RESUMO
The most prevalent rare genetic disease affecting young individuals is spinal muscular atrophy (SMA), which is caused by a loss-of-function mutation in the telomeric gene survival motor neuron (SMN) 1. The high heterogeneity of the SMA pathophysiology is determined by the number of copies of SMN2, a separate centromeric gene that can transcribe for the same protein, although it is expressed at a slower rate. SMA affects motor neurons. However, a variety of different tissues and organs may also be affected depending on the severity of the condition. Novel pharmacological treatments, such as Spinraza, Onasemnogene abeparvovec-xioi, and Evrysdi, are considered to be disease modifiers because their use can change the phenotypes of the patients. Since oxidative stress has been reported in SMA-affected cells, we studied the impact of antioxidant therapy on neural stem cells (NSCs) that have the potential to differentiate into motor neurons. Antioxidants can act through various pathways; for example, some of them exert their function through nuclear factor (erythroid-derived 2)-like 2 (NRF2). We found that curcumin is able to induce positive effects in healthy and SMA-affected NSCs by activating the nuclear translocation of NRF2, which may use a different mechanism than canonical redox regulation through the antioxidant-response elements and the production of antioxidant molecules.
Assuntos
Antioxidantes , Curcumina , Modelos Animais de Doenças , Atrofia Muscular Espinal , Fator 2 Relacionado a NF-E2 , Células-Tronco Neurais , Curcumina/farmacologia , Antioxidantes/farmacologia , Animais , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patologia , Atrofia Muscular Espinal/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Neurônios Motores/metabolismo , Neurônios Motores/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Humanos , Células CultivadasRESUMO
Dogs are commonly affected by Osteoarthritis (OA). Different approaches can be used to alleviate animals' symptoms. In this randomised, placebo-controlled and double-blind clinical trial, we performed a three months follow-up study assessing the efficacy of a food supplement containing natural ingredients (Cannabis sativa oil, Boswellia serrata Roxb. Phytosome® and Zingiber officinale extract) in dogs with OA after the interruption of physiotherapy that was performed during the previous three months. Inflammation and oxidative stress were reduced in the treated group (higher glutathione (GSH) and lower C-reactive protein [CRP] levels in blood) as well as chronic pain.
Assuntos
Boswellia , Cannabis , Osteoartrite , Animais , Cães , Dieta , Suplementos Nutricionais , Método Duplo-Cego , Seguimentos , Glutationa , Osteoartrite/tratamento farmacológico , Osteoartrite/veterinária , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
While the U.S. Food and Drug Administration and the European Medicines Evaluation Agency have recently approved new drugs to treat spinal muscular atrophy 1 (SMA1) in young patients, they are mostly ineffective in older patients since many motor neurons have already been lost. Therefore, understanding nervous system (NS) physiology in SMA patients is essential. Consequently, studying neural stem cells (NSCs) from SMA patients is of significant interest in searching for new treatment targets that will enable researchers to identify new pharmacological approaches. However, studying NSCs in these patients is challenging since their isolation damages the NS, making it impossible with living patients. Nevertheless, it is possible to study NSCs from animal models or create them by differentiating induced pluripotent stem cells obtained from SMA patient peripheral tissues. On the other hand, therapeutic interventions such as NSCs transplantation could ameliorate SMA condition. This review summarizes current knowledge on the physiological properties of NSCs from animals and human cellular models with an SMA background converging on the molecular and neuronal circuit formation alterations of SMA fetuses and is not focused on the treatment of SMA. By understanding how SMA alters NSC physiology, we can identify new and promising interventions that could help support affected patients.
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Células-Tronco Pluripotentes Induzidas , Atrofia Muscular Espinal , Células-Tronco Neurais , Animais , Humanos , Idoso , Modelos Animais de Doenças , Atrofia Muscular Espinal/tratamento farmacológico , Neurônios Motores , Proteína 1 de Sobrevivência do Neurônio Motor/genéticaRESUMO
Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the protumorigenic activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not only rely on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV protumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behavior of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2-dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockade of NOTCH activation by γ-secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the protumorigenic role of EV in MM as well as other tumors.
Assuntos
Vesículas Extracelulares , Mieloma Múltiplo , Medula Óssea/patologia , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Mieloma Múltiplo/patologia , Microambiente TumoralRESUMO
This study is a randomized, placebo-controlled, double-blinded trial performed to investigate the effects of a dietary supplement containing a mixture of Boswellia serrata Roxb., chlorophyll, green tea extract, glucosamine, chondroitin sulfate, hyaluronic acid, and further in the manuscript: non-hydrolised type II collagen in dogs with osteoarthritis (OA). A total of 40 dogs were enrolled in the study, they were randomly divided in control (CTR) and treatment (TRT) groups. The TRT group received the dietary supplement for 60 days. The CTR group received a placebo for the same number of days. All the subjects had veterinary evaluations during the trial and owners were requested to fill in questionnaires on chronic pain using the Helsinki Chronic Pain Index. The product was easy to administer and no side effects were reported. Combining results from veterinarian and owner evaluations, the tested product proved to be significantly beneficial in alleviating pain and in reducing the clinical signs in dogs with OA.
Assuntos
Sulfatos de Condroitina/administração & dosagem , Suplementos Nutricionais , Glucosamina/administração & dosagem , Ácido Hialurônico/administração & dosagem , Osteoartrite do Joelho/dietoterapia , Animais , Cães , Método Duplo-Cego , Masculino , Resultado do Tratamento , Viscossuplementos/administração & dosagemRESUMO
Objectives: The beneficial effects of many substances have been discovered because of regular dietary consumption. This is also the case with curcumin, whose effects have been known for more than 4,000 years in Eastern countries such as China and India. A curcumin-rich diet has been known to counteract many human diseases, including cancer and diabetes, and has been shown to reduce inflammation. The effect of a curcumin treatment for neurological diseases, such as spinal muscular atrophy; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; multiple sclerosis; and others, has only recently been brought to the attention of researchers and the wider population.Methods: In this paper, we summarise the studies on this natural product, from its isolation two centuries ago to its characterisation a century later.Results: We describe its role in the treatment of neurological diseases, including its cellular and common molecular mechanisms, and we report on the clinical trials of curcumin with healthy people and patients.Discussion: Commenting on the different approaches adopted by the efforts made to increase its bioavailability.
Assuntos
Doença de Alzheimer , Esclerose Lateral Amiotrófica , Curcumina , Esclerose Múltipla , Doença de Parkinson , Doença de Alzheimer/tratamento farmacológico , Esclerose Lateral Amiotrófica/tratamento farmacológico , Curcumina/farmacologia , Curcumina/uso terapêutico , Humanos , Doença de Parkinson/tratamento farmacológicoRESUMO
The production of induced pluripotent stem cells (iPSCs) represent a breakthrough in regenerative medicine, providing new opportunities for understanding basic molecular mechanisms of human development and molecular aspects of degenerative diseases. In contrast to human embryonic stem cells (ESCs), iPSCs do not raise any ethical concerns regarding the onset of human personhood. Still, they present some technical issues related to immune rejection after transplantation and potential tumorigenicity, indicating that more steps forward must be completed to use iPSCs as a viable tool for in vivo tissue regeneration. On the other hand, cell source origin may be pivotal to iPSC generation since residual epigenetic memory could influence the iPSC phenotype and transplantation outcome. In this paper, we first review the impact of reprogramming methods and the choice of the tissue of origin on the epigenetic memory of the iPSCs or their differentiated cells. Next, we describe the importance of induction methods to determine the reprogramming efficiency and avoid integration in the host genome that could alter gene expression. Finally, we compare the significance of the tissue of origin and the inter-individual genetic variation modification that has been lightly evaluated so far, but which significantly impacts reprogramming.
Assuntos
Reprogramação Celular , Epigênese Genética , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Animais , Metilação de DNA , HumanosRESUMO
Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.
RESUMO
S-adenosylmethionine supplies methyl groups to many acceptors, including lipids, proteins, RNA, DNA, and a wide range of small molecules. It acts as the precursor in the biosynthesis of metal ion chelating compounds, such as nicotianamine and phytosiderophores, of the polyamines spermidine and spermine and of some plant hormones. Finally, it is the source of catalytic 5'-deoxyadenosyl radicals. Radical S-adenosylmethionine (SAM) enzymes (RS) represent one of the most abundant groups (more than 100,000) of enzymes, exerting a plethora of biological functions, some of which are still unknown. In this work, we will focus on two RS: CDK5RAP1 and CDKAL1, both of which are involved in tRNA modifications that result in important tRNA folding and stability and in maintaining high translational fidelity. Based on this crucial role, their impairment can be important in the development of different human diseases.
Assuntos
Proteínas , S-Adenosilmetionina , Humanos , RNA de Transferência/genética , S-Adenosilmetionina/metabolismoRESUMO
Almost no neurological disease exists without microglial activation. Microglia has exert a pivotal role in the maintenance of the central nervous system and its response to external and internal insults. Microglia have traditionally been classified as, in the healthy central nervous system, "resting", with branched morphology system and, as a response to disease, "activated", with amoeboid morphology; as a response to diseases but this distinction is now outmoded. The most devastating disease that hits the brain is cancer, in particular glioblastoma. Glioblastoma multiforme is the most aggressive glioma with high invasiveness and little chance of being surgically removed. During tumor onset, many brain alterations are present and microglia have a major role because the tumor itself changes microglia from the pro-inflammatory state to the anti-inflammatory and protects the tumor from an immune intervention. What are the determinants of these changes in the behavior of the microglia? In this review, we survey and discuss the role of sphingolipids in microglia activation in the progression of brain tumors, with a particular focus on glioblastoma.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Encéfalo , Humanos , Macrófagos , Microglia , EsfingolipídeosRESUMO
Spinal Muscular Atrophy (SMA) is a neurodegenerative disease characterized by specific and predominantly lower motor neuron (MN) loss. SMA is the main reason for infant death, while about one in 40 children born is a healthy carrier. SMA is caused by decreased levels of production of a ubiquitously expressed gene: the survival motor neuron (SMN). All SMA patients present mutations of the telomeric SMN1 gene, but many copies of a centromeric, partially functional paralog gene, SMN2, can somewhat compensate for the SMN1 deficiency, scaling inversely with phenotypic harshness. Because the study of neural tissue in and from patients presents too many challenges and is very often not feasible; the use of animal models, such as the mouse, had a pivotal impact in our understanding of SMA pathology but could not portray totally satisfactorily the elaborate regulatory mechanisms that are present in higher animals, particularly in humans. And while recent therapeutic achievements have been substantial, especially for very young infants, some issues should be considered for the treatment of older patients. An alternative way to study SMA, and other neurological pathologies, is the use of induced pluripotent stem cells (iPSCs) derived from patients. In this work, we will present a wide analysis of the uses of iPSCs in SMA pathology, starting from basic science to their possible roles as therapeutic tools.
Assuntos
Diferenciação Celular , Modelos Animais de Doenças , Células-Tronco Pluripotentes Induzidas/citologia , Atrofia Muscular Espinal/terapia , Transplante de Células-Tronco/métodos , Animais , Humanos , Atrofia Muscular Espinal/patologiaRESUMO
Until a few years ago, the majority of cell functions were envisioned as the result of protein and DNA activity. The cell membranes were considered as a mere structure of support and/or separation. In the last years, the function of cell membranes has, however, received more attention and their components of lipid nature have also been depicted as important cell mediators and the membrane organization was described as an important determinant for membrane-anchored proteins activity. In particular, because of their high diversity, glycosphingolipids offer a wide possibility of regulation. Specifically, the role of glycosphingolipids, in the fine-tuning of neuron activity, has recently received deep attention. For their pivotal role in vertebrate and mammals neural development, neural stem cells regulation is of main interest especially concerning their further functions in neurological pathology progression and treatment. Glycosphingolipids expression present a developmental regulation. In this view, glycosphingolipids can hold an important role in neural stem cells features because of their heterogeneity and their consequent capacity for eclectic interaction with other cell components.
Assuntos
Glicoesfingolipídeos/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Receptor Cross-Talk/fisiologia , Animais , Membrana Celular/metabolismo , HumanosRESUMO
Cornelia de Lange syndrome (CdLS), which is reported to affect â¼1 in 10 000 to 30 000 newborns, is a multisystem organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition. CdLS can result from mutations in at least five genes: nipped-B-like protein, structural maintenance of chromosomes 1A, structural maintenance of chromosomes 3, RAD21 cohesin complex component and histone deacetylase 8 (HDAC8). It is believed that mutations in these genes cause CdLS by impairing the function of the cohesin complex (to which all the aforementioned genes contribute to the structure or function), disrupting gene regulation during critical stages of early development. Since intellectual disorder might result from alterations in neural development, in this work, we studied the role of Hdac8 gene in mouse neural stem cells (NSCs) and in vertebrate (Danio rerio) brain development by knockdown and chemical inhibition experiments. Underlying features of Hdac8 deficiency is an increased cell death in the developing neural tissues, either in mouse NSCs or in zebrafish embryos.
Assuntos
Proteínas de Ciclo Celular/fisiologia , Proteínas Cromossômicas não Histona/fisiologia , Síndrome de Cornélia de Lange/genética , Histona Desacetilases/genética , Animais , Proteínas de Ciclo Celular/genética , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/fisiopatologia , Regulação da Expressão Gênica/genética , Histona Desacetilases/metabolismo , Histona Desacetilases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia , Fenótipo , Proteínas Repressoras/genética , Peixe-Zebra , Proteínas de Peixe-Zebra , CoesinasRESUMO
Both astronauts and patients affected by chronic movement-limiting pathologies face impairment in muscle and/or brain performance. Increased patient survival expectations and the expected longer stays in space by astronauts may result in prolonged motor deprivation and consequent pathological effects. Severe movement limitation can influence not only the motor and metabolic systems but also the nervous system, altering neurogenesis and the interaction between motoneurons and muscle cells. Little information is yet available about the effect of prolonged muscle disuse on neural stem cells characteristics. Our in vitro study aims to fill this gap by focusing on the biological and molecular properties of neural stem cells (NSCs). Our analysis shows that NSCs derived from the SVZ of HU mice had shown a reduced proliferation capability and an altered cell cycle. Furthermore, NSCs obtained from HU animals present an incomplete differentiation/maturation. The overall results support the existence of a link between reduction of exercise and muscle disuse and metabolism in the brain and thus represent valuable new information that could clarify how circumstances such as the absence of load and the lack of movement that occurs in people with some neurological diseases, may affect the properties of NSCs and contribute to the negative manifestations of these conditions.
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Our aim was to use quantitative and qualitative analyses to gain further insight into the role of ceramide in cystic fibrosis (CF). Sphingolipid ceramide is a known inflammatory mediator, and its accumulation in inflamed lung has been reported in different types of emphysema, chronic obstructive pulmonary disease and CF. CF is caused by a mutation of the chloride channel and associated with hyperinflammation of the respiratory airways and high susceptibility to ongoing infections. We have previously demonstrated that de novo ceramide synthesis is enhanced in lung inflammation and sustains Pseudomonas aeruginosa pulmonary infection in a CF murine model. We used liquid chromatography and matrix-assisted laser desorption/ionization (MALDI) imaging coupled with mass spectrometry, confocal laser scan microscopy and histology analyses to reveal otherwise undecipherable information. We demonstrated that (i) upregulated ceramide synthesis in the alveoli is strictly related to alveolar infection and inflammation, (ii) alveolar ceramide (C16) can be specifically targeted by nanocarrier delivery of the ceramide synthesis inhibitor myriocin (Myr) and (iii) Myr is able to downmodulate pro-inflammatory lyso-PC, favouring an increase in anti-inflammatory PCs. We concluded that Myr modulates alveolar lipids milieu, reducing hyperinflammation and favouring anti-microbial effective response in CF mouse model.
Assuntos
Ceramidas/metabolismo , Fibrose Cística/metabolismo , Ácidos Graxos Monoinsaturados/farmacologia , Pulmão/efeitos dos fármacos , Infecções por Pseudomonas/metabolismo , Infecções Respiratórias/metabolismo , Animais , Fibrose Cística/microbiologia , Fibrose Cística/patologia , Ácidos Graxos Monoinsaturados/administração & dosagem , Feminino , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Knockout , Nanopartículas/administração & dosagem , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/isolamento & purificação , Infecções Respiratórias/microbiologia , Infecções Respiratórias/patologiaRESUMO
The saying "mens sana in corpore sano" has a particular resonance these days because, for the majority who have a very sedentary occupation, the everyday rhythms of life do not compel us to do much physical exercise. Recently published data indicate that exercise can counteract the effects of neurological diseases such as Alzheimer's disease and have prompted research on the beneficial effects of movement on the brain and brain neurogenesis. This might lead us to hypothesize that the absence or reduction of movements, especially those with antigravity effects, could induce a deterioration of the brain. This Review discusses current knowledge of the relationship between neurogenic capacity and the lack of motor activity in human and animal models.
Assuntos
Encéfalo/fisiologia , Atividade Motora/fisiologia , Neurogênese/fisiologia , Animais , HumanosRESUMO
Neurological diseases afflict a growing proportion of the human population. There are two reasons for this: first, the average age of the population (especially in the industrialized world) is increasing, and second, the diagnostic tools to detect these pathologies are now more sophisticated and can be used on a higher percentage of the population. In many cases, neurological disease has a pharmacological treatment which, as in the case of Alzheimer's disease, Parkinson's disease, Epilepsy, and Multiple Sclerosis can reduce the symptoms and slow down the course of the disease but cannot reverse its effects or heal the patient. In the last two decades the transplantation approach, by means of stem cells of different origin, has been suggested for the treatment of neurological diseases. The choice of slightly different animal models and the differences in methods of stem cell preparation make it difficult to compare the results of transplantation experiments. Moreover, the translation of these results into clinical trials with human subjects is difficult and has so far met with little success. This review seeks to discuss the reasons for these difficulties by considering the differences between human and animal cells (including isolation, handling and transplantation) and between the human disease model and the animal disease model.
RESUMO
Spinal cord injury presents a significant therapeutic challenge since the treatments available are mostly vain. The use of stem cells to treat this condition represents a promising new therapeutic strategy; therefore, a variety of stem cell treatments have been recently examined in animal models of CNS trauma. In this work, we analyzed the effects of third trimester amniotic fluid cells in a mouse model of spinal cord injury. Among the different cultures used for transplantation, some were able to induce a significant improvement in motor recovery (cultures #3.5, #3.6 and #7.30), evaluated by means of open field free locomotion. All effective cell cultures expressed the surface marker nerve/glial antigen 2, ortholog of the human chondroitin sulfate proteoglycan 4, which is present on several types of immature progenitor cells. The improved motor functional recovery was correlated with higher myelin preservation in the ventral horn white matter and an increased vascularization in the peri-lesion area. Real-Time PCR analysis showed higher expression levels of vascular endothelial growth factor and hypoxia-inducible factor-1α mRNA two days after cells transplantation compared to PBS-treated animals, indicating that an angiogenic pathway might have been activated by these cells, possibly through the production of hepatocyte growth factor. This cytokine appears to be produced mostly in filtering organs, such as the lung, of the transplanted animals and is likely released in the blood suggesting an endocrine role of hepatocyte growth factor in targeting the injury site.
Assuntos
Líquido Amniótico/citologia , Células-Tronco Pluripotentes/transplante , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia , Medula Espinal/patologia , Transplante de Células-Tronco/métodos , Proteínas Angiogênicas/genética , Animais , Antígenos/metabolismo , Biomarcadores/metabolismo , Modelos Animais de Doenças , Feminino , Fator de Crescimento de Hepatócito/sangue , Fator de Crescimento de Hepatócito/genética , Humanos , Pulmão/citologia , Masculino , Camundongos , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Gravidez , Terceiro Trimestre da Gravidez , Proteoglicanas/metabolismo , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/irrigação sanguínea , Resultado do TratamentoRESUMO
Understanding the events that are responsible for a disease is mandatory for setting up a therapeutic strategy. Although spinal muscular atrophy (SMA) is considered a rare neurodegenerative pathology, its impact in our society is really devastating as it strikes young people from birth onward, and it affects their families either emotionally or financially. Moreover, it requires intensive care for the children, and this diverts both parents and relatives from their occupations. Each neuron is very different from one another; therefore, in a neurodegenerative disease, the population of axons, synapses and cell bodies degenerate asynchronously, and subpopulations of neurons have different vulnerabilities. The knowledge of the sequence of events along the lengths of individual neurons is crucial to understand if each synapse degenerates before the corresponding axon, or if each axon degenerates before the corresponding cell body. Early degeneration of one neuronal compartment in disease often reflects molecular defects somewhere else. Up until now, SMA is considered mostly a lower motor neuron disease caused by the loss-of-function mutations in the SMN1 gene; here, we inspect other features that can be altered by this defect, such as the cross talk between muscle and motor neuron and the role of physical inactivity.
Assuntos
Atrofias Musculares Espinais da Infância/etiologia , Humanos , Neurônios Motores/metabolismo , Neurônios/metabolismo , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/genéticaRESUMO
PURPOSE: Our aim was the search for new sources of cells potentially useful for central nervous system regenerative medicine. Extra-embryonic tissues are promising sources of pluripotent stem cells. Among these, human second-trimester amniotic fluid (AF) contains cell populations exhibiting self-renewal capacity, multipotency and the expression of embryonic cell markers. METHODS: Here we report the properties of the easily available third-trimester AF cells (AFCs). Different cell types from 6 of 9 AF samples were separated, expanded, and characterized by assessing their morphological, proliferative, and differentiative properties. RESULTS: All isolated cultures presented CD105, CD90 and CD73 mesenchymal markers, whereas they differed among themselves in CD117, CD146, CD31, NG2 and CD133 expression. Their doubling time and telomere length were conserved throughout many passages. Importantly, immunofluorescence and Real-time PCR showed that, during their proliferative state and differentiation, several cultures expressed neuronal and glial markers such as nestin, GFAP, ß-tubulin III and neurofilament H indicating their potential attitude towards a neural fate. Indeed, these cells showed a rather poor capacity to differentiate in adipogenic and osteogenic lineages. CONCLUSIONS: In this work we report that cells with neural differentiation capability can be isolated from third-trimester AF, such properties could be useful for neuro-regenerative purposes.