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1
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Nemati S, Kilcoyne M, Zeugolis D, McMahon SS. The effect of macromolecular crowders on deposition of extracellular matrix in astrocyte cultures. Cell Tissue Res 2025:10.1007/s00441-025-03980-4. [PMID: 40387922 DOI: 10.1007/s00441-025-03980-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 05/06/2025] [Indexed: 05/20/2025]
Abstract
Macromolecular crowding (MMC) is a biophysical phenomenon that has proven effective in enhancing extracellular matrix (ECM) deposition in vitro. However, MMCs potential in neuroglial cell cultures remains underexplored. This study investigates the effects of three distinct MMC agents [carrageenan (CR), dextran sulphate (DxS) and FicollⓇ cocktail (FC)] on ECM deposition and cell behaviour of Neu7 and primary astrocytes. While the viability and metabolic activity of Neu7 astrocytes were unaffected by any of the crowding agents, primary astrocytes exhibited a significant decrease in viability and metabolic activity in the presence of CR and DxS. The addition of CR, DxS, and FC resulted in a significant increase in deposition of fibronectin, collagen IV, collagen I, GFAP and CS56 in Neu7 astrocytes. In primary astrocytes, FC significantly enhanced the expression of astrocytic markers and increased the deposition of ECM proteins, including fibronectin and collagen IV. This study highlights the advantages of using FC as a MMC agent for enhancing ECM deposition in astrocytes. The method demonstrates potential for developing fast and more physiologically relevant in vitro models and improving drug screening processes for future studies. The observed benefits underscore the utility of FC in creating advanced cellular models that better mimic the native neural environment.
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Affiliation(s)
- Sorour Nemati
- Anatomy, School of Medicine, University of Galway, Galway, Ireland
- CÚRAM Research Ireland Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Michelle Kilcoyne
- Carbohydrate Signalling Group, Infectious Disease Section, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland
| | - Dimitrios Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research and School of Mechanical & Materials Engineering, University College Dublin (UCD), Dublin, Ireland
| | - Siobhan S McMahon
- Anatomy, School of Medicine, University of Galway, Galway, Ireland.
- CÚRAM Research Ireland Centre for Medical Devices, University of Galway, Galway, Ireland.
- Galway Neuroscience Centre, University of Galway, Galway, Ireland.
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2
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Bakhtiarydavijani A, Stone TW. Impact of prior axonal injury on subsequent injury during brain tissue stretching - A mesoscale computational approach. J Mech Behav Biomed Mater 2024; 153:106489. [PMID: 38428206 DOI: 10.1016/j.jmbbm.2024.106489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 02/24/2024] [Accepted: 02/26/2024] [Indexed: 03/03/2024]
Abstract
Epidemiology studies of traumatic brain injury (TBI) show individuals with a prior history of TBI experience an increased risk of future TBI with a significantly more detrimental outcome. But the mechanisms through which prior head injuries may affect risks of injury during future head insults have not been identified. In this work, we show that prior brain tissue injury in the form of mechanically induced axonal injury and glial scar formation can facilitate future mechanically induced tissue injury. To achieve this, we use finite element computational models of brain tissue and a history-dependent pathophysiology-based mechanically-induced axonal injury threshold to determine the evolution of axonal injury and scar tissue formation and their effects on future brain tissue stretching. We find that due to the reduced stiffness of injured tissue and glial scars, the existence of prior injury can increase the risk of future injury in the vicinity of prior injury during future brain tissue stretching. The softer brain scar tissue is shown to increase the strain and strain rate in its vicinity by as much as 40% in its vicinity during dynamic stretching that reduces the global strain required to induce injury by 20% when deformed at 15 s-1 strain rate. The results of this work highlight the need to account for patient history when determining the risk of brain injury.
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Affiliation(s)
| | - Tonya W Stone
- Center for Advanced Vehicular Systems, Mississippi State University, Starkville, MS, 39759, USA; Department of Mechanical Engineering, Mississippi State University, Mississippi State, MS, 39762, USA
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3
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Amlerova Z, Chmelova M, Anderova M, Vargova L. Reactive gliosis in traumatic brain injury: a comprehensive review. Front Cell Neurosci 2024; 18:1335849. [PMID: 38481632 PMCID: PMC10933082 DOI: 10.3389/fncel.2024.1335849] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/01/2024] [Indexed: 01/03/2025] Open
Abstract
Traumatic brain injury (TBI) is one of the most common pathological conditions impacting the central nervous system (CNS). A neurological deficit associated with TBI results from a complex of pathogenetic mechanisms including glutamate excitotoxicity, inflammation, demyelination, programmed cell death, or the development of edema. The critical components contributing to CNS response, damage control, and regeneration after TBI are glial cells-in reaction to tissue damage, their activation, hypertrophy, and proliferation occur, followed by the formation of a glial scar. The glial scar creates a barrier in damaged tissue and helps protect the CNS in the acute phase post-injury. However, this process prevents complete tissue recovery in the late/chronic phase by producing permanent scarring, which significantly impacts brain function. Various glial cell types participate in the scar formation, but this process is mostly attributed to reactive astrocytes and microglia, which play important roles in several brain pathologies. Novel technologies including whole-genome transcriptomic and epigenomic analyses, and unbiased proteomics, show that both astrocytes and microglia represent groups of heterogenic cell subpopulations with different genomic and functional characteristics, that are responsible for their role in neurodegeneration, neuroprotection and regeneration. Depending on the representation of distinct glia subpopulations, the tissue damage as well as the regenerative processes or delayed neurodegeneration after TBI may thus differ in nearby or remote areas or in different brain structures. This review summarizes TBI as a complex process, where the resultant effect is severity-, region- and time-dependent and determined by the model of the CNS injury and the distance of the explored area from the lesion site. Here, we also discuss findings concerning intercellular signaling, long-term impacts of TBI and the possibilities of novel therapeutical approaches. We believe that a comprehensive study with an emphasis on glial cells, involved in tissue post-injury processes, may be helpful for further research of TBI and be the decisive factor when choosing a TBI model.
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Affiliation(s)
- Zuzana Amlerova
- Department of Neuroscience, Second Faculty of Medicine, Charles University, Prague, Czechia
| | - Martina Chmelova
- Department of Neuroscience, Second Faculty of Medicine, Charles University, Prague, Czechia
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
| | - Miroslava Anderova
- Department of Neuroscience, Second Faculty of Medicine, Charles University, Prague, Czechia
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
| | - Lydia Vargova
- Department of Neuroscience, Second Faculty of Medicine, Charles University, Prague, Czechia
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
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4
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Benowitz LI, Xie L, Yin Y. Inflammatory Mediators of Axon Regeneration in the Central and Peripheral Nervous Systems. Int J Mol Sci 2023; 24:15359. [PMID: 37895039 PMCID: PMC10607492 DOI: 10.3390/ijms242015359] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Although most pathways in the mature central nervous system cannot regenerate when injured, research beginning in the late 20th century has led to discoveries that may help reverse this situation. Here, we highlight research in recent years from our laboratory identifying oncomodulin (Ocm), stromal cell-derived factor (SDF)-1, and chemokine CCL5 as growth factors expressed by cells of the innate immune system that promote axon regeneration in the injured optic nerve and elsewhere in the central and peripheral nervous systems. We also review the role of ArmC10, a newly discovered Ocm receptor, in mediating many of these effects, and the synergy between inflammation-derived growth factors and complementary strategies to promote regeneration, including deleting genes encoding cell-intrinsic suppressors of axon growth, manipulating transcription factors that suppress or promote the expression of growth-related genes, and manipulating cell-extrinsic suppressors of axon growth. In some cases, combinatorial strategies have led to unprecedented levels of nerve regeneration. The identification of some similar mechanisms in human neurons offers hope that key discoveries made in animal models may eventually lead to treatments to improve outcomes after neurological damage in patients.
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Affiliation(s)
- Larry I. Benowitz
- Department of Neurosurgery, Boston Children’s Hospital, Boston, MA 02115, USA; (L.X.); (Y.Y.)
- F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Neurosurgery, Harvard Medical School, Boston, MA 02115, USA
- Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA
- Department of Ophthalmology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
| | - Lili Xie
- Department of Neurosurgery, Boston Children’s Hospital, Boston, MA 02115, USA; (L.X.); (Y.Y.)
- Department of Neurosurgery, Harvard Medical School, Boston, MA 02115, USA
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yuqin Yin
- Department of Neurosurgery, Boston Children’s Hospital, Boston, MA 02115, USA; (L.X.); (Y.Y.)
- Department of Neurosurgery, Harvard Medical School, Boston, MA 02115, USA
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5
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Perez-Gianmarco L, Kukley M. Understanding the Role of the Glial Scar through the Depletion of Glial Cells after Spinal Cord Injury. Cells 2023; 12:1842. [PMID: 37508505 PMCID: PMC10377788 DOI: 10.3390/cells12141842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/30/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Spinal cord injury (SCI) is a condition that affects between 8.8 and 246 people in a million and, unlike many other neurological disorders, it affects mostly young people, causing deficits in sensory, motor, and autonomic functions. Promoting the regrowth of axons is one of the most important goals for the neurological recovery of patients after SCI, but it is also one of the most challenging goals. A key event after SCI is the formation of a glial scar around the lesion core, mainly comprised of astrocytes, NG2+-glia, and microglia. Traditionally, the glial scar has been regarded as detrimental to recovery because it may act as a physical barrier to axon regrowth and release various inhibitory factors. However, more and more evidence now suggests that the glial scar is beneficial for the surrounding spared tissue after SCI. Here, we review experimental studies that used genetic and pharmacological approaches to ablate specific populations of glial cells in rodent models of SCI in order to understand their functional role. The studies showed that ablation of either astrocytes, NG2+-glia, or microglia might result in disorganization of the glial scar, increased inflammation, extended tissue degeneration, and impaired recovery after SCI. Hence, glial cells and glial scars appear as important beneficial players after SCI.
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Affiliation(s)
- Lucila Perez-Gianmarco
- Achucarro Basque Center for Neuroscience, 48940 Leioa, PC, Spain
- Department of Neurosciences, University of the Basque Country, 48940 Leioa, PC, Spain
| | - Maria Kukley
- Achucarro Basque Center for Neuroscience, 48940 Leioa, PC, Spain
- IKERBASQUE Basque Foundation for Science, 48009 Bilbao, PC, Spain
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Valberg SJ, Williams ZJ, Henry ML, Finno CJ. Cerebellar axonopathy in Shivers horses identified by spatial transcriptomic and proteomic analyses. J Vet Intern Med 2023; 37:1568-1579. [PMID: 37288990 PMCID: PMC10365050 DOI: 10.1111/jvim.16784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 05/21/2023] [Indexed: 06/09/2023] Open
Abstract
BACKGROUND Shivers in horses is characterized by abnormal hindlimb movement when walking backward and is proposed to be caused by a Purkinje cell (PC) axonopathy based on histopathology. OBJECTIVES Define region-specific differences in gene expression within the lateral cerebellar hemisphere and compare cerebellar protein expression between Shivers horses and controls. ANIMALS Case-control study of 5 Shivers and 4 control geldings ≥16.2 hands in height. METHODS Using spatial transcriptomics, gene expression was compared between Shivers and control horses in PC soma and lateral cerebellar hemisphere white matter, consisting primarily of axons. Tandem-mass-tag (TMT-11) proteomic analysis was performed on lateral cerebellar hemisphere homogenates. RESULTS Differences in gene expression between Shivers and control horses were evident in principal component analysis of axon-containing white matter but not PC soma. In white matter, there were 455/1846 differentially expressed genes (DEG; 350 ↓DEG, 105 ↑DEG) between Shivers and controls, with significant gene set enrichment of the Toll-Like Receptor 4 (TLR4) cascade, highlighting neuroinflammation. There were 50/936 differentially expressed proteins (DEP). The 27 ↓DEP highlighted loss of axonal proteins including intermediate filaments (5), myelin (3), cytoskeleton (2), neurite outgrowth (2), and Na/K ATPase (1). The 23 ↑DEP were involved in the extracellular matrix (7), cytoskeleton (7), redox balance (2), neurite outgrowth (1), signal transduction (1), and others. CONCLUSION AND CLINICAL IMPORTANCE Our findings support axonal degeneration as a characteristic feature of Shivers. Combined with histopathology, these findings are consistent with the known distinctive response of PC to injury where axonal changes occur without a substantial impact on PC soma.
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Affiliation(s)
- Stephanie J. Valberg
- Department of Large Animal Clinical Sciences, College of Veterinary MedicineMichigan State UniversityEast LansingMichiganUSA
| | - Zoë J. Williams
- C. Wayne McIlwraith Translational Medicine, College of Veterinary Medicine and Biomedical SciencesColorado State UniversityFort CollinsColoradoUSA
| | - Marisa L. Henry
- Department of Large Animal Clinical Sciences, College of Veterinary MedicineMichigan State UniversityEast LansingMichiganUSA
| | - Carrie J. Finno
- Department of Population Health and Reproduction, School of Veterinary MedicineUniversity of California‐DavisDavisCaliforniaUSA
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7
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Valeri J, Gisabella B, Pantazopoulos H. Dynamic regulation of the extracellular matrix in reward memory processes: a question of time. Front Cell Neurosci 2023; 17:1208974. [PMID: 37396928 PMCID: PMC10311570 DOI: 10.3389/fncel.2023.1208974] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 05/30/2023] [Indexed: 07/04/2023] Open
Abstract
Substance use disorders are a global health problem with increasing prevalence resulting in significant socioeconomic burden and increased mortality. Converging lines of evidence point to a critical role of brain extracellular matrix (ECM) molecules in the pathophysiology of substance use disorders. An increasing number of preclinical studies highlight the ECM as a promising target for development of novel cessation pharmacotherapies. The brain ECM is dynamically regulated during learning and memory processes, thus the time course of ECM alterations in substance use disorders is a critical factor that may impact interpretation of the current studies and development of pharmacological therapies. This review highlights the evidence for the involvement of ECM molecules in reward learning, including drug reward and natural reward such as food, as well as evidence regarding the pathophysiological state of the brain's ECM in substance use disorders and metabolic disorders. We focus on the information regarding time-course and substance specific changes in ECM molecules and how this information can be leveraged for the development of therapeutic strategies.
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Affiliation(s)
- Jake Valeri
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States
- Graduate Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, United States
| | - Barbara Gisabella
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States
- Graduate Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, United States
| | - Harry Pantazopoulos
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States
- Graduate Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, United States
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8
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Lima R, Monteiro A, Salgado AJ, Monteiro S, Silva NA. Pathophysiology and Therapeutic Approaches for Spinal Cord Injury. Int J Mol Sci 2022; 23:ijms232213833. [PMID: 36430308 PMCID: PMC9698625 DOI: 10.3390/ijms232213833] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/07/2022] [Indexed: 11/12/2022] Open
Abstract
Spinal cord injury (SCI) is a disabling condition that disrupts motor, sensory, and autonomic functions. Despite extensive research in the last decades, SCI continues to be a global health priority affecting thousands of individuals every year. The lack of effective therapeutic strategies for patients with SCI reflects its complex pathophysiology that leads to the point of no return in its function repair and regeneration capacity. Recently, however, several studies started to uncover the intricate network of mechanisms involved in SCI leading to the development of new therapeutic approaches. In this work, we present a detailed description of the physiology and anatomy of the spinal cord and the pathophysiology of SCI. Additionally, we provide an overview of different molecular strategies that demonstrate promising potential in the modulation of the secondary injury events that promote neuroprotection or neuroregeneration. We also briefly discuss other emerging therapies, including cell-based therapies, biomaterials, and epidural electric stimulation. A successful therapy might target different pathologic events to control the progression of secondary damage of SCI and promote regeneration leading to functional recovery.
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Affiliation(s)
- Rui Lima
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s Associate Laboratory, PT Government Associated Laboratory, 4806-909 Braga/Guimarães, Portugal
| | - Andreia Monteiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s Associate Laboratory, PT Government Associated Laboratory, 4806-909 Braga/Guimarães, Portugal
| | - António J. Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s Associate Laboratory, PT Government Associated Laboratory, 4806-909 Braga/Guimarães, Portugal
| | - Susana Monteiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s Associate Laboratory, PT Government Associated Laboratory, 4806-909 Braga/Guimarães, Portugal
| | - Nuno A. Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s Associate Laboratory, PT Government Associated Laboratory, 4806-909 Braga/Guimarães, Portugal
- Correspondence:
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9
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Fawcett JW, Fyhn M, Jendelova P, Kwok JCF, Ruzicka J, Sorg BA. The extracellular matrix and perineuronal nets in memory. Mol Psychiatry 2022; 27:3192-3203. [PMID: 35760878 PMCID: PMC9708575 DOI: 10.1038/s41380-022-01634-3] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/09/2022] [Accepted: 05/16/2022] [Indexed: 02/06/2023]
Abstract
All components of the CNS are surrounded by a diffuse extracellular matrix (ECM) containing chondroitin sulphate proteoglycans (CSPGs), heparan sulphate proteoglycans (HSPGs), hyaluronan, various glycoproteins including tenascins and thrombospondin, and many other molecules that are secreted into the ECM and bind to ECM components. In addition, some neurons, particularly inhibitory GABAergic parvalbumin-positive (PV) interneurons, are surrounded by a more condensed cartilage-like ECM called perineuronal nets (PNNs). PNNs surround the soma and proximal dendrites as net-like structures that surround the synapses. Attention has focused on the role of PNNs in the control of plasticity, but it is now clear that PNNs also play an important part in the modulation of memory. In this review we summarize the role of the ECM, particularly the PNNs, in the control of various types of memory and their participation in memory pathology. PNNs are now being considered as a target for the treatment of impaired memory. There are many potential treatment targets in PNNs, mainly through modulation of the sulphation, binding, and production of the various CSPGs that they contain or through digestion of their sulphated glycosaminoglycans.
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Affiliation(s)
- James W Fawcett
- John van Geest Centre for Brain Repair, Department Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0PY, UK.
- Centre for Reconstructive Neuroscience, Institute for Experimental Medicine CAS, Videnska 1083, Prague 4, Prague, Czech Republic.
| | - Marianne Fyhn
- Department of Biosciences, University of Oslo, Oslo, Norway
| | - Pavla Jendelova
- Centre for Reconstructive Neuroscience, Institute for Experimental Medicine CAS, Videnska 1083, Prague 4, Prague, Czech Republic
| | - Jessica C F Kwok
- Centre for Reconstructive Neuroscience, Institute for Experimental Medicine CAS, Videnska 1083, Prague 4, Prague, Czech Republic
- School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, UK
| | - Jiri Ruzicka
- Centre for Reconstructive Neuroscience, Institute for Experimental Medicine CAS, Videnska 1083, Prague 4, Prague, Czech Republic
| | - Barbara A Sorg
- Robert S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR, USA
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10
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Zou Y, Yin Y, Xiao Z, Zhao Y, Han J, Chen B, Xu B, Cui Y, Ma X, Dai J. Transplantation of collagen sponge-based three-dimensional neural stem cells cultured in a RCCS facilitates locomotor functional recovery in spinal cord injury animals. Biomater Sci 2022; 10:915-924. [PMID: 35044381 DOI: 10.1039/d1bm01744f] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Numerous studies have indicated that microgravity induces various changes in the cellular functions of neural stem cells (NSCs), and the use of microgravity to culture tissue engineered seed cells for the treatment of nervous system diseases has drawn increasing attention. The goal of this study was to verify the efficacy of collagen sponge-based 3-dimensional (3D) NSCs cultured in a rotary cell culture system (RCCS) in treating spinal cord injury (SCI). The Basso-Beattie-Bresnahan score, inclined plane test, and electrophysiology results all indicated that 3D cultured NSCs cultured in a RCCS had better therapeutic effects than those cultured in a traditional cell culture environment, suggesting that the microgravity provided by the RCCS could enhance the therapeutic effect of 3D cultured NSCs. Our study indicates the feasibility of combining the RCCS with collagen sponge-based 3D cell culture for producing tissue engineered seed cells for the treatment of SCI. This novel and effective method shows promise for application in cell-based therapy for SCI in the future.
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Affiliation(s)
- Yunlong Zou
- China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China
| | - Yanyun Yin
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing 100101, China.
| | - Zhifeng Xiao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing 100101, China.
| | - Yannan Zhao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing 100101, China.
| | - Jin Han
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing 100101, China.
| | - Bing Chen
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing 100101, China.
| | - Bai Xu
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing 100101, China.
| | - Yi Cui
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100080, China.
| | - Xu Ma
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100080, China.
| | - Jianwu Dai
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 Nanyitiao, Zhongguancun, Beijing 100101, China.
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11
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Zhang Y, Yang S, Liu C, Han X, Gu X, Zhou S. Deciphering glial scar after spinal cord injury. BURNS & TRAUMA 2021; 9:tkab035. [PMID: 34761050 PMCID: PMC8576268 DOI: 10.1093/burnst/tkab035] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/26/2021] [Indexed: 12/25/2022]
Abstract
Spinal cord injury (SCI) often leads to permanent disability, which is mainly caused by the loss of functional recovery. In this review, we aimed to investigate why the healing process is interrupted. One of the reasons for this interruption is the formation of a glial scar around the severely damaged tissue, which is usually covered by reactive glia, macrophages and fibroblasts. Aiming to clarify this issue, we summarize the latest research findings pertaining to scar formation, tissue repair, and the divergent roles of blood-derived monocytes/macrophages, ependymal cells, fibroblasts, microglia, oligodendrocyte progenitor cells (OPCs), neuron-glial antigen 2 (NG2) and astrocytes during the process of scar formation, and further analyse the contribution of these cells to scar formation. In addition, we recapitulate the development of therapeutic treatments targeting glial scar components. Altogether, we aim to present a comprehensive decoding of the glial scar and explore potential therapeutic strategies for improving functional recovery after SCI.
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Affiliation(s)
- Yu Zhang
- Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210000, China
| | - Shuhai Yang
- Medical College of Nantong University, Nantong, 226001, China
| | - Chang Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Xiaoxiao Han
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Xiaosong Gu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Songlin Zhou
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
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12
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Brofiga M, Pisano M, Raiteri R, Massobrio P. On the road to the brain-on-a-chip: a review on strategies, methods, and applications. J Neural Eng 2021; 18. [PMID: 34280903 DOI: 10.1088/1741-2552/ac15e4] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/19/2021] [Indexed: 11/12/2022]
Abstract
The brain is the most complex organ of our body. Such a complexity spans from the single-cell morphology up to the intricate connections that hundreds of thousands of neurons establish to create dense neuronal networks. All these components are involved in the genesis of the rich patterns of electrophysiological activity that characterize the brain. Over the years, researchers coming from different disciplines developedin vitrosimplified experimental models to investigate in a more controllable and observable way how neuronal ensembles generate peculiar firing rhythms, code external stimulations, or respond to chemical drugs. Nowadays, suchin vitromodels are namedbrain-on-a-chippointing out the relevance of the technological counterpart as artificial tool to interact with the brain: multi-electrode arrays are well-used devices to record and stimulate large-scale developing neuronal networks originated from dissociated cultures, brain slices, up to brain organoids. In this review, we will discuss the state of the art of the brain-on-a-chip, highlighting which structural and biological features a realisticin vitrobrain should embed (and how to achieve them). In particular, we identified two topological features, namely modular and three-dimensional connectivity, and a biological one (heterogeneity) that takes into account the huge number of neuronal types existing in the brain. At the end of this travel, we will show how 'far' we are from the goal and how interconnected-brain-regions-on-a-chip is the most appropriate wording to indicate the current state of the art.
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Affiliation(s)
- Martina Brofiga
- Department of Informatics, Bioengineering, Robotics, and Systems Engineering (DIBRIS), University of Genova, Genova, Italy
| | - Marietta Pisano
- Department of Informatics, Bioengineering, Robotics, and Systems Engineering (DIBRIS), University of Genova, Genova, Italy
| | - Roberto Raiteri
- Department of Informatics, Bioengineering, Robotics, and Systems Engineering (DIBRIS), University of Genova, Genova, Italy.,CNR- Institute of Biophysics, Genova, Italy
| | - Paolo Massobrio
- Department of Informatics, Bioengineering, Robotics, and Systems Engineering (DIBRIS), University of Genova, Genova, Italy.,National Institute for Nuclear Physics (INFN), Genova, Italy
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Leite JP, Peixoto-Santos JE. Glia and extracellular matrix molecules: What are their importance for the electrographic and MRI changes in the epileptogenic zone? Epilepsy Behav 2021; 121:106542. [PMID: 31884121 DOI: 10.1016/j.yebeh.2019.106542] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/22/2022]
Abstract
Glial cells and extracellular matrix (ECM) molecules are crucial for the maintenance of brain homeostasis. Especially because of their actions regarding neurotransmitter and ionic control, and synaptic function, these cells can potentially contribute to the hyperexcitability seen in the epileptogenic, while ECM changes are linked to synaptic reorganization. The present review will explore glial and ECM homeostatic roles and their potential contribution to tissue plasticity. Finally, we will address how glial, and ECM changes in the epileptogenic zone can be seen in magnetic resonance imaging (MRI), pointing out their importance as markers for the extension of the epileptogenic area. This article is part of the Special Issue "NEWroscience 2018".
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Affiliation(s)
- Joao Pereira Leite
- Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
| | - Jose Eduardo Peixoto-Santos
- Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; Department of Neurology and Neurosurgery, Paulista School of Medicine, UNIFESP, Sao Paulo, Brazil
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14
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Cao L, Zhou Y, Chen M, Li L, Zhang W. Pericytes for Therapeutic Approaches to Ischemic Stroke. Front Neurosci 2021; 15:629297. [PMID: 34239409 PMCID: PMC8259582 DOI: 10.3389/fnins.2021.629297] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 05/11/2021] [Indexed: 12/18/2022] Open
Abstract
Pericytes are perivascular multipotent cells located on capillaries. Although pericytes are discovered in the nineteenth century, recent studies have found that pericytes play an important role in maintaining the blood—brain barrier (BBB) and regulating the neurovascular system. In the neurovascular unit, pericytes perform their functions by coordinating the crosstalk between endothelial, glial, and neuronal cells. Dysfunction of pericytes can lead to a variety of diseases, including stroke and other neurological disorders. Recent studies have suggested that pericytes can serve as a therapeutic target in ischemic stroke. In this review, we first summarize the biology and functions of pericytes in the central nervous system. Then, we focus on the role of dysfunctional pericytes in the pathogenesis of ischemic stroke. Finally, we discuss new therapies for ischemic stroke based on targeting pericytes.
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Affiliation(s)
- Lu Cao
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanbo Zhou
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengguang Chen
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li Li
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wei Zhang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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15
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Prospects for the application of Müller glia and their derivatives in retinal regenerative therapies. Prog Retin Eye Res 2021; 85:100970. [PMID: 33930561 DOI: 10.1016/j.preteyeres.2021.100970] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 03/28/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023]
Abstract
Neural cell death is the main feature of all retinal degenerative disorders that lead to blindness. Despite therapeutic advances, progression of retinal disease cannot always be prevented, and once neuronal cell damage occurs, visual loss cannot be reversed. Recent research in the stem cell field, and the identification of Müller glia with stem cell characteristics in the human eye, have provided hope for the use of these cells in retinal therapies to restore vision. Müller glial cells, which are the major structural cells of the retina, play a very important role in retinal homeostasis during health and disease. They are responsible for the spontaneous retinal regeneration observed in zebrafish and lower vertebrates during early postnatal life, and despite the presence of Müller glia with stem cell characteristics in the adult mammalian retina, there is no evidence that they promote regeneration in humans. Like many other stem cells and neurons derived from pluripotent stem cells, Müller glia with stem cell potential do not differentiate into retinal neurons or integrate into the retina when transplanted into the vitreous of experimental animals with retinal degeneration. However, despite their lack of integration, grafted Müller glia have been shown to induce partial restoration of visual function in spontaneous or induced experimental models of photoreceptor or retinal ganglion cell damage. This improvement in visual function observed after Müller cell transplantation has been ascribed to the release of neuroprotective factors that promote the repair and survival of damaged neurons. Due to the development and availability of pluripotent stem cell lines for therapeutic uses, derivation of Müller cells from retinal organoids formed by iPSC and ESC has provided more realistic prospects for the application of these cells to retinal therapies. Several opportunities for research in the regenerative field have also been unlocked in recent years due to a better understanding of the genomic and proteomic profiles of the developing and regenerating retina in zebrafish, providing the basis for further studies of the human retina. In addition, the increased interest on the nature and function of cellular organelle release and the characterization of molecular components of exosomes released by Müller glia, may help us to design new approaches that could be applied to the development of more effective treatments for retinal degenerative diseases.
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16
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Jevans B, James ND, Burnside E, McCann CJ, Thapar N, Bradbury EJ, Burns AJ. Combined treatment with enteric neural stem cells and chondroitinase ABC reduces spinal cord lesion pathology. Stem Cell Res Ther 2021; 12:10. [PMID: 33407795 PMCID: PMC7789480 DOI: 10.1186/s13287-020-02031-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 11/16/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Spinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Stem cells have shown promise in replenishing the cells lost to the injury process, but the release of axon growth-inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) by activated cells within the injury site hinders the integration of transplanted cells. We hypothesised that simultaneous application of enteric neural stem cells (ENSCs) isolated from the gastrointestinal tract, with a lentivirus (LV) containing the enzyme chondroitinase ABC (ChABC), would enhance the regenerative potential of ENSCs after transplantation into the injured spinal cord. METHODS ENSCs were harvested from the GI tract of p7 rats, expanded in vitro and characterised. Adult rats bearing a contusion injury were randomly assigned to one of four groups: no treatment, LV-ChABC injection only, ENSC transplantation only or ENSC transplantation+LV-ChABC injection. After 16 weeks, rats were sacrificed and the harvested spinal cords examined for evidence of repair. RESULTS ENSC cultures contained a variety of neuronal subtypes suitable for replenishing cells lost through SCI. Following injury, transplanted ENSC-derived cells survived and ChABC successfully degraded CSPGs. We observed significant reductions in the injured tissue and cavity area, with the greatest improvements seen in the combined treatment group. ENSC-derived cells extended projections across the injury site into both the rostral and caudal host spinal cord, and ENSC transplantation significantly increased the number of cells extending axons across the injury site. Furthermore, the combined treatment resulted in a modest, but significant functional improvement by week 16, and we found no evidence of the spread of transplanted cells to ectopic locations or formation of tumours. CONCLUSIONS Regenerative effects of a combined treatment with ENSCs and ChABC surpassed either treatment alone, highlighting the importance of further research into combinatorial therapies for SCI. Our work provides evidence that stem cells taken from the adult gastrointestinal tract, an easily accessible source for autologous transplantation, could be strongly considered for the repair of central nervous system disorders.
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Affiliation(s)
- Benjamin Jevans
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
- Present Address: German Centre for Neurodegenerative diseases (DZNE), Bonn, Germany
| | - Nicholas D James
- Regeneration Group, The Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, Guy's Campus, London, UK
| | - Emily Burnside
- Regeneration Group, The Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, Guy's Campus, London, UK
| | - Conor J McCann
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Nikhil Thapar
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
- Neurogastroenterology and Motility Unit, Department of Gastroenterology, Great Ormond Street Hospital, London, UK
- Present Address: Department of Paediatric Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia
| | - Elizabeth J Bradbury
- Regeneration Group, The Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, Guy's Campus, London, UK
| | - Alan J Burns
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
- Present Address: Gastrointestinal Drug Discovery Unit, Takeda Pharmaceuticals International, Cambridge, USA.
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17
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Al’joboori YD, Edgerton VR, Ichiyama RM. Effects of Rehabilitation on Perineural Nets and Synaptic Plasticity Following Spinal Cord Transection. Brain Sci 2020; 10:brainsci10110824. [PMID: 33172143 PMCID: PMC7694754 DOI: 10.3390/brainsci10110824] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/27/2020] [Accepted: 11/03/2020] [Indexed: 01/08/2023] Open
Abstract
Epidural electrical stimulation (ES) of the lumbar spinal cord combined with daily locomotor training has been demonstrated to enhance stepping ability after complete spinal transection in rodents and clinically complete spinal injuries in humans. Although functional gain is observed, plasticity mechanisms associated with such recovery remain mostly unclear. Here, we investigated how ES and locomotor training affected expression of chondroitin sulfate proteoglycans (CSPG), perineuronal nets (PNN), and synaptic plasticity on spinal motoneurons. To test this, adult rats received a complete spinal transection (T9-T10) followed by daily locomotor training performed under ES with administration of quipazine (a serotonin (5-HT) agonist) starting 7 days post-injury (dpi). Excitatory and inhibitory synaptic changes were examined at 7, 21, and 67 dpi in addition to PNN and CSPG expression. The total amount of CSPG expression significantly increased with time after injury, with no effect of training. An interesting finding was that γ-motoneurons did not express PNNs, whereas α-motoneurons demonstrated well-defined PNNs. This remarkable difference is reflected in the greater extent of synaptic changes observed in γ-motoneurons compared to α-motoneurons. A medium negative correlation between CSPG expression and changes in putative synapses around α-motoneurons was found, but no correlation was identified for γ-motoneurons. These results suggest that modulation of γ-motoneuron activity is an important mechanism associated with functional recovery induced by locomotor training under ES after a complete spinal transection.
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Affiliation(s)
- Yazi D. Al’joboori
- Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK;
| | - V. Reggie Edgerton
- Physiological Science, Neurobiology and Brain Research Institute, University of California, Los Angeles, CA 90095, USA;
| | - Ronaldo M. Ichiyama
- Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK;
- Correspondence: ; Tel.: +44-113-343-4291
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18
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Burgos-Bravo F, Martínez-Meza S, Quest AFG, Wilson CAM, Leyton L. Application of Force to a Syndecan-4 Containing Complex With Thy-1-α Vβ 3 Integrin Accelerates Neurite Retraction. Front Mol Biosci 2020; 7:582257. [PMID: 33134319 PMCID: PMC7550751 DOI: 10.3389/fmolb.2020.582257] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 08/25/2020] [Indexed: 12/23/2022] Open
Abstract
Inflammation contributes to the genesis and progression of chronic diseases, such as cancer and neurodegeneration. Upregulation of integrins in astrocytes during inflammation induces neurite retraction by binding to the neuronal protein Thy-1, also known as CD90. Additionally, Thy-1 alters astrocyte contractility and movement by binding to the mechano-sensors αVβ3 integrin and Syndecan-4. However, the contribution of Syndecan-4 to neurite shortening following Thy-1-αVβ3 integrin interaction remains unknown. To further characterize the contribution of Syndecan-4 in Thy-1-dependent neurite outgrowth inhibition and neurite retraction, cell-based assays under pro-inflammatory conditions were performed. In addition, using Optical Tweezers, we studied single-molecule binding properties between these proteins, and their mechanical responses. Syndecan-4 increased the lifetime of Thy-1-αVβ3 integrin binding by interacting directly with Thy-1 and forming a ternary complex (Thy-1-αVβ3 integrin + Syndecan-4). Under in vitro-generated pro-inflammatory conditions, Syndecan-4 accelerated the effect of integrin-engaged Thy-1 by forming this ternary complex, leading to faster neurite retraction and the inhibition of neurite outgrowth. Thus, Syndecan-4 controls neurite cytoskeleton contractility by modulating αVβ3 integrin mechano-receptor function. These results suggest that mechano-transduction, cell-matrix and cell-cell interactions are likely critical events in inflammation-related disease development.
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Affiliation(s)
- Francesca Burgos-Bravo
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer, Institute of Biomedical Sciences, Santiago, Chile.,Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Single Molecule Biochemistry and Mechanobiology Laboratory, Department of Biochemistry and Molecular Biology, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Samuel Martínez-Meza
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer, Institute of Biomedical Sciences, Santiago, Chile.,Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Andrew F G Quest
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer, Institute of Biomedical Sciences, Santiago, Chile.,Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Christian A M Wilson
- Single Molecule Biochemistry and Mechanobiology Laboratory, Department of Biochemistry and Molecular Biology, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Lisette Leyton
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer, Institute of Biomedical Sciences, Santiago, Chile.,Advanced Center for Chronic Diseases, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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19
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Recent progress in therapeutic drug delivery systems for treatment of traumatic CNS injuries. Future Med Chem 2020; 12:1759-1778. [PMID: 33028091 DOI: 10.4155/fmc-2020-0178] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Most therapeutics for the treatment of traumatic central nervous system injuries, such as traumatic brain injury and spinal cord injury, encounter various obstacles in reaching the target tissue and exerting pharmacological effects, including physiological barriers like the blood-brain barrier and blood-spinal cord barrier, instability rapid elimination from the injured tissue or cerebrospinal fluid and off-target toxicity. For central nervous system delivery, nano- and microdrug delivery systems are regarded as the most suitable and promising carriers. In this review, the pathophysiology and biomarkers of traumatic central nervous system injuries (traumatic brain injury and spinal cord injury) are introduced. Furthermore, various drug delivery systems, novel combinatorial therapies and advanced therapies for the treatment of traumatic brain injury and spinal cord injury are emphasized.
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20
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He Y, Liu X, Chen Z. Glial Scar-a Promising Target for Improving Outcomes After CNS Injury. J Mol Neurosci 2019; 70:340-352. [PMID: 31776856 DOI: 10.1007/s12031-019-01417-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/10/2019] [Indexed: 12/14/2022]
Abstract
After central nervous system (CNS) injury, a series of stress responses induce astrocytes activation. Reactive astrocytes, which are typically different from astrocytes in normal conditions in altered morphology and gene expression, combine with extracellular matrix (ECM) components to form a glial scar at the lesion site, which walls of the injured region from neighboring healthier tissue. However, as a physical and molecular barrier, glial scar can impede patients' functional recovery in the late period of CNS injury. Thus, inhibiting glial scar formation in the chronic stage after CNS injury may be a promising target to improve outcomes. Since the therapeutic strategies targeting on mediating glial scar formation are regarded as an important part on improving functional recovery after CNS injury, in this review, we focus on the regulating effects of related signaling pathways and other molecules on glial scar, and the process of glial scar formation and the roles that it plays during the acute and chronic stages are also expounded in this article. We hope to get a comprehensive understanding of glial scar during CNS injury based on current researches and to open new perspectives for the therapies to promote functional recovery after CNS injury.
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Affiliation(s)
- Yuanyuan He
- Department of Pharmacy, Xuyi People's Hospital, 28 Hongwu Road, Xuyi, 211700, Jiangsu, People's Republic of China
| | - Xiaoyan Liu
- Department of Pharmacy, Xuyi People's Hospital, 28 Hongwu Road, Xuyi, 211700, Jiangsu, People's Republic of China
| | - Zhongying Chen
- Department of Pharmacy, Xuyi People's Hospital, 28 Hongwu Road, Xuyi, 211700, Jiangsu, People's Republic of China.
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21
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Ng SY, Lee AYW. Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets. Front Cell Neurosci 2019; 13:528. [PMID: 31827423 PMCID: PMC6890857 DOI: 10.3389/fncel.2019.00528] [Citation(s) in RCA: 449] [Impact Index Per Article: 74.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023] Open
Abstract
Traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality amongst civilians and military personnel globally. Despite advances in our knowledge of the complex pathophysiology of TBI, the underlying mechanisms are yet to be fully elucidated. While initial brain insult involves acute and irreversible primary damage to the parenchyma, the ensuing secondary brain injuries often progress slowly over months to years, hence providing a window for therapeutic interventions. To date, hallmark events during delayed secondary CNS damage include Wallerian degeneration of axons, mitochondrial dysfunction, excitotoxicity, oxidative stress and apoptotic cell death of neurons and glia. Extensive research has been directed to the identification of druggable targets associated with these processes. Furthermore, tremendous effort has been put forth to improve the bioavailability of therapeutics to CNS by devising strategies for efficient, specific and controlled delivery of bioactive agents to cellular targets. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by an update on novel therapeutic targets and agents. Recent development of various approaches of drug delivery to the CNS is also discussed.
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Affiliation(s)
- Si Yun Ng
- Neurobiology/Ageing Program, Centre for Life Sciences, Department of Physiology, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Alan Yiu Wah Lee
- Neurobiology/Ageing Program, Centre for Life Sciences, Department of Physiology, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore, Singapore.,School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia
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22
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Recent advances in the therapeutic uses of chondroitinase ABC. Exp Neurol 2019; 321:113032. [PMID: 31398353 DOI: 10.1016/j.expneurol.2019.113032] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 07/19/2019] [Accepted: 08/03/2019] [Indexed: 12/18/2022]
Abstract
Many studies, using pre-clinical models of SCI, have demonstrated the efficacy of chondroitinase ABC as a treatment for spinal cord injury and this has been confirmed in laboratories worldwide and in several animal models. The aim of this review is report the current state of research in the field and to compare the relative efficacies of these new interventions to improve outcomes in both acute and chronic models of SCI. We also report new methods of chondroitinase delivery and the outcomes of two clinical trials using the enzyme to treat spinal cord injury in dogs and disc herniation in human patients. Recent studies have assessed the outcomes of combining chondroitinase with other strategies known to promote recovery following spinal cord injury and new approaches. Evidence is emerging that one of the most powerful combinations is that of chondroitinase with cell transplants. The particular benefits of each of the different cell types used for these transplant experiments are discussed. Combining chondroitinase with rehabilitation also improves outcomes. Gene therapy is an efficient method of enzyme delivery to the injured spinal cord and circumvents the issue of the enzyme's thermo-instability. Other methods of delivery, such as via nanoparticles or synthetic scaffolds, have shown promise; however, the outcomes from these experiments suggest that these methods of delivery require further optimization to achieve similar levels of efficacy to that obtained by a gene therapy approach. Pre-clinical models have also shown chondroitinase is efficacious in the treatment of other conditions, such as peripheral nerve injury, stroke, coronary reperfusion, Parkinson's disease and certain types of cancer. The wide range of conditions where the benefits of chondroitinase treatment have been demonstrated reflects the complex roles that chondroitin sulphate proteoglycans (its substrate) play in health and disease and warrants the enzyme's further development as a therapy.
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23
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Mohammadyari H, Shirdel SA, Jafarian V, Khalifeh K. Designing and construction of novel variants of Chondroitinase ABC I to reduce aggregation rate. Arch Biochem Biophys 2019; 668:46-53. [PMID: 31103558 DOI: 10.1016/j.abb.2019.05.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/11/2019] [Accepted: 05/15/2019] [Indexed: 01/25/2023]
Abstract
Chondroitinase ABC I (cABC I) can degrade inhibitory molecules for axon regrowth at the site of damage after spinal cord injury (SCI). One of the main problems in the practical application is the possibility of structural changes that lead to the inactivation of the enzyme. In current work, three variants of cABC I was designed and constructed by manipulation of a short helix conformation (Gln678-Leu679-Ser680-Gln681); where Gln residues were converted to Glu. According to the enzyme kinetics studies, the catalytic efficiency of the Q681E and double mutant (Q678E/Q681E) increases in comparison with WT enzyme; while that of Q678E decreases. It was also shown that the rate of the inactivation of the enzyme variants over time is greater in WT and Q678E variants than that of the Q681E and double mutant. Negative values of entropy change of thermal inactivation measurements; demonstrate that inactivation of the WT and Q678E variants are mainly originated from aggregation. These observations can be explained by considering the repulsive electrostatic interaction between enzyme molecules that prevents protein aggregation over time. It is concluded that increasing the solubility of the Q681E and double mutant via favorable interactions of surface-exposed charged residues with dipole momentum of water molecules accompanied by the presence of intermolecular repulsive electrostatic interaction leads to decreasing the rate of aggregation in both long-term storage and heat-induced structural changes.
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Affiliation(s)
- Hamed Mohammadyari
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran
| | - S Akram Shirdel
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Vahab Jafarian
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran
| | - Khosrow Khalifeh
- Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran.
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24
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Miki K, Yagi K, Nonaka M, Iwaasa M, Abe H, Morishita T, Arima H, Inoue T. Spot sign as a predictor of rebleeding after endoscopic surgery for intracerebral hemorrhage. J Neurosurg 2019; 130:1485-1490. [PMID: 29799345 DOI: 10.3171/2017.12.jns172335] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 12/11/2017] [Indexed: 12/25/2022]
Abstract
OBJECTIVE In patients with spontaneous intracerebral hemorrhage (sICH), postoperative recurrent hemorrhage (PRH) is one of the most severe complications after endoscopic evacuation of hematoma (EEH). However, no predictors of this complication have been identified. In the present study, the authors retrospectively investigated whether PRH can be preoperatively predicted by the presence of the spot sign on CT scans. METHODS In total, 143 patients with sICH were treated by EEH between June 2009 and March 2017, and 127 patients who underwent preoperative CT angiography were included in this study. Significant correlations of PRH with the patients' baseline, clinical, and radiographic characteristics, including the spot sign, were evaluated using multivariable logistic regression models. RESULTS The incidence of and risk factors for PRH were assessed in 127 patients with available data. PRH occurred in 9 (7.1%) patients. Five (21.7%) cases of PRH were observed among 23 patients with the spot sign, whereas only 4 (3.8%) cases of PRH occurred among 104 patients without the spot sign. The spot sign was the only independent predictor of PRH (OR 5.81, 95% CI 1.26-26.88; p = 0.02). The following factors were not independently associated with PRH: age, hypertension, poor consciousness, antihemostatic factors (thrombocytopenia, coagulopathy, and use of antithrombotic drugs), the location and size of the sICH, other radiographic findings (black hole sign and blend sign), surgical duration and procedures, and early surgery. CONCLUSIONS The spot sign is likely to be a strong predictor of PRH after EEH among patients with sICH. Complete and careful control of bleeding in the operative field should be ensured when surgically treating such patients. New surgical strategies and procedures might be needed to improve these patients' outcomes.
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Affiliation(s)
| | | | | | | | | | | | - Hisatomi Arima
- 3Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University Hospital and School of Medicine, Fukuoka University, Fukuoka, Japan
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Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T. Layer-specific expression of extracellular matrix molecules in the mouse somatosensory and piriform cortices. IBRO Rep 2018; 6:1-17. [PMID: 30582064 PMCID: PMC6293036 DOI: 10.1016/j.ibror.2018.11.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 11/24/2018] [Indexed: 02/04/2023] Open
Abstract
In the developing central nervous system (CNS), extracellular matrix (ECM) molecules have regulating roles such as in brain development, neural-circuit maturation, and synaptic-function control. However, excluding the perineuronal net (PNN) area, the distribution, constituent elements, and expression level of granular ECM molecules (diffuse ECM) present in the mature CNS remain unclear. Diffuse ECM molecules in the CNS share the components of PNNs and are likely functional. As cortical functions are greatly region-dependent, we hypothesized that ECM molecules would differ in distribution, expression level, and components in a region- and layer-dependent manner. We examined the layer-specific expression of several chondroitin sulfate proteoglycans (aggrecan, neurocan, and brevican), tenascin-R, Wisteria floribunda agglutinin (WFA)-positive molecules, hyaluronic acid, and link protein in the somatosensory and piriform cortices of mature mice. Furthermore, we investigated expression changes in WFA-positive molecules due to aging. In the somatosensory cortex, PNN density was particularly high at layer 4 (L4), but not all diffuse ECM molecules were highly expressed at L4 compared to the other layers. There was almost no change in tenascin-R and hyaluronic acid in any somatosensory-cortex layer. Neurocan showed high expression in L1 of the somatosensory cortex. In the piriform cortex, many ECM molecules showed higher expression in L1 than in the other layers. However, hyaluronic acid showed high expression in deep layers. Here, we clarified that ECM molecules differ in constituent elements and expression in a region- and layer-dependent manner. Region-specific expression of ECM molecules is possibly related to functions such as region-specific plasticity and vulnerability.
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Key Words
- CNS, central nervous system
- CSPG, chondroitin sulfate proteoglycans
- ChABC, chondroitinase ABC
- ECM, extracellular cellular matrix
- Extracellular matrix
- HA, hyaluronic acid
- HABP, hyaluronic acid binding protein
- Hapln1, hyaluronan and proteoglycan link protein 1
- PNN, perineuronal ntes
- Perineuronal nets
- Piriform cortex
- Proteoglycans
- Somatosensory cortex
- WFA, Wisteria floribunda agglutinin
- Wisteria floribunda
- a.u., arbitrary units
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Affiliation(s)
- Hiroshi Ueno
- Department of Medical Technology, Kawasaki University of Medical Welfare, 288, Matsushima, Kurashiki, Okayama, 701-0193, Japan
| | - Shunsuke Suemitsu
- Department of Psychiatry, Kawasaki Medical School, Kurashiki, 701-0192, Japan
| | - Shinji Murakami
- Department of Psychiatry, Kawasaki Medical School, Kurashiki, 701-0192, Japan
| | - Naoya Kitamura
- Department of Psychiatry, Kawasaki Medical School, Kurashiki, 701-0192, Japan
| | - Kenta Wani
- Department of Psychiatry, Kawasaki Medical School, Kurashiki, 701-0192, Japan
| | - Yosuke Matsumoto
- Department of Neuropsychiatry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8558, Japan
| | - Motoi Okamoto
- Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama, 700-8558, Japan
| | - Takeshi Ishihara
- Department of Psychiatry, Kawasaki Medical School, Kurashiki, 701-0192, Japan
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Chakravarthy H, Devanathan V. Molecular Mechanisms Mediating Diabetic Retinal Neurodegeneration: Potential Research Avenues and Therapeutic Targets. J Mol Neurosci 2018; 66:445-461. [PMID: 30293228 DOI: 10.1007/s12031-018-1188-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 09/25/2018] [Indexed: 12/16/2022]
Abstract
Diabetic retinopathy (DR) is a devastating complication of diabetes with a prevalence rate of 35%, and no effective treatment options. Since the most visible clinical features of DR are microvascular irregularities, therapeutic interventions often attempt to reduce microvascular injury, but only after permanent retinal damage has ensued. However, recent data suggests that diabetes initially affects retinal neurons, leading to neurodegeneration as an early occurrence in DR, before onset of the more noticeable vascular abnormalities. In this review, we delineate the sequence of initiating events leading to retinal degeneration in DR, considering neuronal dysfunction as a primary event. Key molecular mechanisms and potential biomarkers associated with retinal neuronal degeneration in diabetes are discussed. In addition to glial reactivity and inflammation in the diabetic retina, the contribution of neurotrophic factors, cell adhesion molecules, apoptosis markers, and G protein signaling to neurodegenerative pathways warrants further investigation. These studies could complement recent developments in innovative treatment strategies for diabetic retinopathy, such as targeting retinal neuroprotection, promoting neuronal regeneration, and attempts to re-program other retinal cell types into functional neurons. Indeed, several ongoing clinical trials are currently attempting treatment of retinal neurodegeneration by means of such novel therapeutic avenues. The aim of this article is to highlight the crucial role of neurodegeneration in early retinopathy progression, and to review the molecular basis of neuronal dysfunction as a first step toward developing early therapeutic interventions that can prevent permanent retinal damage in diabetes. ClinicalTrials.gov: NCT02471651, NCT01492400.
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Affiliation(s)
- Harshini Chakravarthy
- Department of Biology, Indian Institute of Science Education and Research (IISER), Transit campus: C/o. Sree Rama Engineering College Campus, Karakambadi Road, Mangalam, Tirupati, 517507, India
| | - Vasudharani Devanathan
- Department of Biology, Indian Institute of Science Education and Research (IISER), Transit campus: C/o. Sree Rama Engineering College Campus, Karakambadi Road, Mangalam, Tirupati, 517507, India.
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Abstract
Stroke is a cerebrovascular disorder that affects many people worldwide. In addition to the well-established functions of astrocytes and microglia in stroke pathogenesis, pericytes also play an important role in stroke progression and recovery. As perivascular multi-potent cells and an important component of the blood–brain barrier (BBB), pericytes have been shown to exert a large variety of functions, including serving as stem/progenitor cells and maintaining BBB integrity. Here in this review, we summarize the roles of pericytes in stroke pathogenesis, with a focus on their effects in cerebral blood flow, BBB integrity, angiogenesis, immune responses, scar formation and fibrosis.
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Affiliation(s)
- Jyoti Gautam
- 1 Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA
| | - Yao Yao
- 1 Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA
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28
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Li X, Yang B, Xiao Z, Zhao Y, Han S, Yin Y, Chen B, Dai J. Comparison of subacute and chronic scar tissues after complete spinal cord transection. Exp Neurol 2018; 306:132-137. [PMID: 29753649 DOI: 10.1016/j.expneurol.2018.05.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 05/02/2018] [Accepted: 05/09/2018] [Indexed: 11/27/2022]
Abstract
Traditional views consider scar tissue formed in the lesion epicenter after severe spinal cord injury (SCI) as both a physical barrier and chemical impediment for axonal regeneration. Recently, a controversial opinion suggested that astrocyte scar formation aids rather than prevents axonal regeneration in the CNS. Here, following complete transection of the thoracic spinal cord (T8) in rats, we found that scar tissue showed greater growth factor expression at 2 weeks than 8 weeks post-SCI. Further, tandem mass tag (TMT)-based quantitative proteomic analysis revealed that the components of scar tissue formed in the subacute phase are quite different from that formed in the chronic phase. We also found significantly increased axonal regrowth of sensory axons into the lesion center after chronically formed scar tissue was removed. This indicates that scar tissue formed at the chronic phase actually inhibits axonal regeneration, and that chronic removal of scar tissue may have clinical significance and benefit for SCI repair. Taken together, our study suggests that the features and roles of subacute and chronic scar tissues formed post-SCI is different and scar tissue-targeted strategies for spinal cord regeneration cannot be generalized.
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Affiliation(s)
- Xing Li
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Bin Yang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhifeng Xiao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yannan Zhao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Sufang Han
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yanyun Yin
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Bing Chen
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jianwu Dai
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
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Xu X, Bass B, McKillop WM, Mailloux J, Liu T, Geremia NM, Hryciw T, Brown A. Sox9 knockout mice have improved recovery following stroke. Exp Neurol 2018; 303:59-71. [DOI: 10.1016/j.expneurol.2018.02.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 12/13/2017] [Accepted: 02/04/2018] [Indexed: 12/17/2022]
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30
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Synaptic and circuit development of the primary sensory cortex. Exp Mol Med 2018; 50:1-9. [PMID: 29628505 PMCID: PMC5938038 DOI: 10.1038/s12276-018-0029-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 12/06/2017] [Indexed: 01/06/2023] Open
Abstract
Animals, including humans, optimize their primary sensory cortex through the use of input signals, which allow them to adapt to the external environment and survive. The time window at the beginning of life in which external input signals are connected sensitively and strongly to neural circuit optimization is called the critical period. The critical period has attracted the attention of many neuroscientists due to the rapid activity-/experience-dependent circuit development that occurs, which is clearly differentiated from other developmental time periods and brain areas. This process involves various types of GABAergic inhibitory neurons, the extracellular matrix, neuromodulators, transcription factors, and neurodevelopmental factors. In this review, I discuss recent progress regarding the biological nature of the critical period that contribute to a better understanding of brain development.
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31
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Tassew NG, Charish J, Shabanzadeh AP, Luga V, Harada H, Farhani N, D'Onofrio P, Choi B, Ellabban A, Nickerson PEB, Wallace VA, Koeberle PD, Wrana JL, Monnier PP. Exosomes Mediate Mobilization of Autocrine Wnt10b to Promote Axonal Regeneration in the Injured CNS. Cell Rep 2018; 20:99-111. [PMID: 28683327 DOI: 10.1016/j.celrep.2017.06.009] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 04/19/2017] [Accepted: 05/28/2017] [Indexed: 12/29/2022] Open
Abstract
Developing strategies that promote axonal regeneration within the injured CNS is a major therapeutic challenge, as axonal outgrowth is potently inhibited by myelin and the glial scar. Although regeneration can be achieved using the genetic deletion of PTEN, a negative regulator of the mTOR pathway, this requires inactivation prior to nerve injury, thus precluding therapeutic application. Here, we show that, remarkably, fibroblast-derived exosomes (FD exosomes) enable neurite growth on CNS inhibitory proteins. Moreover, we demonstrate that, upon treatment with FD exosomes, Wnt10b is recruited toward lipid rafts and activates mTOR via GSK3β and TSC2. Application of FD exosomes shortly after optic nerve injury promoted robust axonal regeneration, which was strongly reduced in Wnt10b-deleted animals. This work uncovers an intercellular signaling pathway whereby FD exosomes mobilize an autocrine Wnt10b-mTOR pathway, thereby awakening the intrinsic capacity of neurons for regeneration, an important step toward healing the injured CNS.
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Affiliation(s)
- Nardos G Tassew
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada
| | - Jason Charish
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
| | - Alireza P Shabanzadeh
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada
| | - Valbona Luga
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 982 University Avenue, Toronto, ON M5G 1X5, Canada
| | - Hidekiyo Harada
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada
| | - Nahal Farhani
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada
| | - Philippe D'Onofrio
- Department of Anatomy, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
| | - Brian Choi
- Department of Anatomy, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
| | - Ahmad Ellabban
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada
| | - Philip E B Nickerson
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada
| | - Valerie A Wallace
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Ophthalmology and Vision Science, Faculty of Medicine, University of Toronto, 340 College Street, Toronto, ON M5T 3A9, Canada
| | - Paulo D Koeberle
- Department of Anatomy, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
| | - Jeffrey L Wrana
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 982 University Avenue, Toronto, ON M5G 1X5, Canada
| | - Philippe P Monnier
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Ophthalmology and Vision Science, Faculty of Medicine, University of Toronto, 340 College Street, Toronto, ON M5T 3A9, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
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32
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Yin W, Li X, Zhao Y, Tan J, Wu S, Cao Y, Li J, Zhu H, Liu W, Tang G, Meng L, Wang L, Zhu B, Wang G, Zhong M, Liu X, Xie D, Chen B, Ren C, Xiao Z, Jiang X, Dai J. Taxol-modified collagen scaffold implantation promotes functional recovery after long-distance spinal cord complete transection in canines. Biomater Sci 2018. [PMID: 29528079 DOI: 10.1039/c8bm00125a] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
LOCS + Taxol implantation, a promising treatment for acute spinal cord injury, promotes endogenous neurogenesis, axon regeneration and locomotion recovery.
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33
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Integrated Stress Response as a Therapeutic Target for CNS Injuries. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6953156. [PMID: 28536699 PMCID: PMC5425910 DOI: 10.1155/2017/6953156] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 02/24/2017] [Accepted: 04/05/2017] [Indexed: 11/25/2022]
Abstract
Central nervous system (CNS) injuries, caused by cerebrovascular pathologies or mechanical contusions (e.g., traumatic brain injury, TBI) comprise a diverse group of disorders that share the activation of the integrated stress response (ISR). This pathway is an innate protective mechanism, with encouraging potential as therapeutic target for CNS injury repair. In this review, we will focus on the progress in understanding the role of the ISR and we will discuss the effects of various small molecules that target the ISR on different animal models of CNS injury.
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34
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Dauth S, Maoz BM, Sheehy SP, Hemphill MA, Murty T, Macedonia MK, Greer AM, Budnik B, Parker KK. Neurons derived from different brain regions are inherently different in vitro: a novel multiregional brain-on-a-chip. J Neurophysiol 2017; 117:1320-1341. [PMID: 28031399 PMCID: PMC5350271 DOI: 10.1152/jn.00575.2016] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 12/28/2016] [Accepted: 12/28/2016] [Indexed: 12/30/2022] Open
Abstract
Brain in vitro models are critically important to developing our understanding of basic nervous system cellular physiology, potential neurotoxic effects of chemicals, and specific cellular mechanisms of many disease states. In this study, we sought to address key shortcomings of current brain in vitro models: the scarcity of comparative data for cells originating from distinct brain regions and the lack of multiregional brain in vitro models. We demonstrated that rat neurons from different brain regions exhibit unique profiles regarding their cell composition, protein expression, metabolism, and electrical activity in vitro. In vivo, the brain is unique in its structural and functional organization, and the interactions and communication between different brain areas are essential components of proper brain function. This fact and the observation that neurons from different areas of the brain exhibit unique behaviors in vitro underline the importance of establishing multiregional brain in vitro models. Therefore, we here developed a multiregional brain-on-a-chip and observed a reduction of overall firing activity, as well as altered amounts of astrocytes and specific neuronal cell types compared with separately cultured neurons. Furthermore, this multiregional model was used to study the effects of phencyclidine, a drug known to induce schizophrenia-like symptoms in vivo, on individual brain areas separately while monitoring downstream effects on interconnected regions. Overall, this work provides a comparison of cells from different brain regions in vitro and introduces a multiregional brain-on-a-chip that enables the development of unique disease models incorporating essential in vivo features.NEW & NOTEWORTHY Due to the scarcity of comparative data for cells from different brain regions in vitro, we demonstrated that neurons isolated from distinct brain areas exhibit unique behaviors in vitro. Moreover, in vivo proper brain function is dependent on the connection and communication of several brain regions, underlining the importance of developing multiregional brain in vitro models. We introduced a novel brain-on-a-chip model, implementing essential in vivo features, such as different brain areas and their functional connections.
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Affiliation(s)
- Stephanie Dauth
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; and
| | - Ben M Maoz
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; and
| | - Sean P Sheehy
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; and
| | - Matthew A Hemphill
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; and
| | - Tara Murty
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; and
| | - Mary Kate Macedonia
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; and
| | - Angie M Greer
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; and
| | - Bogdan Budnik
- Mass Spectrometry and Proteomics Resource Laboratory, Harvard University, Cambridge, Massachusetts
| | - Kevin Kit Parker
- Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; and
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35
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Chondroitin sulfates and their binding molecules in the central nervous system. Glycoconj J 2017; 34:363-376. [PMID: 28101734 PMCID: PMC5487772 DOI: 10.1007/s10719-017-9761-z] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 12/31/2016] [Accepted: 01/04/2017] [Indexed: 01/05/2023]
Abstract
Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in the central nervous system (CNS) matrix. Its sulfation and epimerization patterns give rise to different forms of CS, which enables it to interact specifically and with a significant affinity with various signalling molecules in the matrix including growth factors, receptors and guidance molecules. These interactions control numerous biological and pathological processes, during development and in adulthood. In this review, we describe the specific interactions of different families of proteins involved in various physiological and cognitive mechanisms with CSs in CNS matrix. A better understanding of these interactions could promote a development of inhibitors to treat neurodegenerative diseases.
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36
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Cen LP, Liang JJ, Chen JH, Harvey AR, Ng TK, Zhang M, Pang CP, Cui Q, Fan YM. AAV-mediated transfer of RhoA shRNA and CNTF promotes retinal ganglion cell survival and axon regeneration. Neuroscience 2016; 343:472-482. [PMID: 28017835 DOI: 10.1016/j.neuroscience.2016.12.027] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 12/14/2016] [Accepted: 12/18/2016] [Indexed: 12/09/2022]
Abstract
The aim of the present study was to determine whether adeno-associated viral vector (AAV) mediated transfer of ciliary neurotrophic factor (CNTF) and RhoA shRNA has additive effects on promoting the survival and axon regeneration of retinal ganglion cells (RGCs) after optic nerve crush (ONC). Silencing effects of AAV-RhoA shRNA were confirmed by examining neurite outgrowth in PC12 cells, and by quantifying RhoA expression levels with western blotting. Young adult Fischer rats received an intravitreal injection of (i) saline, (ii) AAV green fluorescent protein (GFP), (iii) AAV-CNTF, (iv) AAV-RhoA shRNA, or (v) a combination of both AAV-CNTF and AAV-RhoA shRNA. Two weeks later, the ON was completely crushed. Three weeks after ONC, RGC survival was estimated by counting βIII-tubulin-positive neurons in retinal whole mounts. Axon regeneration was evaluated by counting GAP-43-positive axons in the crushed ON. It was found that AAV-RhoA shRNA decreased RhoA expression levels and promoted neurite outgrowth in vitro. In the ONC model, AAV-RhoA shRNA by itself had only weak beneficial effects on RGC axon regeneration. However, when combined with AAV-CNTF, AAV-RhoA shRNA significantly improved the therapeutic effect of AAV-CNTF on axon regeneration by nearly two fold, even though there was no significant change in RGC viability. In sum, this combination of vectors increases the regenerative response and can lead to more successful therapeutic outcomes following neurotrauma.
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Affiliation(s)
- Ling-Ping Cen
- Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou, PR China.
| | - Jia-Jian Liang
- Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou, PR China
| | - Jian-Huan Chen
- Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou, PR China
| | - Alan R Harvey
- School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia
| | - Tsz Kin Ng
- Department of Ophthalmology and Visual Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - Mingzhi Zhang
- Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou, PR China
| | - Chi Pui Pang
- Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou, PR China; Department of Ophthalmology and Visual Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - Qi Cui
- Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou, PR China; Department of Ophthalmology and Visual Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China
| | - You-Ming Fan
- Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou, PR China; Department of Neurology, Affiliated Hospital of Hubei University for Nationalities, Enshi, PR China.
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37
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Abu-Rub MT, Newland B, Naughton M, Wang W, McMahon S, Pandit A. Non-viral xylosyltransferase-1 siRNA delivery as an effective alternative to chondroitinase in an in vitro model of reactive astrocytes. Neuroscience 2016; 339:267-275. [PMID: 27743984 DOI: 10.1016/j.neuroscience.2016.10.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 10/05/2016] [Accepted: 10/06/2016] [Indexed: 12/25/2022]
Abstract
Reactive astrocytosis and the subsequent glial scar is ubiquitous to injuries of the central nervous system, especially spinal cord injury (SCI) and primarily serves to protect against further damage, but is also a prominent inhibitor of regeneration. Manipulating the glial scar by targeting chondroitin sulfate proteoglycans (CSPGs) has been the focus of much study as a means to improve axon regeneration and subsequently functional recovery. In this study we investigate the ability of small interfering RNA (siRNA) delivered by a non-viral polymer vector to silence the rate-limiting enzyme involved in CSPG synthesis. Gene expression of this enzyme, xylosyltransferase-1, was silenced by 65% in Neu7 astrocytes which conferred a reduced expression of CSPGs. Furthermore, conditioned medium taken from treated Neu7s, or co-culture experiments with dorsal root ganglia (DRG) showed that siRNA treatment resulted in a more permissive environment for DRG neurite outgrowth than treatment with chondroitinase ABC alone. These results indicate that there is a role for targeted siRNA therapy using polymeric vectors to facilitate regeneration of injured axons following central nervous system injury.
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Affiliation(s)
- Mohammad T Abu-Rub
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway, Ireland
| | - Ben Newland
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway, Ireland
| | - Michelle Naughton
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway, Ireland
| | - Wenxin Wang
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway, Ireland
| | - Siobhan McMahon
- Department of Anatomy, National University of Ireland, Galway, Ireland
| | - Abhay Pandit
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway, Ireland.
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38
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Conditional Sox9 ablation improves locomotor recovery after spinal cord injury by increasing reactive sprouting. Exp Neurol 2016; 283:1-15. [DOI: 10.1016/j.expneurol.2016.05.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 05/18/2016] [Accepted: 05/21/2016] [Indexed: 12/23/2022]
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Petersen GF, Strappe PM. Generation of diverse neural cell types through direct conversion. World J Stem Cells 2016; 8:32-46. [PMID: 26981169 PMCID: PMC4766249 DOI: 10.4252/wjsc.v8.i2.32] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 11/18/2015] [Accepted: 01/04/2016] [Indexed: 02/06/2023] Open
Abstract
A characteristic of neurological disorders is the loss of critical populations of cells that the body is unable to replace, thus there has been much interest in identifying methods of generating clinically relevant numbers of cells to replace those that have been damaged or lost. The process of neural direct conversion, in which cells of one lineage are converted into cells of a neural lineage without first inducing pluripotency, shows great potential, with evidence of the generation of a range of functional neural cell types both in vitro and in vivo, through viral and non-viral delivery of exogenous factors, as well as chemical induction methods. Induced neural cells have been proposed as an attractive alternative to neural cells derived from embryonic or induced pluripotent stem cells, with prospective roles in the investigation of neurological disorders, including neurodegenerative disease modelling, drug screening, and cellular replacement for regenerative medicine applications, however further investigations into improving the efficacy and safety of these methods need to be performed before neural direct conversion becomes a clinically viable option. In this review, we describe the generation of diverse neural cell types via direct conversion of somatic cells, with comparison against stem cell-based approaches, as well as discussion of their potential research and clinical applications.
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Dauth S, Grevesse T, Pantazopoulos H, Campbell PH, Maoz BM, Berretta S, Parker KK. Extracellular matrix protein expression is brain region dependent. J Comp Neurol 2016; 524:1309-36. [PMID: 26780384 DOI: 10.1002/cne.23965] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 01/06/2016] [Accepted: 01/13/2016] [Indexed: 01/11/2023]
Abstract
In the brain, extracellular matrix (ECM) components form networks that contribute to structural and functional diversity. Maladaptive remodeling of ECM networks has been reported in neurodegenerative and psychiatric disorders, suggesting that the brain microenvironment is a dynamic structure. A lack of quantitative information about ECM distribution in the brain hinders an understanding of region-specific ECM functions and the role of ECM in health and disease. We hypothesized that each ECM protein as well as specific ECM structures, such as perineuronal nets (PNNs) and interstitial matrix, are differentially distributed throughout the brain, contributing to the unique structure and function in the various regions of the brain. To test our hypothesis, we quantitatively analyzed the distribution, colocalization, and protein expression of aggrecan, brevican, and tenascin-R throughout the rat brain utilizing immunohistochemistry and mass spectrometry analysis and assessed the effect of aggrecan, brevican, and/or tenascin-R on neurite outgrowth in vitro. We focused on aggrecan, brevican, and tenascin-R as they are especially expressed in the mature brain, and have established roles in brain development, plasticity, and neurite outgrowth. The results revealed a differentiated distribution of all three proteins throughout the brain and indicated that their presence significantly reduces neurite outgrowth in a 3D in vitro environment. These results underline the importance of a unique and complex ECM distribution for brain physiology and suggest that encoding the distribution of distinct ECM proteins throughout the brain will aid in understanding their function in physiology and in turn assist in identifying their role in disease. J. Comp. Neurol. 524:1309-1336, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Stephanie Dauth
- Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, 02138
| | - Thomas Grevesse
- Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, 02138
| | - Harry Pantazopoulos
- Translational Neuroscience Laboratory, McLean Hospital, Belmont, Massachusetts, 02478.,Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, 02115
| | - Patrick H Campbell
- Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, 02138
| | - Ben M Maoz
- Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, 02138
| | - Sabina Berretta
- Translational Neuroscience Laboratory, McLean Hospital, Belmont, Massachusetts, 02478.,Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, 02115.,Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, 02115
| | - Kevin Kit Parker
- Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, 02138
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Radulovic M, Yoon H, Wu J, Mustafa K, Fehlings MG, Scarisbrick IA. Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury. Neurobiol Dis 2015; 83:75-89. [PMID: 26316358 DOI: 10.1016/j.nbd.2015.08.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 08/01/2015] [Accepted: 08/19/2015] [Indexed: 11/25/2022] Open
Abstract
Inflammatory-astrogliosis exacerbates damage in the injured spinal cord and limits repair. Here we identify Protease Activated Receptor 2 (PAR2) as an essential regulator of these events with mice lacking the PAR2 gene showing greater improvements in motor coordination and strength after compression-spinal cord injury (SCI) compared to wild type littermates. Molecular profiling of the injury epicenter, and spinal segments above and below, demonstrated that mice lacking PAR2 had significantly attenuated elevations in key hallmarks of astrogliosis (glial fibrillary acidic protein (GFAP), vimentin and neurocan) and in expression of pro-inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor (TNF) and interleukin-1 beta (IL-1β)). SCI in PAR2-/- mice was also accompanied by improved preservation of protein kinase C gamma (PKCγ)-immunopositive corticospinal axons and reductions in GFAP-immunoreactivity, expression of the pro-apoptotic marker BCL2-interacting mediator of cell death (BIM), and in signal transducer and activator of transcription 3 (STAT3). The potential mechanistic link between PAR2, STAT3 and astrogliosis was further investigated in primary astrocytes to reveal that the SCI-related serine protease, neurosin (kallikrein 6) promotes IL-6 secretion in a PAR2 and STAT3-dependent manner. Data point to a signaling circuit in primary astrocytes in which neurosin signaling at PAR2 promotes IL-6 secretion and canonical STAT3 signaling. IL-6 promotes expression of GFAP, vimentin, additional IL-6 and robust increases in both neurosin and PAR2, thereby driving the PAR2-signaling circuit forward. Given the significant reductions in astrogliosis and inflammation as well as superior neuromotor recovery observed in PAR2 knockout mice after SCI, we suggest that this receptor and its agonists represent new drug targets to foster neuromotor recovery.
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Affiliation(s)
- Maja Radulovic
- Neurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States
| | - Hyesook Yoon
- Department of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States; Department of Physiology and Biomedical Engineering, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States
| | - Jianmin Wu
- Department of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States
| | - Karim Mustafa
- Neurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States
| | - Michael G Fehlings
- Department of Surgery, Toronto Western Research Institute, Toronto, ON M5T 2S8, Canada
| | - Isobel A Scarisbrick
- Neurobiology of Disease Program, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States; Department of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States; Department of Physiology and Biomedical Engineering, Mayo Medical and Graduate School, Rehabilitation Medicine Research Center, Rochester, MN 55905, United States.
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Abstract
Proteoglycans (PGs) regulate diverse functions in the central nervous system (CNS) by interacting with a number of growth factors, matrix proteins, and cell surface molecules. Heparan sulfate (HS) and chondroitin sulfate (CS) are two major glycosaminoglycans present in the PGs of the CNS. The functionality of these PGs is to a large extent dictated by the fine sulfation patterns present on their glycosaminoglycan (GAG) chains. In the past 15 years, there has been a significant expansion in our knowledge on the role of HS and CS chains in various neurological processes, such as neuronal growth, regeneration, plasticity, and pathfinding. However, defining the relation between distinct sulfation patterns of the GAGs and their functionality has thus far been difficult. With the emergence of novel tools for the synthesis of defined GAG structures, and techniques for their characterization, we are now in a better position to explore the structure-function relation of GAGs in the context of their sulfation patterns. In this review, we discuss the importance of GAGs on CNS development, injury, and disorders with an emphasis on their sulfation patterns. Finally, we outline several GAG-based therapeutic strategies to exploit GAG chains for ameliorating various CNS disorders.
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Affiliation(s)
- Vimal P Swarup
- Department of Bioengineering, University of Utah, Salt Lake City, 84112 UT , USA
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Bhattacharyya S, Zhang X, Feferman L, Johnson D, Tortella FC, Guizzetti M, Tobacman JK. Decline in arylsulfatase B and Increase in chondroitin 4-sulfotransferase combine to increase chondroitin 4-sulfate in traumatic brain injury. J Neurochem 2015; 134:728-39. [PMID: 25943740 DOI: 10.1111/jnc.13156] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 04/23/2015] [Accepted: 04/30/2015] [Indexed: 01/11/2023]
Abstract
In an established rat model of penetrating ballistic-like brain injury (PBBI), arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, but unaffected at the contralateral site or in sham controls. In addition, the ARSB substrate chondroitin 4-sulfate (C4S) and total sulfated glycosaminoglycans increased. The mRNA expression of chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contributions from both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia inducible factor-1α increased significantly. In contrast, sulfotransferase activity and chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, but not following scratch. These different pathways by which C4S increased in the cell preparations were both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury because of mechanical disruption inhibiting ARSB and to chemical mediation by TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following traumatic brain injury is because of contributions from impaired degradation and enhanced synthesis of C4S which combine in the pathogenesis of the glial scar. This is the first report of how two mechanisms contribute to the increase in chondroitin 4-sulfate (C4S) in TBI. Following penetrating ballistic-like brain injury in a rat model and in the scratch model of injury in fetal rat astrocytes, Arylsulfatase B activity declined, leading to accumulation of C4S. TGF-β1 exposure increased expression of chondroitin 4-sulfotransferase. Hence, the increase in C4S in TBI is attributable to both impaired degradation and enhanced synthesis, combining in the pathogenesis of the glial scar.
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Affiliation(s)
- Sumit Bhattacharyya
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.,Jesse Brown VA Medical Center, Chicago, Illinois, USA
| | - Xiaolu Zhang
- Jesse Brown VA Medical Center, Chicago, Illinois, USA.,Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Leo Feferman
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.,Jesse Brown VA Medical Center, Chicago, Illinois, USA
| | - David Johnson
- Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
| | - Frank C Tortella
- Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
| | - Marina Guizzetti
- Jesse Brown VA Medical Center, Chicago, Illinois, USA.,Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.,Oregon Health and Science University, Portland, Oregon, USA.,VA Portland Health Care System, Portland, Oregon, USA
| | - Joanne K Tobacman
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.,Jesse Brown VA Medical Center, Chicago, Illinois, USA
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Barreda-Manso MA, Yanguas-Casás N, Nieto-Sampedro M, Romero-Ramírez L. Salubrinal inhibits the expression of proteoglycans and favors neurite outgrowth from cortical neurons in vitro. Exp Cell Res 2015; 335:82-90. [PMID: 25882497 DOI: 10.1016/j.yexcr.2015.04.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 03/25/2015] [Accepted: 04/01/2015] [Indexed: 10/23/2022]
Abstract
After CNS injury, astrocytes and mesenchymal cells attempt to restore the disrupted glia limitans by secreting proteoglycans and extracellular matrix proteins (ECMs), forming the so-called glial scar. Although the glial scar is important in sealing the lesion, it is also a physical and functional barrier that prevents axonal regeneration. The synthesis of secretory proteins in the RER is under the control of the initiation factor of translation eIF2α. Inhibiting the synthesis of secretory proteins by increasing the phosphorylation of eIF2α, might be a pharmacologically efficient way of reducing proteoglycans and other profibrotic proteins present in the glial scar. Salubrinal, a neuroprotective drug, decreased the expression and secretion of proteoglycans and other profibrotic proteins induced by EGF or TGFβ, maintaining eIF2α phosphorylated. Besides, Salubrinal also reduced the transcription of proteoglycans and other profibrotic proteins, suggesting that it induced the degradation of non-translated mRNA. In a model in vitro of the glial scar, cortical neurons grown on cocultures of astrocytes and fibroblasts with TGFβ treated with Salubrinal, showed increased neurite outgrowth compared to untreated cells. Our results suggest that Salubrinal may be considered of therapeutic value facilitating axonal regeneration, by reducing overproduction and secretion of proteoglycans and profibrotic protein inhibitors of axonal growth.
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Affiliation(s)
- M Asunción Barreda-Manso
- Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain; Laboratorio de Plasticidad Neural, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071 Toledo, Spain
| | - Natalia Yanguas-Casás
- Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain
| | - Manuel Nieto-Sampedro
- Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain; Laboratorio de Plasticidad Neural, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071 Toledo, Spain
| | - Lorenzo Romero-Ramírez
- Laboratorio de Plasticidad Neural, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Finca la Peraleda s/n, 45071 Toledo, Spain.
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Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:610813. [PMID: 25834699 PMCID: PMC4365363 DOI: 10.1155/2015/610813] [Citation(s) in RCA: 507] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Accepted: 02/18/2015] [Indexed: 12/22/2022]
Abstract
Neuroinflammation and mitochondrial dysfunction are common features of chronic neurodegenerative diseases of the central nervous system. Both conditions can lead to increased oxidative stress by excessive release of harmful reactive oxygen and nitrogen species (ROS and RNS), which further promote neuronal damage and subsequent inflammation resulting in a feed-forward loop of neurodegeneration. The cytokine tumor necrosis factor (TNF), a master regulator of the immune system, plays an important role in the propagation of inflammation due to the activation and recruitment of immune cells via its receptor TNF receptor 1 (TNFR1). Moreover, TNFR1 can directly induce oxidative stress by the activation of ROS and RNS producing enzymes. Both TNF-induced oxidative stress and inflammation interact and cooperate to promote neurodegeneration. However, TNF plays a dual role in neurodegenerative disease, since stimulation via its second receptor, TNFR2, is neuroprotective and promotes tissue regeneration. Here we review the interrelation of oxidative stress and inflammation in the two major chronic neurodegenerative diseases, Alzheimer's and Parkinson's disease, and discuss the dual role of TNF in promoting neurodegeneration and tissue regeneration via its two receptors.
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Gause Ii TM, Sivak WN, Marra KG. The role of chondroitinase as an adjuvant to peripheral nerve repair. Cells Tissues Organs 2015; 200:59-68. [PMID: 25766067 DOI: 10.1159/000369449] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2014] [Indexed: 11/19/2022] Open
Abstract
Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of neural regeneration in the peripheral nervous system. Following nerve injury, inhibitory CSPGs accumulate within the endoneurium and Schwann cell basal lamina of the distal nerve stump. The utilization of chondroitinase ABC (chABC) has led to a marked increase in the ability of injured axons to regenerate across gaps through the CSPG-laden extracellular matrix. Experimental models have repeatedly shown chABC to be capable of degrading the CSPGs that hinder neurite outgrowth. In this article, the characterization of CSPGs, their upregulation following peripheral nerve injury, and potential mechanisms behind their growth and inhibition are described. To date, the literature supports that the adjunct use of chABC may be beneficial to peripheral nerve repair in digesting inhibitory CSPGs. chABC has also shown some indication of synergism with other therapies, such as stem cell transplantation. Evidence supporting the use of chondroitinase as a treatment modality in nerve repair, either alone or in combination with other agents, is reviewed within. Finally, several shortcomings of chABC are addressed, notably its thermal stability and physiologic longevity - both hindering its widespread clinical adoption. Future studies are warranted in order to optimize the therapeutic benefits of the chondroitinase enzyme.
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Traumatic Brain Injury and the Neuronal Microenvironment: A Potential Role for Neuropathological Mechanotransduction. Neuron 2015; 85:1177-92. [DOI: 10.1016/j.neuron.2015.02.041] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Scar-modulating treatments for central nervous system injury. Neurosci Bull 2014; 30:967-984. [PMID: 24957881 DOI: 10.1007/s12264-013-1456-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 04/09/2014] [Indexed: 02/04/2023] Open
Abstract
Traumatic injury to the adult mammalian central nervous system (CNS) leads to complex cellular responses. Among them, the scar tissue formed is generally recognized as a major obstacle to CNS repair, both by the production of inhibitory molecules and by the physical impedance of axon regrowth. Therefore, scar-modulating treatments have become a leading therapeutic intervention for CNS injury. To date, a variety of biological and pharmaceutical treatments, targeting scar modulation, have been tested in animal models of CNS injury, and a few are likely to enter clinical trials. In this review, we summarize current knowledge of the scar-modulating treatments according to their specific aims: (1) inhibition of glial and fibrotic scar formation, and (2) blockade of the production of scar-associated inhibitory molecules. The removal of existing scar tissue is also discussed as a treatment of choice. It is believed that only a combinatorial strategy is likely to help eliminate the detrimental effects of scar tissue on CNS repair.
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Miyamoto K, Tanaka N, Moriguchi K, Ueno R, Kadomatsu K, Kitagawa H, Kusunoki S. Chondroitin 6-O-sulfate ameliorates experimental autoimmune encephalomyelitis. Glycobiology 2014; 24:469-75. [PMID: 24584141 DOI: 10.1093/glycob/cwu014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023] Open
Abstract
Chondroitin sulfate proteoglycans (CSPGs) are the main component of the extracellular matrix in the central nervous system (CNS) and influence neuroplasticity. Although CSPG is considered an inhibitory factor for nerve repair in spinal cord injury, it is unclear whether CSPG influences the pathogenetic mechanisms of neuroimmunological diseases. We induced experimental autoimmune encephalomyelitis (EAE) in chondroitin 6-O-sulfate transferase 1-deficient (C6st1(-/-)) mice. C6ST1 is the enzyme that transfers sulfate residues to position 6 of N-acetylgalactosamine in the sugar chain of CSPG. The phenotypes of EAE in C6st1(-/-) mice were more severe than those in wild-type (WT) mice were. In adoptive-transfer EAE, in which antigen-reactive T cells from WT mice were transferred to C6st1(-/-) and WT mice, phenotypes were significantly more severe in C6st1(-/-) than in WT mice. The recall response of antigen-reactive T cells was not significantly different among the groups. Furthermore, the number of pathogenic T cells within the CNS was also not considerably different. When EAE was induced in C6ST1 transgenic mice with C6ST1 overexpression, the mice showed considerably milder symptoms compared with those in WT mice. In conclusion, the presence of sulfate at position 6 of N-acetylgalactosamine of CSPG may influence the effecter phase of EAE to prevent the progression of pathogenesis. Thus, modification of the carbohydrate residue of CSPG may be a novel therapeutic strategy for neuroimmunological diseases such as multiple sclerosis.
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MESH Headings
- Acetylglucosamine/genetics
- Acetylglucosamine/immunology
- Acetylglucosamine/metabolism
- Animals
- Chondroitin Sulfates/genetics
- Chondroitin Sulfates/immunology
- Chondroitin Sulfates/metabolism
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Gene Expression Regulation, Enzymologic/genetics
- Gene Expression Regulation, Enzymologic/immunology
- Mice
- Mice, Knockout
- Multiple Sclerosis/genetics
- Multiple Sclerosis/immunology
- Multiple Sclerosis/metabolism
- Multiple Sclerosis/pathology
- Sulfotransferases/genetics
- Sulfotransferases/immunology
- Sulfotransferases/metabolism
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- T-Lymphocytes/pathology
- Carbohydrate Sulfotransferases
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Affiliation(s)
- Katsuichi Miyamoto
- Department of Neurology, Kinki University School of Medicine, Osaka-Sayama, Japan
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