Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy

Despite the extensive research effort that has been made in the field, motor neuron diseases, namely, amyotrophic lateral sclerosis and spinal muscular atrophies, still represent an overwhelming cause of morbidity and mortality worldwide. Exogenous neural stem cell-based transplantation approaches have been investigated as multifaceted strategies to both protect and repair upper and lower motor neurons from degeneration and inflammation. Transplanted neural stem cells (NSCs) exert their beneficial effects not only through the replacement of damaged cells but also via bystander immunomodulatory and neurotrophic actions. Notwithstanding these promising findings, the clinical translatability of such techniques is jeopardized by the limited engraftment success and survival of transplanted cells within the hostile disease microenvironment. To overcome this obstacle, different methods to enhance graft survival, stability, and therapeutic potential have been developed, including environmental stress preconditioning, biopolymers scaffolds, and genetic engineering. In this review, we discuss current engineering techniques aimed at the exploitation of the migratory, proliferative, and secretive capacity of NSCs and their relevance for the therapeutic arsenal against motor neuron disorders and other neurological disorders

Use of Preputial Skin as Cutaneous Graft after Nevus Excision

We report a four-year-old boy with a nevus covering all the plantar side of his second finger on the left foot. He was also affected by congenital phimosis. Surgical excision of the nevus was indicated, but the skin defect would have been too large to be directly closed. The foreskin was taken as a full-thickness skin graft to cover the cutaneous defect of the finger. The graft intake was favourable and provided a functional repair with good aesthetic characteristic

Silence superoxide dismutase 1 (SOD1): a promising therapeutic target for amyotrophic lateral sclerosis (ALS)

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disorder that targets upper and lower motor neurons and leads to fatal muscle paralysis. Mutations in the superoxide dismutase 1 (SOD1) gene are responsible for 15% of familial ALS cases, but several studies have indicated that SOD1 dysfunction may also play a pathogenic role in sporadic ALS. SOD1 induces numerous toxic effects through the pathological misfolding and aggregation of mutant SOD1 species, hence a reduction of the levels of toxic variants appears to be a promising therapeutic strategy for SOD1-related ALS. Several methods are used to modulate gene expression in vivo; these include RNA interference, antisense oligonucleotides (ASOs) and CRISPR/Cas9 technology. Areas covered: This paper examines the current approaches for gene silencing and the progress made in silencing SOD1 in vivo. It progresses to shed light on the key results and pitfalls of these studies and highlights the future challenges and new perspectives for this exciting research field. Expert opinion: Gene silencing strategies targeting SOD1 may represent effective approaches for familial and sporadic ALS-related neurodegeneration; however, the risk of off-target effects must be minimized, and effective and minimally invasive delivery strategies should be fine-tuned

Glial cells involvement in spinal muscular atrophy: Could SMA be a neuroinflammatory disease?

Spinal muscular atrophy (SMA) is a severe, inherited disease characterized by the progressive degeneration and death of motor neurons of the anterior horns of the spinal cord, which results in muscular atrophy and weakness of variable severity. Its early-onset form is invariably fatal in early childhood, while milder forms lead to permanent disability, physical deformities and respiratory complications. Recently, two novel revolutionary therapies, antisense oligonucleotides and gene therapy, have been approved, and might prove successful in making long-term survival of these patients likely. In this perspective, a deep understanding of the pathogenic mechanisms and of their impact on the interactions between motor neurons and other cell types within the central nervous system (CNS) is crucial. Studies using SMA animal and cellular models have taught us that the survival and functionality of motor neurons is highly dependent on a whole range of other cell types, namely glial cells, which are responsible for a variety of different functions, such as neuronal trophic support, synaptic remodeling, and immune surveillance. Thus, it emerges that SMA is likely a non-cell autonomous, multifactorial disease in which the interaction of different cell types and disease mechanisms leads to motor neurons failure and loss. This review will introduce the different glial cell types in the CNS and provide an overview of the role of glial cells in motor neuron degeneration in SMA. Furthermore, we will discuss the relevance of these findings so far and the potential impact on the success of available therapies and on the development of novel ones

Germination performance of grain sorghum hybrid seeds treated with bioregulator under water deficit

Water stress can reduce the speed and percentage of germination, damaging the development of seedlings. Thus it is necessary to find alternatives they can mitigate these effects. The plant growth regulators has been heavily used in agricultural production and can proporcionarum increase in the growth and development of plants. Thus, the objective of this study was to evaluate the germination performance of seeds of two hybrids of sorghum under simulated water stress, treated with plant growth regulator. The experimental design was completely randomized in a factorial 2 x 4, establishing itself as factors, two seed treatments (with and without plant growth regulator) and four water potential (0, -0.4, -0.8, -1.2 MPa) with four replications, separately for single hybrid grain sorghum: 1G100 and 1G233. Germination, the first count of germination, shoot and root length and dry matter of shoot and root were evaluated. Data were subjected to analysis of variance and means compared by Tukey test at 5% probability and regression analysis. The osmotic potential reduction to the level of -1.2 MPa reduced seed quality, however the application of plant growth regulator did not improve seed quality before the water stress. The plant growth regulator increased root length, dry weight of shoot and root of sorghum seedlings grow 1G233, in the absence of water deficit.Water stress can reduce seed germination speed and percentage, harming the development of seedlings. Thus, it is necessary to find alternatives that can mitigate these effects. Bioregulators have been intensively used in agricultural production and can provide increase in plant growth and development. Therefore, the aim of this work was to evaluate the germination performance of seeds of two grain sorghum hybrids under simulated water deficit treated with bioregulator. The experimental design was completely randomized in a 2 x 4 factorial scheme, with the following factors: two seed treatments (with and without bioregulator) and four osmotic potentials (0; -0.4; -0.8 and -1.2 MPa), with four replicates, separately for the following grain sorghum hybrids: 1G100 and 1G233. Germination, first germination count, shoot and root length and shoot and root dry matter were evaluated. Data obtained were submitted to analysis of variance and means were compared by the Tukey test at 5% probability and regression analysis. The reduction of the osmotic potential to the level of -1.2 MPa reduced the physiological quality of seeds; however, bioregulator application did not result in better seed quality under water stress. Bioregulator Stimulate® increased root length and shoot dry matter of seedlings of grain sorghum cultivar 1G233 in the absence of water deficit

Lixiviação de íons potássio, cálcio e magnésio para determinação do vigor em sementes de milho doce.

O teste de lixiviação de íons de potássio, cálcio e magnésio é baseado na integridade das membranas celulares das sementes, sendo considerado um procedimento rápido para a avaliação do vigor em sementes de várias espécies. Porém, para sementes de milho doce não se têm informações necessárias para a validação deste procedimento. Com isso, o trabalho teve como objetivo obter informações que permitam o aperfeiçoamento dos testes de lixiviação de potássio, cálcio e magnésio para a avaliação do vigor em sementes de milho doce. Foram utilizados 14 lotes de sementes de milho doce de duas cultivares, BR-401 e BR-402. O delineamento utilizado foi inteiramente casualizado com três repetições. A qualidade fisiológica das sementes foi avaliada por meio dos testes de germinação, condutividade elétrica, emergência a campo, lixiviação de potássio, de cálcio e de magnésio. Os testes de lixiviação de potássio e magnésio foram eficientes na avaliação do vigor em sementes de milho doce. A condutividade elétrica apresentou correlação negativa com a emergência de plântulas e positiva com a lixiviação de íons de potássio e magnésio

In vitro models of multiple system atrophy from primary cells to induced pluripotent stem cells

Multiple system atrophy (MSA) is a rare neurodegenerative disease with a fatal outcome. Nowadays, only symptomatic treatment is available for MSA patients. The hallmarks of the disease are glial cytoplasmic inclusions (GCIs), proteinaceous aggregates mainly composed of alpha-synuclein, which accumulate in oligodendrocytes. However, despite the extensive research efforts, little is known about the pathogenesis of MSA. Early myelin dysfunction and alpha-synuclein deposition are thought to play a major role, but the origin of the aggregates and the causes of misfolding are obscure. One of the reasons for this is the lack of a reliable model of the disease. Recently, the development of induced pluripotent stem cell (iPSC) technology opened up the possibility of elucidating disease mechanisms in neurodegenerative diseases including MSA. Patient specific iPSC can be differentiated in glia and neurons, the cells involved in MSA, providing a useful human disease model. Here, we firstly review the progress made in MSA modelling with primary cell cultures. Subsequently, we focus on the first iPSC-based model of MSA, which showed that alpha-synuclein is expressed in oligodendrocyte progenitors, whereas its production decreases in mature oligodendrocytes. We then highlight the opportunities offered by iPSC in studying disease mechanisms and providing innovative models for testing therapeutic strategies, and we discuss the challenges connected with this technique

Neural stem cell transplantation for neurodegenerative diseases

Neurodegenerative diseases are disabling and fatal neurological disorders that currently lack effective treatment. Neural stem cell (NSC) transplantation has been studied as a potential therapeutic approach and appears to exert a beneficial effect against neurodegeneration via different mechanisms, such as the production of neurotrophic factors, decreased neuroinflammation, enhanced neuronal plasticity and cell replacement. Thus, NSC transplantation may represent an effective therapeutic strategy. To exploit NSCs\u2019 potential, some of their essential biological characteristics must be thoroughly investigated, including the specific markers for NSC subpopulations, to allow profiling and selection. Another key feature is their secretome, which is responsible for the regulation of intercellular communication, neuroprotection, and immunomodulation. In addition, NSCs must properly migrate into the central nervous system (CNS) and integrate into host neuronal circuits, enhancing neuroplasticity. Understanding and modulating these aspects can allow us to further exploit the therapeutic potential of NSCs. Recent progress in gene editing and cellular engineering techniques has opened up the possibility of modifying NSCs to express select candidate molecules to further enhance their therapeutic effects. This review summarizes current knowledge regarding these aspects, promoting the development of stem cell therapies that could be applied safely and effectively in clinical settings

Ophthalmoplegia due to Miller Fisher syndrome in a patient with myasthenia gravis

Here, we describe a 79-year-old man, admitted to our unit for worsening diplopia and fatigue, started a few weeks after an episode of bronchitis and flu vaccination. Past medical history includes myasthenia gravis (MG), well-controlled by Pyridostigmine, Azathioprine, and Prednisone. During the first days, the patient developed progressive ocular movement abnormalities up to complete external ophthalmoplegia, severe limb and gait ataxia, and mild dysarthria. Deep tendon reflexes were absent in lower limbs. Since not all the symptoms were explainable with the previous diagnosis of myasthenia gravis, other etiologies were investigated. Brain MRI and cerebrospinal fluid analysis were normal. Electromyography showed a pattern of predominantly sensory multiple radiculoneuritis. Suspecting Miller Fisher syndrome (MFS), the patient was treated with plasmapheresis with subsequent clinical improvement. Antibodies against GQ1b turned out to be positive. MFS is an immune-mediated neuropathy presenting with ophthalmoplegia, ataxia, and areflexia. Even if only a few cases of MFS overlapping with MG have been described so far, the coexistence of two different autoimmune disorders can occur. It is always important to evaluate possible differential diagnosis even in case of known compatible diseases, especially when some clinical features seem atypical