplantation
• Quality of Life
• Spinal Cord Injuries/therapy
• Transplantation, Autologous/methods

• HMGB1
• autophagy
• spinal root avulsion

• Adipose Tissue/cytology
• Adipose Tissue/transplantation
• Animals
• Heterografts
• Humans
• Immunomodulation
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Motor Neurons/pathology
• Nerve Regeneration
• Neuroprotection
• Radiculopathy/immunology
• Radiculopathy/metabolism
• Radiculopathy/pathology
• Radiculopathy/therapy
• Rats
• Spinal Cord/physiopathology
• Spinal Cord/transplantation
• Spinal Nerve Roots/physiopathology
• Synapses/immunology
• Synapses/metabolism
• Synapses/pathology
• Synaptophysin/metabolism
• T-Lymphocytes/immunology

• brachial plexus
• chronic injury
• motoneuron
• peripheral nerve regeneration
• spinal cord

Musculoskeletal-related pain is one of the most disabling health conditions affecting more than one third of the adult population worldwide. Pain from various mechanisms and origins is currently underdiagnosed and undertreated. The complexity of molecular mechanisms correlating pain and the progression of musculoskeletal diseases is not yet fully understood. Molecular biomarkers for objective evaluation and treatment follow-up are needed as a step towards targeted treatment of pain as a symptom or as a disease. Stem cell therapy is already under investigation for the treatment of different types of musculoskeletal-related pain. Mesenchymal stem cell-based therapies are already being tested in various clinical trials that use musculoskeletal system-related pain as the primary or secondary endpoint. Genetically engineered stem cells, as well as induced pluripotent stem cells, offer promising novel perspectives for pain treatment. It is possible that a more focused approach and reassessment of therapeutic goals will contribute to the overall efficacy, as well as to the clinical acceptance of regenerative medicine therapies. This article briefly describes the principal types of musculoskeletal-related pain and reviews the stem cell-based therapies that have been specifically designed for its treatment.

• Molecular biomarkers
• Musculoskeletal pain
• Stem cells

• cell therapy
• immunosuppression
• mesenchymal stem cells
• spinal cord injury
• transplantation

• Animals
• Brain-Derived Neurotrophic Factor/genetics
• Brain-Derived Neurotrophic Factor/metabolism
• Cranial Nerve Injuries
• Female
• Fibrin Tissue Adhesive/therapeutic use
• Gene Expression
• Glial Cell Line-Derived Neurotrophic Factor/genetics
• Glial Cell Line-Derived Neurotrophic Factor/metabolism
• Glial Fibrillary Acidic Protein/metabolism
• Leukocytes, Mononuclear/transplantation
• Microglia/physiology
• Nerve Tissue/transplantation
• Rats, Inbred Lew
• Recovery of Function
• Spinal Nerve Roots/pathology

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