DOCSLIB.ORG

Depletion of Microglia Exacerbates Injury and Impairs Function Recovery

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Depletion of Microglia Exacerbates Injury and Impairs Function Recovery Fu et al. Cell Death and Disease (2020) 11:528 https://doi.org/10.1038/s41419-020-2733-4 Cell Death & Disease ARTICLE Open Access Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice Haitao Fu1,2, Yanpeng Zhao1,DieHu3,SongWang4, Tengbo Yu2 and Licheng Zhang1 Abstract The role of microglia in spinal cord injury (SCI) remains ambiguous, partially due to the paucity of efficient methods to discriminate these resident microglia with blood-derived monocytes/macrophages. Here, we used pharmacological treatments to specifically eliminate microglia and subsequently to investigate the response of microglia after SCI in mice. We showed that treatment with colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 eliminated ~90% microglia and did not affect other cell types in mouse spinal cord. PLX3397 treatment also induced a strong decrease in microglial proliferation induced by SCI. Depletion of microglia after SCI disrupted glial scar formation, enhanced immune cell infiltrates, reduced neuronal survival, delayed astrocyte repopulation, exacerbated axonal dieback, and impaired locomotor recovery. Therefore, our findings suggest microglia may play a protective role after SCI in mice. Introduction after spinal cord injury (SCI)6,7. Conversely, several stu- fi 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Microglia are derived from primitive myeloid progeni- dies demonstrate bene cial roles of microglia in CNS tors in the yolk sac during embryonic development1.As injury. In a mouse model of stroke, microglia are proved the main immune cells in central nervous system (CNS), to play a role in protecting neurons by regulating intra- microglia help to sculpt the mature CNS during devel- cellular calcium levels8. In a mouse model of contusive opment by removing apoptotic cells and inappropriate SCI, microglia are identified as a key cellular component neural connections2. In the adult CNS, microglia con- of the scar that develops after SCI to protect neural tis- stantly surveil the microenvironment for alterations sue9. In addition, one study show that microglia are resulting from injury or disease2,3. After sensing pertur- irrelevant for neuronal degeneration and axon regenera- bations, microglia become activated, reorient their pro- tion after acute crush injury of optic nerve10. Therefore, cesses towards the lesion, and phagocytose cellular debris4. microglia may exert diverging roles depending on the However, the role of microglia in CNS injury remains context. Whether microglia are beneficial or detrimental controversial. Activated microglia release proin- for recovery after SCI remains unclear. flammatory factors that cause neuronal death and con- In addition to their potentially conflicting roles, the tribute to the secondary tissue damage2,5. Inhibition of paucity of efficient methods to distinguish these resident microglia proliferation reduces inflammatory response, microglia with blood-derived monocytes/ macrophages alleviates neuronal death, and improves motor recovery hamper the exploration of the specific roles of microglia after a CNS injury11. The newly developed pharmacologic strategies based on CSF1R inhibition specifically eliminate Correspondence: Tengbo Yu ([email protected])or Licheng Zhang ([email protected]) ~99% microglia in adult brain, whereas peripheral mac- 1Department of Orthopedics, Chinese PLA General Hospital, Beijing, China rophages and other immune cells remained unaf- 2 fi Department of Orthopaedics, The Af liated Hospital of Qingdao University, fected10,12. This method allows the study of the specific Qingdao, China Full list of author information is available at the end of the article. roles of microglia in CNS injury. Edited by K. Blomberg © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Fu et al. Cell Death and Disease (2020) 11:528 Page 2 of 12 Here, we used PLX3397, a CSF1R inhibitor that speci- capillary-based size sorting system (ProteinSimple, San fically eliminate microglia to investigate the specific roles Jose, CA, USA)14. All procedures were performed of microglia in spinal cord. We showed that PLX3397 according to the manufacturer’s protocol. Briefly, 8 μLof treatment eliminated almost all microglia and the absence diluted protein lysate was mixed with 2 μLof5×fluor- of microglia did not affect other cell types in spinal cord. escent master mix and heated at 95 °C for 5 min. The Depletion of microglia in the context of SCI was asso- samples, blocking reagent, wash buffer, primary anti- ciated with disorganized astroglial scar, reduced neuronal bodies, secondary antibodies, and chemiluminescent number, delayed astrocyte repopulation, aggravated axo- substrate were dispensed into designated wells in a nal dieback, and reduced functional recovery. Therefore, microplate provided by the manufacturer. The plate was microglia may have a beneficial effect on function loaded into the instrument and protein was drawn into recovery after SCI. individual capillaries on a 25 capillary cassette provided by the manufacturer. Protein separation and immunodetec- Materials and methods tion was performed automatically on the individual Animal experiments capillaries using default settings. The data was analyzed Female C57BL/6 mice (6-week-old) were used for all with Compass software (ProteinSimple). Primary anti- experiments. Mice were housed under controlled condi- bodies used were anti-Iba1 antibody (abcam, ab153696), tions with 12 h light/dark cycle and had free access to anti-βIII Tubulin antibody (abcam, ab78078), anti-GFAP food and water at all time. All animal procedures were antibody (abcam, ab4674), and anti-Olig2 antibody approved by the Institutional Animal Care and Use (abcam, ab109186). Committee of the Chinese PLA General Hospital and conducted in accordance with relevant guides of the BDA tracing Chinese Ministry of Public Health on the care and use of This procedure is similar to what was described pre- laboratory animals and in compliance with the ARRIVE viously with modifications13,15. A midline incision was (Animal Research: Reporting In Vivo Experiments) made over the skull to reveal bregma after mice were guidelines. anesthetized. Then, a window in the skull was made with a microdrill to expose the sensorimotor cortex. To label Microglia depletion corticospinal tract (CST) axons by anterograde tracing, To deplete microglia in vivo, mice were given the four injections of 500 nl BDA (10%, Invitrogen, D1956) CSF1R inhibitor PLX3397 (pexidartinib; Selleckchem, were injected into sensorimotor cortex at four sites Houston, TX, USA) formulated into AIN-76A standard through a glass pipette attached to a nanoliter injector at a diet at 290 mg/kg for 7 days5. AIN-76A standard diet was rate of 1 nl/s. The four coordinates were as follows: used as respective controls. 1.5 mm lateral, 0.6 mm deep, and 0.5 mm anterior; 0.0 mm, 0.5 mm, and 1.0 mm caudal to bregma. In order Spinal cord injury to prevent the backflow of the injection, the needle was A full crush injury was performed similar to that pre- kept in situ for 1 min before moving to the next site. The viously described by Liu et al.13. Mice were anesthetized skin was sutured and mice were then placed on a warming by intraperitoneal injections of sodium pentobarbital at blanket. These BDA-injected mice were kept for an 80 mg/kg. A midline incision was made over the thoracic additional 2 weeks before termination. vertebrae. Then, a laminectomy was conducted at the level of T10 segment until the spinal cord was exposed Tissue processing completely from side to side. The exposed spinal cord was For the purpose of histology and immunofluorescence then crushed for 2 s with modified forceps. The forceps experiments, mice were anesthetized and transcardially were filed to a width of 0.1 mm for the last 4–5 mm of the perfused with cold PBS followed by 4% paraformaldehyde tips. The spinal dura was intact after crushing. The muscle (PFA). Spinal columns were isolated and post-fixed in the and skin were sutured. Post-operatively, mice were placed 4% PFA overnight at 4 °C. A spinal cord segment of on a warming blanket until fully awake. Bladders were 10 mm containing the lesion site were dissected out and emptied manually twice daily to prevent urinary tract then immersed for 3 days at 4 °C in a PBS solution con- infections until mice were able to urinate independently. taining 30% sucrose for cryoprotection. Tissues were then embedded in OCT compound, snap-frozen in dry ice and Automated capillary western blot (WES) stored at −20 °C until processed. Mice were transcardially perfused with cold phosphate- buffered saline (PBS) and then
Load more

Recommended publications
  • Fibrotic Scar in Neurodegenerative Diseases
    MINI REVIEW published: 14 August 2020 doi: 10.3389/fimmu.2020.01394 Fibrotic Scar in Neurodegenerative Diseases Nadia D’Ambrosi* and Savina Apolloni* Department of Biology, Tor Vergata University, Rome, Italy The process of uncontrolled internal scarring, called fibrosis, is now emerging as a pathological feature shared by both peripheral and central nervous system diseases. In the CNS, damaged neurons are not replaced by tissue regeneration, and scar-forming cells such as endothelial cells, inflammatory immune cells, stromal fibroblasts, and astrocytes can persist chronically in brain and spinal cord lesions. Although this process was extensively described in acute CNS damages, novel evidence indicates the involvement of a fibrotic reaction in chronic CNS injuries as those occurring during neurodegenerative diseases, where inflammation and fibrosis fuel degeneration. In this mini review, we discuss recent advances around the role of fibrotic scar formation and function in different neurodegenerative conditions, particularly focusing on the rising role of scarring in the pathogenesis of amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer’s disease and highlighting the therapeutic relevance of targeting fibrotic scarring to slow and reverse neurodegeneration. Edited by: Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, astrocytes, fibroblasts, microglia, multiple sclerosis Anna-Maria Hoffmann-Vold, Oslo University Hospital, Norway Reviewed by: INTRODUCTION Carlo Chizzolini, Université de Genève, Switzerland Fibrosis identifies
    [Show full text]
  • Astrogliosis in an Experimental Model of Hypovitaminosis B12: a Cellular Basis of Neurological Disorders Due to Cobalamin Deficiency
    cells Article Astrogliosis in an Experimental Model of Hypovitaminosis B12: A Cellular Basis of Neurological Disorders Due to Cobalamin Deficiency Zuzanna Rzepka 1 , Jakub Rok 1 , Justyna Kowalska 1, Klaudia Banach 1, Justyna Magdalena Hermanowicz 2 , Artur Beberok 1 , Beata Sieklucka 2 , Dorota Gryko 3 and Dorota Wrze´sniok 1,* 1 Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiello´nska4, 41-200 Sosnowiec, Poland; [email protected] (Z.R.); [email protected] (J.R.); [email protected] (J.K.); [email protected] (K.B.); [email protected] (A.B.) 2 Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; [email protected] (J.M.H.); [email protected] (B.S.) 3 Institute of Organic Chemistry, Polish Academy of Science, Kasprzaka 44/52, 01-224 Warsaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-3-2364-1050 Received: 16 September 2020; Accepted: 7 October 2020; Published: 9 October 2020 Abstract: Cobalamin deficiency affects human physiology with sequelae ranging from mild fatigue to severe neuropsychiatric abnormalities. The cellular and molecular aspects of the nervous system disorders associated with hypovitaminosis B12 remain largely unknown. Growing evidence indicates that astrogliosis is an underlying component of a wide range of neuropathologies. Previously, we developed an in vitro model of cobalamin deficiency in normal human astrocytes (NHA) by culturing the cells with c-lactam of hydroxycobalamin (c-lactam OH-Cbl). We revealed a non-apoptotic activation of caspases (3/7, 8, 9) in cobalamin-deficient NHA, which may suggest astrogliosis.
    [Show full text]
  • Reversing Glial Scar Back to Neural Tissue Through Neurod1-Mediated Astrocyte-To-Neuron Conversion
    bioRxiv preprint doi: https://doi.org/10.1101/261438; this version posted February 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Reversing Glial Scar Back To Neural Tissue Through NeuroD1-Mediated Astrocyte-To-Neuron Conversion Lei Zhang1, Zhuofan Lei1, Ziyuan Guo1, Zifei Pei1, Yuchen Chen1, Fengyu Zhang1, Alice Cai1, Yung Kin Mok1, Grace Lee1, Vishal Swaminnathan1, Fan Wang1, Yuting Bai1, Gong Chen1,* 1. Department of Biology, Huck Institute of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA. Keywords: glial scar, NeuroD1, stab injury, in vivo conversion, glia to neuron ratio, brain repair * Correspondence should be addressed to: Gong Chen, Ph.D. Professor and Verne M. Willaman Chair in Life Sciences Department of Biology, Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Email: [email protected] Phone: 814-865-2488 Website: http://bio.psu.edu/directory/guc2 1 bioRxiv preprint doi: https://doi.org/10.1101/261438; this version posted February 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Nerve injury often causes neuronal loss and glial proliferation, disrupting the delicate balance between neurons and glial cells in the brain. Recently, we have developed an innovative technology to convert internal reactive glial cells into functional neurons inside the mouse brain. Here, we further demonstrate that such glia-to-neuron conversion can rebalance neuron-glia ratio and reverse glial scar back to neural tissue.
    [Show full text]
  • Glial Scar-Modulation As Therapeutic Tool in Spinal Cord Injury in Animal Models1
    9-Review Glial scar-modulation as therapeutic tool in spinal cord injury in animal models1 Jéssica Rodrigues OrlandinI, Carlos Eduardo AmbrósioIII, Valéria Maria LaraII IFellow Master degree, Postgraduate Program in Animal Bioscience, Veterinary Medicine Department, Faculty of Animal Science and Food Engineering, Universidade de São Paulo (FZEA/USP), Pirassununga-SP, Brazil. Intellectual, scientific, conception and design of the study; acquisition, analysis and interpretation of data; manuscript writing. IIPostdoctoral Researcher, Postgraduate Program in Animal Bioscience, Veterinary Medicine Department, FZEA/USP, Pirassununga-SP, Brazil. Conception and design of the study, critical revision, final approval. IIIResearcher, CNPq Grant Level 1A – CA VT, Veterinary Medicine Department, FZEA/USP, Pirassununga-SP, Brazil. Conception and design of the study, manuscript writing, critical revision, final approval. Abstract Purpose: Spinal Cord injury represents, in veterinary medicine, most of the neurological attendances and may result in permanent disability, death or euthanasia. Due to inflammation resulting from trauma, it originates the glial scar, which is a cell interaction complex system. Its function is to preserve the healthy circuits, however, it creates a physical and molecular barrier that prevents cell migration and restricts the neuroregeneration ability. Methods: This review aims to present innovations in the scene of treatment of spinal cord injury, approaching cell therapy, administration of enzyme, anti-inflammatory, and other active principles capable of modulating the inflammatory response, resulting in glial scar reduction and subsequent functional improvement of animals. Results: Some innovative therapies as cell therapy, administration of enzymes, immunosuppressant or other drugs cause the modulation of inflammatory response proved to be a promising tool for the reduction of gliosis Conclusion: Those tools promise to reduce gliosis and promote locomotor recovery in animals with spinal cord injury.
    [Show full text]
  • Reactive Gliosis and the Multicellular Response to CNS Damage and Disease
    Neuron Review Reactive Gliosis and the Multicellular Response to CNS Damage and Disease Joshua E. Burda1 and Michael V. Sofroniew1,* 1Department of Neurobiology and Brain Research Institute, University of California Los Angeles, Los Angeles, CA 90095-1763, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2013.12.034 The CNS is prone to heterogeneous insults of diverse etiologies that elicit multifaceted responses. Acute and focal injuries trigger wound repair with tissue replacement. Diffuse and chronic diseases provoke gradually escalating tissue changes. The responses to CNS insults involve complex interactions among cells of numerous lineages and functions, including CNS intrinsic neural cells, CNS intrinsic nonneural cells, and CNS extrinsic cells that enter from the circulation. The contributions of diverse nonneuronal cell types to outcome after acute injury, or to the progression of chronic disease, are of increasing interest as the push toward understanding and ameliorating CNS afflictions accelerates. In some cases, considerable information is available, in others, comparatively little, as examined and reviewed here. Introduction enter from the circulation. The biology of cell types that partici- A major goal of contemporary neuroscience is to understand and pate in CNS responses to injury and disease models has gener- ameliorate a wide range of CNS disorders. Toward this end, ally been studied in isolation. There is increasing need to study there is increasing interest in cellular and molecular mechanisms interplay of different cells to understand mechanisms. This Re- of CNS responses to damage, disease, and repair. Neurons are view examines and reviews the multiple cell types involved in, the principal cells executing neural functions and have long and contributing to, different types of CNS insults.
    [Show full text]
  • Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease
    cells Review Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease Zachary Finkel, Fatima Esteban, Brianna Rodriguez, Tianyue Fu, Xin Ai and Li Cai * Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA; [email protected] (Z.F.); [email protected] (F.E.); [email protected] (B.R.); [email protected] (T.F.); [email protected] (X.A.) * Correspondence: [email protected] Abstract: Adult neural stem and progenitor cells (NSPCs) contribute to learning, memory, main- tenance of homeostasis, energy metabolism and many other essential processes. They are highly heterogeneous populations that require input from a regionally distinct microenvironment including a mix of neurons, oligodendrocytes, astrocytes, ependymal cells, NG2+ glia, vasculature, cere- brospinal fluid (CSF), and others. The diversity of NSPCs is present in all three major parts of the CNS, i.e., the brain, spinal cord, and retina. Intrinsic and extrinsic signals, e.g., neurotrophic and growth factors, master transcription factors, and mechanical properties of the extracellular matrix (ECM), collectively regulate activities and characteristics of NSPCs: quiescence/survival, prolifer- ation, migration, differentiation, and integration. This review discusses the heterogeneous NSPC populations in the normal physiology and highlights their potentials and roles in injured/diseased states for regenerative medicine. Citation: Finkel, Z.; Esteban, F.; Keywords: central nervous system (CNS); ependymal cells; neural stem and progenitor cells (NSPC); Rodriguez, B.; Fu, T.; Ai, X.; Cai, L. NG2+ cells; neurodegenerative diseases; regenerative medicine; retina injury; spinal cord injury Diversity of Adult Neural Stem and (SCI); traumatic brain injury (TBI) Progenitor Cells in Physiology and Disease. Cells 2021, 10, 2045.
    [Show full text]
  • Grant Project Che 575 Friday, April 29, 2016 By: Julie Boshar, Matthew
    Grant Project ChE 575 Friday, April 29, 2016 By: Julie Boshar, Matthew Long, Andrew Mason, Chelsea Orefice, Gladys Saruchera, Cory Thomas Specific Aims The spinal cord is the body’s most important organ for relaying nerve signals to and from the brain and the body. However, when an individual's spinal cord becomes injured due to trauma, their quality of life is greatly diminished. In the United States today, there are an estimated quarter of a million individuals living with a spinal cord injury (SCI). With an additional 12,000 cases being added every year. Tragically, there is no approved FDA treatment strategy to help restore function to these individuals. SCIs are classified as either primary or secondary events. Primary injuries occur when the spinal cord is displaced by bone fragments or disk material. In this case, nerve signaling rarely ceases upon injury but in severe cases axons are beyond repair. Secondary injuries occur when biochemical processes kill neural cells and strip axons of their myelin sheaths, inducing an inflammatory immune response. In the CNS, natural repair mechanisms are inhibited by proteins and matrix from glial cells, which embody the myelin sheath of axons. This actively prevents the repair of axons, via growth cone inhibition by oligodendrocytes and axon extension inhibition by astrocytes. A promising treatment to SCI use tissue engineered scaffolds that are biocompatible, biodegradable and have strong mechanical properties in vivo. These scaffolds can secrete neurotrophic factors and contain neural progenitor cells to promote axon regeneration, but further research is required to develop this into a comprehensive treatment.
    [Show full text]
  • Exploring the Production of Extracellular Matrix by Astrocytes in Response to Mimetic Traumatic Brain Injury Addison Walker University of Arkansas, Fayetteville
    University of Arkansas, Fayetteville ScholarWorks@UARK Theses and Dissertations 12-2016 Exploring the Production of Extracellular Matrix by Astrocytes in Response to Mimetic Traumatic Brain Injury Addison Walker University of Arkansas, Fayetteville Follow this and additional works at: http://scholarworks.uark.edu/etd Part of the Bioelectrical and Neuroengineering Commons, Cell Biology Commons, and the Molecular and Cellular Neuroscience Commons Recommended Citation Walker, Addison, "Exploring the Production of Extracellular Matrix by Astrocytes in Response to Mimetic Traumatic Brain Injury" (2016). Theses and Dissertations. 1754. http://scholarworks.uark.edu/etd/1754 This Thesis is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of ScholarWorks@UARK. For more information, please contact [email protected], [email protected]. Exploring the Production of Extracellular Matrix by Astrocytes in Response to Mimetic Traumatic Brain Injury A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Biomedical Engineering by Addison Walker University of Arkansas Bachelor of Science in Biomedical Engineering, 2014 December 2016 University of Arkansas This thesis is approved for recommendation to the Graduate Council. ________________________________ Dr. Jeff Wolchok Thesis Director _________________________________ _________________________________ Dr. Kartik Balachandran Dr. Woodrow Shew Committee Member Committee Member Abstract and Key Terms Following injury to the central nervous system, extracellular modulations are apparent at the site of injury, often resulting in a glial scar. Astrocytes are mechanosensitive cells, which can create a neuroinhibitory extracellular environment in response to injury. The aim for this research was to gain a fundamental understanding of the affects a diffuse traumatic brain injury has on the astrocyte extracellular environment after injury.
    [Show full text]
  • Portrait of Glial Scar in Neurological Diseases
    IJI0010.1177/2058738418801406International Journal of Immunopathology and PharmacologyWang et al. 801406letter2018 Letter to the Editor International Journal of Immunopathology and Pharmacology Portrait of glial scar in neurological Volume 31: 1–6 © The Author(s) 2018 Article reuse guidelines: diseases sagepub.com/journals-permissions DOI:https://doi.org/10.1177/2058738418801406 10.1177/2058738418801406 journals.sagepub.com/home/iji Haijun Wang1, Guobin Song1, Haoyu Chuang2,3,4, Chengdi Chiu4,5, Ahmed Abdelmaksoud1, Youfan Ye6 and Lei Zhao7 Abstract Fibrosis is formed after injury in most of the organs as a common and complex response that profoundly affects regeneration of damaged tissue. In central nervous system (CNS), glial scar grows as a major physical and chemical barrier against regeneration of neurons as it forms dense isolation and creates an inhibitory environment, resulting in limitation of optimal neural function and permanent deficits of human body. In neurological damages, glial scar is mainly attributed to the activation of resident astrocytes which surrounds the lesion core and walls off intact neurons. Glial cells induce the infiltration of immune cells, resulting in transient increase in extracellular matrix deposition and inflammatory factors which inhibit axonal regeneration, impede functional recovery, and may contribute to the occurrence of neurological complications. However, recent studies have underscored the importance of glial scar in neural protection and functional improvement depending on the specific insults which involves various pivotal molecules and signaling. Thus, to uncover the veil of scar formation in CNS may provide rewarding therapeutic targets to CNS diseases such as chronic neuroinflammation, brain stroke, spinal cord injury (SCI), traumatic brain injury (TBI), brain tumor, and epileptogenesis.
    [Show full text]
  • Intracerebral Chondroitinase ABC and Heparan Sulfate Proteoglycan Glypican Improve Outcome from Chronic Stroke in Rats
    Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats Justin J. Hilla, Kunlin Jina,b, Xiao Ou Maoa, Lin Xiea, and David A. Greenberga,1 aBuck Institute for Research on Aging, Novato, CA 94945; and bDepartment of Pharmacology and Neuroscience, University of North Texas, Fort Worth, TX 76107 Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 27, 2012 (received for review April 4, 2012) Physical and chemical constraints imposed by the periinfarct glial cosaminoglycan side chains (12). ChABC also increases axonal scar may contribute to the limited clinical improvement often regeneration following nigrostriatal tractotomy (13) and im- observed after ischemic brain injury. To investigate the role of proves nerve regeneration (14) and functional recovery after some of these mediators in outcome from cerebral ischemia, we spinal cord injury (15, 16) in rats in vivo. Like CSPGs, HSPGs treated rats with the growth-inhibitory chondroitin sulfate pro- are extracellular proteins that exist in several isoforms (17, 18). teoglycan neurocan, the growth-stimulating heparan sulfate pro- HSPG isoforms share a conserved glycosaminoglycan side chain, teoglycan glypican, or the chondroitin sulfate proteoglycan- which has more sulfur groups compared with CSPGs. HSPGs degrading enzyme chondroitinase ABC. Neurocan, glypican, or appear to up-regulate fibroblast growth factor (FGF)2 and en- chondroitinase ABC was infused directly into the infarct cavity hance neurogenesis in the olfactory system (19). The role of for 7 d, beginning 7 d after middle cerebral artery occlusion. Gly- HSPGs in the chronic phase of the glial scar in stroke is unclear.
    [Show full text]
  • Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration After Spinal Cord Injury
    Research Articles: Development/Plasticity/Repair Astrocytic YAP promotes the formation of glia scars and neural regeneration after spinal cord injury https://doi.org/10.1523/JNEUROSCI.2229-19.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.2229-19.2020 Received: 15 September 2019 Revised: 3 February 2020 Accepted: 5 February 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 the authors 1 Astrocytic YAP promotes the formation of glia scars and neural regeneration 2 after spinal cord injury 3 Changnan Xie1, 2#, Xiya Shen2, 3#, Xingxing Xu2#, Huitao Liu1, 2, Fayi Li1, 2, Sheng Lu1, 4 2, Ziran Gao4, Jingjing Zhang2, Qian Wu5, Danlu Yang2, Xiaomei Bao2, Fan Zhang2, 5 Shiyang Wu1ˈZhaoting Lv5, Minyu Zhu1, Dingjun Xu1, Peng Wang1, Liying Cao3, 6 Wei Wang 5, Zengqiang Yuan6, Ying Wang7, Zhaoyun Li8, Honglin Teng1*, Zhihui 7 Huang1, 2, 3* 8 1. Department of Spine Surgery, Wenzhou Medical University First Affiliated 9 Hospital, Wenzhou, Zhejiang, 325000, China. 10 2. School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 11 Zhejiang, 325035, China. 12 3. Key Laboratory of Elemene Anti-cancer Medicine of Zhejiang Province and 13 Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, 14 311121, China. 15 4. Graduate school of Youjiang Medical University for Nationalities, Basie, Guangxi, 16 533000, China.
    [Show full text]
  • Near Infrared Raman Spectroscopic Study of Reactive Gliosis and the Glial Scar in Injured Rat Spinal Cords
    Near Infrared Raman Spectroscopic Study of Reactive Gliosis and the Glial Scar in Injured Rat Spinal Cords. Tarun Saxenaa, Bin Denga, Eric Lewis-Clarkb, Kyle Hoellgerc, Dennis Stelznerd, Julie Hasenwinkela, Joseph Chaiken*e Department of Biomedical and Chemical Engineering a, and the Department of Chemistry e Syracuse University, Syracuse, New York, 13244, Department of Chemistryb, and the Department of Biomedical Engineeringc SUNY Binghamton, Binghamton, New York, 13902, Department of Cell and Developmental Biology d, SUNY Upstate Medical University, Syracuse, New York, 13210 ABSTRACT Comparative Raman spectra of ex vivo, saline-perfused, injured and healthy rat spinal cord as well as experiments using enzymatic digestion suggest that proteoglycan over expression may be observable in injured tissue. Comparison with authentic materials in vitro suggest the occurrence of side reactions between products of cord digestion with chondroitinase (cABC) that produce lactones and similar species with distinct Raman features that are often not overlapped with Raman features from other chemical species. Since the glial scar is thought to be a biochemical and physical barrier to nerve regeneration, this observation suggests the possibility of using near infrared Raman spectroscopy to study disease progression and explore potential treatments ex vivo and if potential treatments can be designed, perhaps to monitor potential remedial treatments within the spinal cord in vivo. Keywords: Spinal cord injury, glial scar, Raman, chondroitin sulfate proteoglycans, chondroitinase ABC 1. INTRODUCTION Spinal cord injury (SCI) is a debilitating condition leading to paralysis and is currently affecting more than a million Americans with annual healthcare costs exceeding 40 billion dollars1, 2. Intensive research efforts are ongoing to understand and treat SCI.
    [Show full text]