Saratoga, CA, United States
Saratoga, CA, United States

Time filter

Source Type

Rafalski V.A.,Stanford University | Rafalski V.A.,University of California at San Francisco | Ho P.P.,Stanford University | Brett J.O.,Stanford University | And 11 more authors.
Nature Cell Biology | Year: 2013

Oligodendrocytes - the myelin-forming cells of the central nervous system - can be regenerated during adulthood. In adults, new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs), but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized, the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1, a protein deacetylase implicated in energy metabolism, increases the production of new OPCs in the adult mouse brain, in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally, generating fully myelinating oligodendrocytes. Remarkably, SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling, in particular PDGF receptor α (PDGFRα). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK - signalling molecules downstream of PDGFRα. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases, such as multiple sclerosis. © 2013 Macmillan Publishers Limited. All rights reserved.


News Article | December 21, 2015
Site: www.biosciencetechnology.com

Multiple sclerosis (MS) may be triggered by the death of brain cells that make the insulation around nerve fibers, a surprising new view of the disease reported in a study from Northwestern Medicine and The University of Chicago. And a specially developed nanoparticle prevented MS even after the death of those brain cells, an experiment in the study showed. The nanoparticles are being developed for clinical trials that could lead to new treatments -- without the side effects of current therapies -- in adults. MS can be initiated when damage to the brain destroys the cells that make myelin, the scientists showed. Myelin is the insulating sheath around nerve fibers that enables nerve impulses to be transmitted. The death of these cells, oligodendrocytes, can activate the autoimmune response against myelin, which is the main feature of MS. Oligodendrocytes can possibly be destroyed by developmental abnormalities, viruses, bacterial toxins or environmental pollutants. The scientists also developed the first mouse model of the progressive form of the autoimmune disease, which will enable the testing of new drugs against progressive MS. In the study, nanoparticles creating tolerance to the myelin antigen were administered and prevented progressive MS from developing. The study was published in Nature Neuroscience December 14. The lead investigators are Stephen Miller, Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine, and Brian Popko, the Jack Miller Professor of Neurological Disorders at the University of Chicago. The nanoparticle technology was developed in Miller’s lab and has been licensed to Cour Pharmaceutical Development Company, which is developing the technology for human trials in autoimmune disease. “We’re encouraged that immune tolerance induced with nanoparticles could stop disease progression in a model of chronic MS as efficiently as it can in progressive-remitting models of MS,” Miller said. The timing of therapy is important, Popko pointed out. “Protecting oligodendrocytes in susceptible individuals might help delay or prevent MS from initiating,” Popko said. “It’s likely that therapeutic strategies that intervene early in the disease process will have greater impact.” In the experiment, scientists developed a genetically engineered mouse model in which the oligodendrocytes died, affecting the animals’ ability to walk. The central nervous system regenerated the myelin-producing cells, enabling the mice to walk again. But about six months later, the MS-like disease came barreling back. This demonstrated the scientists’ theory that the death of oligodendrocytes can initiate MS. In humans, the scientists posit, the disease develops years after the initial injury to the brain. The current prevailing theory is that an event outside of the nervous system triggers MS in susceptible individuals who may have a genetic predisposition to the disease. In these individuals, the immune cells that normally fight infections confuse a component of the myelin sheath as foreign. These confused immune cells enter the brain and begin their mistaken attack on myelin, thus initiating MS. But the new study demonstrates the possibility that MS can begin from the inside out, in which damage to oligodendrocytes in the central nervous system can trigger an immune response directly. Oligodendrocytes are responsible for the maintenance of myelin. If they die, the myelin sheath falls apart. The inside-out hypothesis suggests that when myelin falls apart, the products of its degradation are presented to the immune system as foreign bodies or antigens. The immune system then erroneously views them as invaders and begins a full-scale attack on myelin, initiating MS. An estimated 400,000 people in the U.S. and 2.5 million worldwide have MS. Of those with long-standing disease, 50 to 60 percent have progressive MS. The other authors on the paper are Maria Traka of U of C, and Joseph Podojil and Derrick McCarthy of Northwestern. Miller, a founder and chief of the scientific advisory board of Cour Pharmaceutical, does not receive financial compensation from the company. The research was supported by grants from the Myelin Repair Foundation and the National Multiple Sclerosis Society.


Home > Press > Brain cell death is a possible trigger of multiple sclerosis: New study in mice finds the death of a specific class of brain cells triggers an MS-like immune response, which can be prevented by nanoparticle therapy Abstract: Multiple sclerosis (MS) may be triggered by the death of brain cells that make myelin, the insulation around nerve fibers, according to research on a novel mouse model developed by scientists from the University of Chicago and Northwestern Medicine. The death of these cells initiates an autoimmune response against myelin, the main characteristic of the disease, which leads to MS-like symptoms in mice. This reaction can be prevented, however, through the application of specially developed nanoparticles, even after the loss of those brain cells. The nanoparticles are being developed for clinical trials that could lead to new treatments in humans. The study was published in Nature Neuroscience on Dec. 14, 2015. "Although this was a study in mice, we've shown for the first time one possible mechanism that can trigger MS -- the death of the cells responsible for generating myelin can lead to the activation of an autoimmune response against myelin," said study co-senior author Brian Popko, PhD, Jack Miller Professor of Neurological Disorders at the University of Chicago. "Protecting these cells in susceptible individuals might help delay or prevent MS." Multiple sclerosis is a neurological disease involving an abnormal immune response against myelin, which leads to the progressive deterioration of a wide range of body functions. MS is thought to affect 2.5 million people worldwide, and has unclear causes and no known cure. To study how MS is triggered, Popko, with collaborator Stephen Miller, PhD, Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine, and their teams developed a genetically engineered mouse model that allowed them to target oligodendrocytes, the brain cells that produce myelin. By specifically killing oligodendrocytes, the team observed MS-like symptoms that affected the ability of the mice to walk. After this initial event, the central nervous systems of the mice regenerated their myelin-producing cells, enabling them to walk again. But about six months later, the MS-like symptoms came barreling back. "To our knowledge, this is the first evidence that oligodendrocyte death can trigger myelin autoimmunity, initiating inflammation and tissue damage in the central nervous system during MS," said study co-author Maria Traka, PhD, research associate professor in neurology at the University of Chicago. Possible causes of oligodendrocyte death are developmental abnormalities, viruses, bacterial toxins or environmental pollutants. In humans, the researchers hypothesize MS could develop years after an initial injury to the brain triggers oligodendrocyte death. The mouse model also enabled the testing of new drugs against progressive MS. In the study, nanoparticles creating tolerance to the myelin antigen were administered and prevented progressive MS from developing. The nanoparticle technology was developed in Miller's lab and has been licensed to Cour Pharmaceutical Development Company, which is developing the technology for human trials in autoimmune disease. "We're encouraged that the nanoparticles could stop disease progression in a model of chronic MS as efficiently as it can in progressive-remitting models of MS," Miller said. The timing of therapy is important, Popko pointed out. "It's likely that therapeutic strategies that intervene early in the disease process will have greater impact," he said. Inside-out The current prevailing theory is that an event outside of the nervous system triggers MS in susceptible individuals who may have a genetic predisposition to the disease. In these individuals, the immune cells that normally fight infections confuse a component of the myelin sheath as foreign. These confused immune cells enter the brain and begin their mistaken attack on myelin. But the new study demonstrates the possibility that MS can begin from the inside out, in which damage to oligodendrocytes in the central nervous system can trigger an immune response directly. Oligodendrocytes are responsible for the maintenance of myelin. If they die, the myelin sheath falls apart. The inside-out hypothesis suggests that when myelin falls apart, its components are presented to the immune system as foreign bodies or antigens. The immune system then erroneously views them as invaders and begins a full scale attack on myelin, initiating MS. "It will be exciting to determine the nature of this process in humans--its precise role in MS and whether therapies to prevent it are effective," Popko said. ### The study, 'Oligodendrocyte death results in immune-mediated CNS demyelination,' was supported by the Myelin Repair Foundation and the National Multiple Sclerosis Society. Additional authors include Joseph Podojil and Derrick McCarthy of Northwestern University. Miller, a founder and chief of the Scientific Advisory Board of Cour Pharmaceutical, does not receive financial compensation from the company. Northwestern Medicine is the shared strategic vision of Northwestern Memorial HealthCare and Northwestern University Feinberg School of Medicine to transform the future of healthcare and become one of the nation's premier destinations for patient care. Each day, 26,500 clinical and administrative staff, medical and science faculty and medical students come together with a shared commitment to superior quality, academic excellence, scientific discovery and patient safety. About University of Chicago Medical Center The University of Chicago Medicine & Biological Sciences is one of the nation's leading academic medical institutions. It comprises the Pritzker School of Medicine, a top 10 medical school in the nation; the University of Chicago Biological Sciences Division; and the University of Chicago Medical Center, which recently opened the Center for Care and Discovery, a $700 million specialty medical facility. Twelve Nobel Prize winners in physiology or medicine have been affiliated with the University of Chicago Medicine. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


Rodgers J.M.,Northwestern University | Robinson A.P.,Northwestern University | Rosler E.S.,Myelin Repair Foundation | Lariosa-Willingham K.,Myelin Repair Foundation | And 3 more authors.
GLIA | Year: 2015

Inflammatory signals present in demyelinated multiple sclerosis lesions affect the reparative remyelination process conducted by oligodendrocyte progenitor cells (OPCs). Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 have differing effects on the viability and growth of OPCs, however the effects of IL-17A are largely unknown. Primary murine OPCs were stimulated with IL-17A and their viability, proliferation, and maturation were assessed in culture. IL-17A-stimulated OPCs exited the cell cycle and differentiated with no loss in viability. Expression of the myelin-specific protein, proteolipid protein, increased in a cerebellar slice culture assay in the presence of IL-17A. Downstream, IL-17A activated ERK1/2 within 15 min and induced chemokine expression in 2 days. These results demonstrate that IL-17A exposure stimulates OPCs to mature and participate in the inflammatory response. © 2014 Wiley Periodicals, Inc.


Way S.W.,University of Chicago | Podojil J.R.,Northwestern University | Clayton B.L.,University of Chicago | Zaremba A.,Case Western Reserve University | And 7 more authors.
Nature Communications | Year: 2015

Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease. Here we demonstrate that enhancement of the integrated stress response using the FDA-approved drug guanabenz increases oligodendrocyte survival in culture and prevents hypomyelination in cerebellar explants in the presence of interferon-γ, a pro-inflammatory cytokine implicated in MS pathogenesis. In vivo, guanabenz treatment protects against oligodendrocyte loss caused by CNS-specific expression of interferon-γ. In a mouse model of MS, experimental autoimmune encephalomyelitis, guanabenz alleviates clinical symptoms, which correlates with increased oligodendrocyte survival and diminished CNS CD4+ T cell accumulation. Moreover, guanabenz ameliorates relapse in relapsing-remitting experimental autoimmune encephalomyelitis. Our results provide support for a MS therapy that enhances the integrated stress response to protect oligodendrocytes against the inflammatory CNS environment. © 2015 Macmillan Publishers Limited. All rights reserved.


Getts D.R.,Northwestern University | Martin A.J.,Northwestern University | Mccarthy D.P.,Northwestern University | Terry R.L.,Robert Bosch GmbH | And 8 more authors.
Nature Biotechnology | Year: 2012

Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide-co-glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease. These beneficial effects require microparticle uptake by marginal zone macrophages expressing the scavenger receptor MARCO and are mediated in part by the activity of regulatory T cells, abortive T-cell activation and T-cell anergy. Together these data highlight the potential for using microparticles to target natural apoptotic clearance pathways to inactivate pathogenic T cells and halt the disease process in autoimmunity. © 2012 Nature America, Inc.


Dugas J.C.,Myelin Repair Foundation | Dugas J.C.,Stanford University | Emery B.,University of Melbourne
Cold Spring Harbor Protocols | Year: 2013

This protocol describes how to purify oligodendrocyte precursor cells (OPCs) from postnatal rodent brains. The method utilizes an immunopanning technique to first remove unwanted cells by negative selection and then purify OPCs by positive selection and subsequent enzymatic release from the final panning plate. Included are modifications that allow for purification and culturing of OPCs from mouse instead of rat tissue and for use of optic nerves instead of whole brains. The method for isolating OPCs from whole brain can be used for isolating OPCs from any specific region of the brain, provided that the area can be dissected away from the rest of the tissue. Suggested culture media for maintaining proliferating OPCs or inducing oligodendrocyte (OL) differentiation are also described. © 2013 Cold Spring Harbor Laboratory Press.


Reich D.S.,U.S. National Institutes of Health | White R.,University of British Columbia | Cortese I.C.M.,U.S. National Institutes of Health | Vuolo L.,U.S. National Institutes of Health | And 3 more authors.
Multiple Sclerosis | Year: 2015

Background: New multiple sclerosis (MS) lesion activity on magnetic resonance imaging (MRI) can test immunomodulatory therapies in proof-of-concept trials. Comparably powerful endpoints to assess tissue protection or repair are lacking. Objective: The objective of this paper is to report sample-size calculations for assessment of new lesion recovery. Methods: In two sets of six active MS cases, new lesions were observed by monthly MRI for approximately 12 months. Averages and quartiles of normalized (proton density/T1/T2 weighted) and quantitative (T1/T2 and mean diffusivity maps for dataset 1, T2 and magnetization transfer ratio maps for dataset 2) measures were used to compare the lesion area before lesion appearance to afterward. A linear mixed-effects model incorporating lesion- and participant-specific random effects estimated average levels and variance components for sample-size calculations. Results: In both datasets, greatest statistical sensitivity was observed for the 25th percentile of normalized proton density-weighted signal. At 3T, using new lesions 3/415 mm3, as few as nine participants/arm may be required for a six-month placebo-controlled add-on trial postulating a therapeutic effect size of 20% and statistical power of 90%. Conclusion: Lesion recovery is a powerful outcome measure for proof-of-concept clinical trials of tissue protection and repair in MS. The trial design requires active cases and is therefore best implemented near disease onset. © SAGE Publications.


Emery B.,University of Melbourne | Dugas J.C.,Myelin Repair Foundation | Dugas J.C.,Stanford University
Cold Spring Harbor Protocols | Year: 2013

Oligodendrocytes are the myelinating cells of the vertebrate central nervous system, responsible for generating the myelin sheath necessary for saltatory conduction. The use of increasingly sophisticated genetic tools, particularly in mice, has vastly increased our understanding of the molecular mechanisms that regulate development of the oligodendrocyte lineage. This increased reliance on the mouse as a genetic model has led to a need for the development of culture methods to allow the use of mouse cells in vitro as well as in vivo. Here, we present a protocol for the isolation of different stages of the oligodendrocyte lineage, oligodendrocyte precursor cells (OPCs) and/or postmitotic oligodendrocytes, from the postnatal mouse cortex using immunopanning. This protocol allows for the subsequent culture or biochemical analysis of these cells. © 2013 Cold Spring Harbor Laboratory Press.


Dugas J.C.,Stanford University | Dugas J.C.,Myelin Repair Foundation | Emery B.,Stanford University | Emery B.,University of Melbourne
Cold Spring Harbor Protocols | Year: 2013

Oligodendrocytes are the cells of the vertebrate central nervous system responsible for forming myelin sheaths, which are essential for the rapid propagation of action potential. The formation of oligodendrocytes and myelin sheaths is tightly regulated, both temporally and spatially, by a number of extracellular and intracellular factors. For example, notch ligands, thyroid hormones, and mitogens such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) can all interact with oligodendrocyte precursor cell-expressed receptors to impact proliferation, differentiation, and myelin gene expression. To facilitate oligodendrocyte biology research, we have developed a technique using immunopanning to isolate different stages of the oligodendrocyte lineage, oligodendrocyte precursor cells and/or postmitotic oligodendrocytes, from postnatal rat or mouse brains. These cells can be cultured in defined, serum-free media in conditions that either promote differentiation into mature oligodendrocytes or continued proliferation as immature oligodendrocyte precursors. These cells represent an ideal system in which to study the regulation of oligodendrocyte proliferation, migration, differentiation, myelin gene expression, or other fundamental aspects of oligodendrocyte biology. © 2013 Cold Spring Harbor Laboratory Press.

Loading Myelin Repair Foundation collaborators
Loading Myelin Repair Foundation collaborators