Understanding the Molecular Basis of Cell Migration; Implications for Clinical Therapy in Multiple Sclerosis

1997 ◽  
Vol 92 (2) ◽  
pp. 113-122 ◽  
Author(s):  
Richard Milner
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Cell Migration ◽  
Molecular Mechanisms ◽  
Autoimmune Response ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Oligodendrocyte Precursors

1. Multiple sclerosis is characterized by areas of demyelination spread throughout the central nervous system, in which the myelin sheaths surrounding axons are destroyed. While therapies aimed at suppressing the autoimmune response, such as β-interferon, may prevent further damage, they cannot repair or replace the lost myelin. To this end, an additional therapy has been proposed, which involves transplanting cells of the oligodendrocyte lineage into the central nervous system. 2. The cell of interest for transplantation is the oligodendrocyte precursor because, unlike the differentiated cell, it is an intrinsically migratory and proliferative cell. In order to optimize the transplant strategy we have investigated the molecular mechanisms that control migration in vitro, so that these mechanisms might be upregulated to maximize cell migration in vivo. We have focused on the integrin family of cell adhesion molecules, known to play a fundamental role in the regulation of migration in other cell types. 3. These studies show that oligodendrocytes express a limited repertoire of integrins consisting of α6β1 and three different αv integrins. α6β1 is expressed throughout development but αv integrins show developmental regulation; differentiation is accompanied by loss of αvβ1 and upregulation of αvβ5. 4. Function-blocking studies show that oligodendrocyte precursor migration in vitro is mediated primarily by the developmentally regulated αvβ1 integrin, but not α6β1 or αvβ3. Taken together with previous evidence that cell migration can be regulated by altering integrin expression, this work suggests that modifying expression levels of αvβ1 on oligodendrocyte precursors may increase the migratory capacity of these cells. If so, this would support a future therapeutic strategy aimed at transplanting genetically modified oligodendrocyte precursors to repair widespread demyelinated lesions.

scholarly journals Novel in vitro Experimental Approaches to Study Myelination and Remyelination in the Central Nervous System

2021 ◽  
Vol 15 ◽  
Author(s):  
Davide Marangon ◽  
Nicolò Caporale ◽  
Marta Boccazzi ◽  
Maria P. Abbracchio ◽  
Giuseppe Testa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mechanisms ◽  
Disease Modeling ◽  
Brain Physiology ◽  
Pathological Conditions ◽  
Approaches To Study ◽  
The Central Nervous System ◽  
Experimental Approaches

Myelin is the lipidic insulating structure enwrapping axons and allowing fast saltatory nerve conduction. In the central nervous system, myelin sheath is the result of the complex packaging of multilamellar extensions of oligodendrocyte (OL) membranes. Before reaching myelinating capabilities, OLs undergo a very precise program of differentiation and maturation that starts from OL precursor cells (OPCs). In the last 20 years, the biology of OPCs and their behavior under pathological conditions have been studied through several experimental models. When co-cultured with neurons, OPCs undergo terminal maturation and produce myelin tracts around axons, allowing to investigate myelination in response to exogenous stimuli in a very simple in vitro system. On the other hand, in vivo models more closely reproducing some of the features of human pathophysiology enabled to assess the consequences of demyelination and the molecular mechanisms of remyelination, and they are often used to validate the effect of pharmacological agents. However, they are very complex, and not suitable for large scale drug discovery screening. Recent advances in cell reprogramming, biophysics and bioengineering have allowed impressive improvements in the methodological approaches to study brain physiology and myelination. Rat and mouse OPCs can be replaced by human OPCs obtained by induced pluripotent stem cells (iPSCs) derived from healthy or diseased individuals, thus offering unprecedented possibilities for personalized disease modeling and treatment. OPCs and neural cells can be also artificially assembled, using 3D-printed culture chambers and biomaterial scaffolds, which allow modeling cell-to-cell interactions in a highly controlled manner. Interestingly, scaffold stiffness can be adopted to reproduce the mechanosensory properties assumed by tissues in physiological or pathological conditions. Moreover, the recent development of iPSC-derived 3D brain cultures, called organoids, has made it possible to study key aspects of embryonic brain development, such as neuronal differentiation, maturation and network formation in temporal dynamics that are inaccessible to traditional in vitro cultures. Despite the huge potential of organoids, their application to myelination studies is still in its infancy. In this review, we shall summarize the novel most relevant experimental approaches and their implications for the identification of remyelinating agents for human diseases such as multiple sclerosis.

scholarly journals Investigating the effects of novel heparan sulfate mimetic 'HS16-35' on immune cell migration in an in vitro model of the blood-CSF barrier.

2021 ◽  
Author(s):  
◽  
Maddie Griffiths
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Heparan Sulfate ◽  
Choroid Plexus ◽  
Immune Cells ◽  
Low Dose ◽  
Interferon Γ ◽  
The Central Nervous System

<p><b>The central nervous system was traditionally considered an immune-privileged site, defined as being immunologically inactive. However, recent studies have elucidated that a number of immune cells traffic into and out of the brain in healthy humans to conduct routine immunosurveillance. A unique immunological interface, the choroid plexus, acts as a gatekeeper for the entry of these immune cells during homeostasis. Although the mechanisms are not well described, the choroid plexus also has the capacity to regulate the responses of migrating leukocytes during inflammation.</b></p> <p>Multiple sclerosis is a complex neuroinflammatory disease characterized by demyelination in the CNS. Autoreactive immune cells invade the central nervous system and orchestrate an attack against myelin sheathes, the insulation layer that protects neurons. The disease affects nearly 1 in 1,000 New Zealanders, and currently has no cure. The most successful treatments for multiple sclerosis target the initial stages by inhibiting the entry of these cells into the central nervous system, however these are often associated with severe side and life-threatening effects and cannot prevent the progression of the disease.</p> <p>Heparanase, the ubiquitously expresses heparan sulfate degrading enzyme has been thoroughly implicated in the disease processes of multiple sclerosis, and its animal model, EAE. Autoreactive lymphocytes exploit heparanase activity to degrade the extracellular matrix and destabilize the barriers that maintain the relative immune privileged status of the central nervous system. Exogenous heparan sulfate mimetics have previously been shown to ameliorate symptoms of EAE by interfering with heparanase activity. However, the commercialization and clinical translation of these inhibitors is currently inhibited by the complexity of their synthesis. ‘HS16-35’ is a novel heparan sulfate mimetic developed by the Ferrier Institute, comprised of a dendritic core with four heavily sulfated oligosaccharide arms. The synthesis of this compound is much shorter due to its smaller size; however, it has been shown to act similarly to native heparan sulfate molecules. We proposed that HS16-35 is protective in preventing the migration of autoreactive immune cells across the choroid plexus by inhibiting lymphocyte heparanase.</p> <p>To investigate the efficacy of HS16-35 in vitro, we first established an experimental transwell model of the choroid plexus. This model incorporated core components of the choroid plexus, including fenestrated capillaries, the stromal matrix and epithelial monolayer. We first showed that the model was capable of mimicking homeostatic trafficking across the choroid plexus epithelium, which formed a selective but permeable barrier. Then, we induced T-cell specific inflammatory migration using Concanavalin A or TH1-type cytokines. This migration was found to be interferon-γ dependent and could be mitigated with anti-interferon-γ treatment.</p> <p>Once this model was established, we next investigated whether HS16-35 was effective in inhibiting inflammatory migration across this structure. To adapt HS16-35 to an in vitro dose, we performed cell viability assays. This confirmed that the compound was mildly cytotoxic to epithelial choroid plexus cells but not murine splenocytes. Further experiments found that low-dose HS16-35 did not impact monolayer permeability. Transwell migration assays showed that low-dose HS16-35 was effective in reducing ConA and interferon-γ mediated inflammatory T-cell migration to a level comparable to homeostatic trafficking. Finally, we assessed cytokine profiles of leukocytes and epithelial choroid plexus cells treated with HS16 35 and found that HS16-35 reduced the expression of key cytokines involved in MS pathogenesis.</p> <p>In summary, the work described in this thesis shows how HS16-35 may be protective during EAE by suppressing the inflammatory response of autoreactive T-cells, in addition to regulating the infiltration of immune cells into the CNS through the choroid plexus. In a broader sense, these findings show that HS16 36 may be effective in treating MS by regulating, not inhibiting lymphocyte migration into the CNS, mitigating some of the severe side effects that other migration-inhibitors face.</p>

scholarly journals Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

2020 ◽  
Vol 21 (12) ◽  
pp. 4229 ◽  
Author(s):  
Kim M. A. De Kleijn ◽  
Gerard J. M. Martens
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Glial Cells ◽  
Molecular Mechanisms ◽  
Dimethyl Fumarate ◽  
Cell Types ◽  
The Central Nervous System ◽  
Molecular Effects ◽  
Approved Drugs

Multiple sclerosis (MS) is characterized by peripheral and central inflammatory features, as well as demyelination and neurodegeneration. The available Food and Drug Administration (FDA)-approved drugs for MS have been designed to suppress the peripheral immune system. In addition, however, the effects of these drugs may be partially attributed to their influence on glial cells and neurons of the central nervous system (CNS). We here describe the molecular effects of the traditional and more recent FDA-approved MS drugs Fingolimod, Dimethyl Fumarate, Glatiramer Acetate, Interferon-β, Teriflunomide, Laquinimod, Natalizumab, Alemtuzumab and Ocrelizumab on microglia, astrocytes, neurons and oligodendrocytes. Furthermore, we point to a possible common molecular effect of these drugs, namely a key role for NFκB signaling, causing a switch from pro-inflammatory microglia and astrocytes to anti-inflammatory phenotypes of these CNS cell types that recently emerged as central players in MS pathogenesis. This notion argues for the need to further explore the molecular mechanisms underlying MS drug action.

scholarly journals Recurrent natalizumab-related aseptic meningitis in a patient with multiple sclerosis

2017 ◽  
Vol 23 (10) ◽  
pp. 1424-1427 ◽  
Author(s):  
Robert W Foley ◽  
Nathan T Tagg ◽  
Matthew K Schindler ◽  
Kaylan M Fenton ◽  
Daniel S Reich ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Monoclonal Antibody ◽  
Nervous System ◽  
Cell Migration ◽  
Aseptic Meningitis ◽  
Cns Infection ◽  
T Cell Migration ◽  
Humanized Monoclonal Antibody ◽  
The Central Nervous System

Natalizumab is a recombinant humanized monoclonal antibody that decreases T-cell migration into the central nervous system (CNS) through α4 integrin:adhesion-molecule inhibition, thereby increasing the risk for opportunistic CNS infection. Herein, we report a case of infusion-associated aseptic meningitis in a patient receiving natalizumab.

scholarly journals Investigating the effects of novel heparan sulfate mimetic 'HS16-35' on immune cell migration in an in vitro model of the blood-CSF barrier.

2021 ◽  
Author(s):  
◽  
Maddie Griffiths
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Heparan Sulfate ◽  
Choroid Plexus ◽  
Immune Cells ◽  
Low Dose ◽  
Interferon Γ ◽  
The Central Nervous System

<p><b>The central nervous system was traditionally considered an immune-privileged site, defined as being immunologically inactive. However, recent studies have elucidated that a number of immune cells traffic into and out of the brain in healthy humans to conduct routine immunosurveillance. A unique immunological interface, the choroid plexus, acts as a gatekeeper for the entry of these immune cells during homeostasis. Although the mechanisms are not well described, the choroid plexus also has the capacity to regulate the responses of migrating leukocytes during inflammation.</b></p> <p>Multiple sclerosis is a complex neuroinflammatory disease characterized by demyelination in the CNS. Autoreactive immune cells invade the central nervous system and orchestrate an attack against myelin sheathes, the insulation layer that protects neurons. The disease affects nearly 1 in 1,000 New Zealanders, and currently has no cure. The most successful treatments for multiple sclerosis target the initial stages by inhibiting the entry of these cells into the central nervous system, however these are often associated with severe side and life-threatening effects and cannot prevent the progression of the disease.</p> <p>Heparanase, the ubiquitously expresses heparan sulfate degrading enzyme has been thoroughly implicated in the disease processes of multiple sclerosis, and its animal model, EAE. Autoreactive lymphocytes exploit heparanase activity to degrade the extracellular matrix and destabilize the barriers that maintain the relative immune privileged status of the central nervous system. Exogenous heparan sulfate mimetics have previously been shown to ameliorate symptoms of EAE by interfering with heparanase activity. However, the commercialization and clinical translation of these inhibitors is currently inhibited by the complexity of their synthesis. ‘HS16-35’ is a novel heparan sulfate mimetic developed by the Ferrier Institute, comprised of a dendritic core with four heavily sulfated oligosaccharide arms. The synthesis of this compound is much shorter due to its smaller size; however, it has been shown to act similarly to native heparan sulfate molecules. We proposed that HS16-35 is protective in preventing the migration of autoreactive immune cells across the choroid plexus by inhibiting lymphocyte heparanase.</p> <p>To investigate the efficacy of HS16-35 in vitro, we first established an experimental transwell model of the choroid plexus. This model incorporated core components of the choroid plexus, including fenestrated capillaries, the stromal matrix and epithelial monolayer. We first showed that the model was capable of mimicking homeostatic trafficking across the choroid plexus epithelium, which formed a selective but permeable barrier. Then, we induced T-cell specific inflammatory migration using Concanavalin A or TH1-type cytokines. This migration was found to be interferon-γ dependent and could be mitigated with anti-interferon-γ treatment.</p> <p>Once this model was established, we next investigated whether HS16-35 was effective in inhibiting inflammatory migration across this structure. To adapt HS16-35 to an in vitro dose, we performed cell viability assays. This confirmed that the compound was mildly cytotoxic to epithelial choroid plexus cells but not murine splenocytes. Further experiments found that low-dose HS16-35 did not impact monolayer permeability. Transwell migration assays showed that low-dose HS16-35 was effective in reducing ConA and interferon-γ mediated inflammatory T-cell migration to a level comparable to homeostatic trafficking. Finally, we assessed cytokine profiles of leukocytes and epithelial choroid plexus cells treated with HS16 35 and found that HS16-35 reduced the expression of key cytokines involved in MS pathogenesis.</p> <p>In summary, the work described in this thesis shows how HS16-35 may be protective during EAE by suppressing the inflammatory response of autoreactive T-cells, in addition to regulating the infiltration of immune cells into the CNS through the choroid plexus. In a broader sense, these findings show that HS16 36 may be effective in treating MS by regulating, not inhibiting lymphocyte migration into the CNS, mitigating some of the severe side effects that other migration-inhibitors face.</p>

Neural Stem Cells to Glial Cells an Important Factor for Brain Injury

2020 ◽  
Author(s):  
Prithiv K R Kumar
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Neural Stem Cells ◽  
Glial Cells ◽  
Brain Injuries ◽  
The Body ◽  
The Central Nervous System ◽  
Near Future

Stem cells have the capacity to differentiate into any type of cell or organ. Stems cell originate from any part of the body, including the brain. Brain cells or rather neural stem cells have the capacitive advantage of differentiating into the central nervous system leading to the formation of neurons and glial cells. Neural stem cells should have a source by editing DNA, or by mixings chemical enzymes of iPSCs. By this method, a limitless number of neuron stem cells can be obtained. Increase in supply of NSCs help in repairing glial cells which in-turn heal the central nervous system. Generally, brain injuries cause motor and sensory deficits leading to stroke. With all trials from novel therapeutic methods to enhanced rehabilitation time, the economy and quality of life is suppressed. Only PSCs have proven effective for grafting cells into NSCs. Neurons derived from stem cells is the only challenge that limits in-vitro usage in the near future.

scholarly journals Beyond Oncological Hyperthermia: Physically Drivable Magnetic Nanobubbles as Novel Multipurpose Theranostic Carriers in the Central Nervous System

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2104 ◽  
Author(s):  
Eleonora Ficiarà ◽  
Shoeb Anwar Ansari ◽  
Monica Argenziano ◽  
Luigi Cangemi ◽  
Chiara Monge ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Tumors ◽  
Ad Hoc ◽  
Superparamagnetic Iron Oxide ◽  
Conventional Radiotherapy ◽  
The Central Nervous System ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

Magnetic Oxygen-Loaded Nanobubbles (MOLNBs), manufactured by adding Superparamagnetic Iron Oxide Nanoparticles (SPIONs) on the surface of polymeric nanobubbles, are investigated as theranostic carriers for delivering oxygen and chemotherapy to brain tumors. Physicochemical and cyto-toxicological properties and in vitro internalization by human brain microvascular endothelial cells as well as the motion of MOLNBs in a static magnetic field were investigated. MOLNBs are safe oxygen-loaded vectors able to overcome the brain membranes and drivable through the Central Nervous System (CNS) to deliver their cargoes to specific sites of interest. In addition, MOLNBs are monitorable either via Magnetic Resonance Imaging (MRI) or Ultrasound (US) sonography. MOLNBs can find application in targeting brain tumors since they can enhance conventional radiotherapy and deliver chemotherapy being driven by ad hoc tailored magnetic fields under MRI and/or US monitoring.

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