1,720,969 research outputs found
TRANSPLANTATION OF A SPECIFIC NEURAL STEM CELL SUBPOPULATION AS A THERAPEUTIC APPROACH FOR AMYOTROPHIC LATERAL SCLEROSIS
Get PDFAmyotrophic Lateral Sclerosis (ALS) is a fatal neuromuscular disorder caused by degeneration of motor neurons (MNs) in the spinal cord, brainstem, and cortex. It belongs to a group of heterogeneous disorders called “motor neuron diseases”, in which ALS is the most common form in adults. The progressive MN degeneration leads to a gradual muscle atrophy and paralysis. Patients affected by ALS usually die 3-5 years after the onset of symptoms due to respiratory failure. Up to now, no effective cure is available for ALS beyond supportive care and Riluzole, which only modestly prolongs Survival. In the early stage of the disease, MN loss and consequent muscle denervation are compensated by axonal sprouting and reinnervation by the remaining MNs, but this mechanism is insufficient in the long term. Thanks to their multiple beneficial mechanisms, stem cell transplantation represents a promising therapeutic strategy for ALS and other neurodegenerative disorders. In fact, transplanted stem cells can provide therapeutic effect by modulating the micro-environment through the production of neurotrophic factors, eliminating toxic molecules, reducing neuroinflammation and generating auxiliary neural networks. Moreover, stem cells can eventually replace degenerating cells. A novel source for stem cell transplantation consists in the reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs). Since iPSCs are directly derived from adult tissues, they bypass ethical issue of the embryo manipulation and are patient-specific, potentially reproducing ALS features in vitro. This means that they are a promising tool for stem cells transplantation and to model human pathologies in vitro.
In this study, we isolated a specific subpopulation of neural stem cells (NSCs) derived from differentiated iPSCs. Compared to other types of stem cell, NSCs are particularly appropriate for ALS treatment due to their peculiar ability to differentiate into neurons, astrocytes and oligodendrocytes.
The rationale of this study consists in the selection of a subpopulation of NSCs able to engraft and migrate through the nervous system parenchyma, to protect degenerating MNs and to improve ALS phenotype. We selected NSCs for the presence of three markers: Lewis X (or LeX), CXCR4 e β1 integrin. Lewis X is a glycoprotein marker of stem cells with a relevant role in cell adhesion and migration. CXCR4 is a chemokine receptor, which increases the sensitivity of the cells to be recruited by the host spinal cord that produces chemoattractant cytokines. β1 integrin is a subunit of VLA4, a receptor that allows cells to cross the blood-brain barrier, particularly in the presence of inflammation as in ALS animal models and human patients. In order to evaluate the ability of LeX+CXCR4+β1+ NSCs to engraft into the nervous system and to improve ALS phenotype, we performed intrathecal injection of these cells in the SOD1G93A mouse model.
Transplantation resulted in an efficient engraftment of the cells, which reached central nervous system bypassing blood brain barrier, and in the protection of MNs and their axons from degeneration.
This determined a preservation of neuromuscular junction (NMJ) innervations by maintaining their integrity and inducing axonal sprouting. These beneficial effects on neuropathological phenotype correlated with a significant increased survival and improved neuromuscular function of transplanted SOD1G93A mice.
We also demonstrated the beneficial effects of LeX+CXCR4+β1+ NSCs in a human in vitro model of ALS. When co-cultured with these cells, iPSC-derived MNs from ALS patients showed an improvement in terms of survival and axonal growth. We then analyzed the molecular mechanisms underlying NSC protection demonstrating that our NSC subpopulation exerted positive effects through neurotrophic factors production, inhibition of the GSK3β activity, and limiting astrocytes proliferation through activation of vanilloid receptor.
The results of this study suggest that effective protection of MNs and NMJs can be achieved targeting multiple deregulated cellular and molecular mechanisms in both MNs and glial cells in ALS models. This is particularly relevant for ALS because different pathological mechanisms likely contribute to its onset, making NSC transplantation a promising therapeutic approach for ALS
Induced neural stem cells: methods of reprogramming and potential therapeutic applications
No full textDevelopmental studies and experimental data have enabled us to assert that the terminal cell differentiation state is reversible, and that altering the balance of specific transcription factors could be a powerful strategy for inducing pluripotency. Due to the risks related to using induced pluripotent cells in clinical applications, biologists are now striving to develop methods to induce a committed differentiated cell type by direct conversion of another cell line. Several reprogramming factors have been discovered, and some cellular phenotypes have been obtained by novel transdifferentiation processes. It has been recently demonstrated that induced neural stem cells (iNSCs) can be obtained from rodent and human somatic cells, like fibroblasts, through the forced expression of defined transcription factors. To date, two different approaches have been successfully used to obtain iNSCs: a direct method and an indirect method that involves an intermediate destabilized state. The possibility to induce characterized iNSCs from human cells, e.g. fibroblasts, has opened new horizons for research in human disease modelling and cellular therapeutic applications in the neurological field. This review focuses on reported reprogramming techniques and innovative techniques that can be further explored in this area, as well as on the criteria for the phenotypic characterization of iNSCs and their use in developing novel therapeutic strategies for neurological diseases
iPSC-derived LewisX+CXCR4+β1-integrin+ neural stem cells improve the amyotrophic lateral sclerosis phenotype by preserving motor neurons and muscle innervation in human and rodent models
No full textAmyotrophic lateral sclerosis (ALS) is a fatal incurable neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs), leading to relentless muscle paralysis. In the early stage of the disease, MN loss and consequent muscle denervation are compensated by axonal sprouting and reinnervation by the remaining MNs, but this mechanism is insufficient in the long term. Here, we demonstrate that induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs), in particular the subpopulation positive for LewisX-CXCR4-β1-integrin, enhance neuronal survival and axonal growth of human ALS-derived MNs co-cultured with toxic ALS astrocytes, acting on both autonomous and non-autonomous ALS disease features. Transplantation of this NSC fraction into transgenic SOD1G93A ALS mice protects MNs in vivo, promoting their ability to maintain neuromuscular junction integrity, inducing novel axonal sprouting and reducing macro- and microgliosis. These effects result in a significant increase in survival and an improved neuromuscular phenotype in transplanted SOD1G93A mice. Our findings suggest that effective protection of MN functional innervation can be achieved by modulation of multiple dysregulated cellular and molecular pathways in both MNs and glial cells. These pathways must be considered in designing therapeutic strategies for ALS patients
Therapeutic Development in Amyotrophic Lateral Sclerosis
No full textPurpose Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. It is almost invariably lethal within a few years after the onset of symptoms. No effective treatment is currently available beyond supportive care and riluzole, a putative glutamate release blocker linked to modestly prolonged survival. This review provides a general overview of preclinical and clinical advances during recent years and summarizes the literature regarding emerging therapeutic approaches, focusing on their molecular targets. Methods A systematic literature review of PubMed was performed, identifying key clinical trials involving molecular therapies for ALS. In addition, the ALS Therapy Development Institute website was carefully analyzed, and a selection of ALS clinical trials registered at ClinicalTrials.gov has been included. Findings In the last several years, strategies have been developed to understand both the genetic and molecular mechanisms of ALS. Several therapeutic targets have been actively pursued, including kinases, inflammation inhibitors, silencing of key genes, and modulation or replacement of specific cell populations. The majority of ongoing clinical trials are investigating the safety profiles and tolerability of pharmacologic, gene, and cellular therapies, and have begun to assess their effects on ALS progression. Implications Currently, no therapeutic effort seems to be efficient, but recent findings in ALS could help accelerate the discovery of an effective treatment for this disease
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?
Get PDFSpinal muscular atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the survival motor neuron 1 gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. Even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches
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