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Gobbo D, Kirchhoff F. Animal-based approaches to understanding neuroglia physiology in vitro and in vivo. HANDBOOK OF CLINICAL NEUROLOGY 2025; 209:229-263. [PMID: 40122627 DOI: 10.1016/b978-0-443-19104-6.00012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
This chapter describes the pivotal role of animal models for unraveling the physiology of neuroglial cells in the central nervous system (CNS). The two rodent species Mus musculus (mice) and Rattus norvegicus (rats) have been indispensable in scientific research due to their remarkable resemblance to humans anatomically, physiologically, and genetically. Their ease of maintenance, short gestation times, and rapid development make them ideal candidates for studying the physiology of astrocytes, oligodendrocyte-lineage cells, and microglia. Moreover, their genetic similarity to humans facilitates the investigation of molecular mechanisms governing neural physiology. Mice are largely the predominant model of neuroglial research, owing to advanced genetic manipulation techniques, whereas rats remain invaluable for applications requiring larger CNS structures for surgical manipulations. Next to rodents, other animal models, namely, Danio rerio (zebrafish) and Drosophila melanogaster (fruit fly), will be discussed to emphasize their critical role in advancing our understanding of glial physiology. Each animal model provides distinct advantages and disadvantages. By combining the strengths of each of them, researchers can gain comprehensive insights into glial function across species, ultimately promoting the understanding of glial physiology in the human CNS and driving the development of novel therapeutic interventions for CNS disorders.
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Affiliation(s)
- Davide Gobbo
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, Homburg, Germany.
| | - Frank Kirchhoff
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, Homburg, Germany; Center for Gender-specific Biology and Medicine (CGBM), University of Saarland, Homburg, Germany.
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Ni Bhraonain EP, Turner JA, Hannigan KI, Sanders KM, Cobine CA. Immunohistochemical characterization of interstitial cells and their spatial relationship to motor neurons within the mouse esophagus. Cell Tissue Res 2025; 399:61-84. [PMID: 39607495 DOI: 10.1007/s00441-024-03929-z] [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: 05/24/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024]
Abstract
Interstitial cells of Cajal (ICC) and PDGFRα+ cells regulate smooth muscle motility in the gastrointestinal (GI) tract, yet their function in the esophagus remains unknown. The mouse esophagus has been described as primarily skeletal muscle; however, ICC have been identified in this region. This study characterizes the distribution of skeletal and smooth muscle cells (SMCs) and their spatial relationship to ICC, PDGFRα+ cells, and intramuscular motor neurons in the mouse esophagus. SMCs occupied approximately 30% of the distal esophagus, but their density declined in more proximal regions. Similarly, ANO1+ intramuscular ICC (ICC-IM) were distributed along the esophagus, with density decreasing proximally. While ICC-IM were closely associated with SMCs, they were also present in regions of skeletal muscle. Intramuscular, submucosal, and myenteric PDGFRα+ cells were densely distributed throughout the esophagus, yet only intramuscular PDGFRα+ cells in the lower esophageal sphincter (LES) and distal esophagus expressed SK3. ICC-IM and PDGFRα+ cells were closely associated with intramuscular nNOS+, VIP+, VAChT+, and TH+ neurons and GFAP+ cells resembling intramuscular enteric glia. These findings suggest that ICC-IM and PDGFRα+ cells may have roles in regulating esophageal motility due to their close proximity to each other and to skeletal muscle and SMCs, although further functional studies are needed to explore their role in this region. The mixed muscular composition and presence of interstitial cells in the mouse distal esophagus is anatomically similar to the transitional zone found in the human esophagus, and therefore, motility studies in the mouse may be translatable to humans.
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Affiliation(s)
- Emer P Ni Bhraonain
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA
| | - Jack A Turner
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA
| | - Karen I Hannigan
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA
| | - Caroline A Cobine
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 N. Virginia St., MS 352, Reno, NV, 89557, USA.
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Santhosh S, Zanoletti L, Stamp LA, Hao MM, Matteoli G. From diversity to disease: unravelling the role of enteric glial cells. Front Immunol 2024; 15:1408744. [PMID: 38957473 PMCID: PMC11217337 DOI: 10.3389/fimmu.2024.1408744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/27/2024] [Indexed: 07/04/2024] Open
Abstract
Enteric glial cells (EGCs) are an essential component of the enteric nervous system (ENS) and play key roles in gastrointestinal development, homeostasis, and disease. Derived from neural crest cells, EGCs undergo complex differentiation processes regulated by various signalling pathways. Being among the most dynamic cells of the digestive system, EGCs react to cues in their surrounding microenvironment and communicate with various cell types and systems within the gut. Morphological studies and recent single cell RNA sequencing studies have unveiled heterogeneity among EGC populations with implications for regional functions and roles in diseases. In gastrointestinal disorders, including inflammatory bowel disease (IBD), infections and cancer, EGCs modulate neuroplasticity, immune responses and tumorigenesis. Recent evidence suggests that EGCs respond plastically to the microenvironmental cues, adapting their phenotype and functions in disease states and taking on a crucial role. They exhibit molecular abnormalities and alter communication with other intestinal cell types, underscoring their therapeutic potential as targets. This review delves into the multifaceted roles of EGCs, particularly emphasizing their interactions with various cell types in the gut and their significant contributions to gastrointestinal disorders. Understanding the complex roles of EGCs in gastrointestinal physiology and pathology will be crucial for the development of novel therapeutic strategies for gastrointestinal disorders.
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Affiliation(s)
- Sneha Santhosh
- Department of Chronic Diseases, Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Lisa Zanoletti
- Department of Chronic Diseases, Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Pavia, Italy
| | - Lincon A. Stamp
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Marlene M. Hao
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Gianluca Matteoli
- Department of Chronic Diseases, Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Leuven Institute for Single-cell Omics (LISCO), KU Leuven, Leuven, Belgium
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Ni Bhraonain E, Turner J, Hannigan K, Sanders K, Cobine C. Immunohistochemical characterization of interstitial cells and their relationship to motor neurons within the mouse esophagus. RESEARCH SQUARE 2024:rs.3.rs-4474290. [PMID: 38947055 PMCID: PMC11213231 DOI: 10.21203/rs.3.rs-4474290/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Interstitial cells of Cajal (ICC) and PDGFRα+ cells regulate smooth muscle motility in the gastrointestinal (GI) tract. However, their role(s) in esophageal motility are still unclear. The mouse esophagus has traditionally been described as almost entirely skeletal muscle in nature though ICC have been identified along its entire length. The current study evaluated the distribution of skeletal and smooth muscle within the esophagus using a mouse selectively expressing eGFP in smooth muscle cells (SMCs). The relationship of SMCs to ICC and PDGFRα+ cells was also examined. SMCs declined in density in the oral direction however SMCs represented ~ 25% of the area in the distal esophagus suggesting a likeness to the transition zone observed in humans. ANO1+ intramuscular ICC (ICC-IM) were distributed along the length of the esophagus though like SMCs, declined proximally. ICC-IM were closely associated with SMCs but were also found in regions devoid of SMCs. Intramuscular and submucosal PDGFRα+ cells were densely distributed throughout the esophagus though only intramuscular PDGFRα+ cells within the LES and distal esophagus highly expressed SK3. ICC-IM and PDGFRα+ cells were closely associated with nNOS+, VIP+, VAChT+ and TH+ neurons throughout the LES and distal esophagus. GFAP+ cells resembling intramuscular enteric glia were observed within the muscle and were closely associated with ICC-IM and PDGFRα+ cells, occupying a similar location to c. These data suggest that the mouse esophagus is more similar to the human than thought previously and thus set the foundation for future functional and molecular studies using transgenic mice.
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Tefr Faridová A, Heřman H, Danačíková Š, Svoboda J, Otáhal J. Serum biomarkers of hypoxic-ischemic brain injury. Physiol Res 2023; 72:S461-S474. [PMID: 38165751 PMCID: PMC10861251 DOI: 10.33549/physiolres.935214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2024] Open
Abstract
Brain injury is a multifaceted condition arising from nonspecific damage to nervous tissue. The resulting cognitive developmental impairments reverberate through patients' lives, affecting their families, and even the broader economic landscape. The significance of early brain injury detection lies in its potential to stave off severe consequences and enhance the effectiveness of tailored therapeutic interventions. While established methods like neuroimaging and neurophysiology serve as valuable diagnostic tools, their demanding nature restricts their accessibility, particularly in scenarios such as small hospitals, nocturnal or weekend shifts, and cases involving unstable patients. Hence, there is a pressing need for more accessible and efficient diagnostic avenues. Among the spectrum of brain injuries, hypoxic-ischemic encephalopathy stands out as a predominant affliction in the pediatric population. Diagnosing brain injuries in newborns presents challenges due to the subjective nature of assessments like Apgar scores and the inherent uncertainty in neurological examinations. In this context, methods like magnetic resonance and ultrasound hold recommendations for more accurate diagnosis. Recognizing the potential of serum biomarkers derived from blood samples, this paper underscores their promise as a more expedient and resource-efficient means of assessing brain injuries. The review compiles current insights into serum biomarkers, drawing from experiments conducted on animal models as well as human brain pathologies. The authors aim to elucidate specific characteristics, temporal profiles, and the available corpus of experimental and clinical data for serum biomarkers specific to brain injuries. These include neuron-specific enolase (NSE), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), S100 calcium-binding protein beta (S100B), glial fibrillary acidic protein (GFAP), and high-mobility-group-protein-box-1 (HMGB1). This comprehensive endeavor contributes to advancing the understanding of brain injury diagnostics and potential avenues for therapeutic intervention.
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Affiliation(s)
- A Tefr Faridová
- A. Tefr Faridová, Department of Pathophysiology, Second Faculty of Medicine, Charles University, Prague 5, Czech Republic. and
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Uztimür M, Dörtbudak MB. Evaluation of brain injury in goats naturally infected with Coenurus cerebralis; brain specific biomarkers, acute inflammation, and DNA oxidation. Res Vet Sci 2023; 165:105043. [PMID: 37856943 DOI: 10.1016/j.rvsc.2023.105043] [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: 07/18/2023] [Revised: 09/14/2023] [Accepted: 10/01/2023] [Indexed: 10/21/2023]
Abstract
This investigate goals are to establish the utility of brain-specific biomarkers (GFAP and S100B) in vivo and to assess the brain damage in C. cerebralis-infected goats using histopathological and immunopathological methods. The animal material of the study consisted of 10 healthy and 20 Coenurus cerebralis infected female hair goats. Serum GFAP and S100B concentrations were measured to determine brain damage. Serum S100B (p < 0.037), GFAP (p < 0.012), urea (p < 0.045), GGT (p < 0.001) and ALT (p < 0.001) concentrations in the C.cerebralis group were significantly higher than the control group. There was no significant difference between the C.cerebralis group and the control group for hsTnI (p > 0.078), creatinine (p > 0.099) and CK-MB (p > 0.725). In the histopathological examination, pressure atrophy and related inflammatory changes were observed due to mechanical damage of the parasite. Immunohistochemical examinations revealed that the parasite stimulated inflammation with the expression of TNF-α and caused DNA damage with the expression of 8-OHdG. As a result, when the data collected for this study are assessed as a whole, it is thought that the use of brainspecific GFAP and S100B biomarkers may be beneficial in determining brain damage in naturally infected hair goats with C.cerebralis. Changes in the levels of brain-specific biomarkers contribute significantly to determining the prognosis of the disease in vivo. Measurement of GFAP and S100B concentrations from serum offers an important alternative to the CSF method.
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Affiliation(s)
- Murat Uztimür
- Bingöl University, Faculty of Veterinary Medicine, Department of Internal Medicine, Bingöl, Türkiye.
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Theuriet J, Cluse F, Gravier-Dumonceau A, Picard G, Closs S, Rogemond V, Timestit N, Bouhour F, Petiot P, Davy V, Chanson E, Arzalluz-Luque J, Marignier R, Honnorat J, Pegat A. Peripheral nervous system involvement accompanies central nervous system involvement in anti-glial fibrillary acidic protein (GFAP) antibody-related disease. J Neurol 2023; 270:5545-5560. [PMID: 37540278 PMCID: PMC10576672 DOI: 10.1007/s00415-023-11908-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND Glial fibrillary acidic protein (GFAP) is expressed by astrocytes in the central nervous system (CNS), but also by immature and regenerative Schwann cells in the peripheral nervous system (PNS). GFAP antibodies (GFAP-Abs) in cerebrospinal fluid (CSF) have been mainly described in patients with meningoencephalomyelitis. We aimed to study PNS symptoms in patients with CSF GFAP-Abs. METHODS We retrospectively included all patients tested positive for GFAP-Abs in the CSF by immunohistochemistry and confirmed by cell-based assay expressing human GFAPα since 2017, from two French reference centers. RESULTS In a cohort of 103 CSF GFAP-Abs patients, 25 (24%) presented with PNS involvement. Among them, the median age at onset was 48 years and 14/25 (56%) were female. Abnormal electroneuromyography was observed in 11/25 patients (44%), including eight isolated radiculopathies, one radiculopathy associated with polyneuropathy, one radiculopathy associated with sensory neuronopathy, and one demyelinating polyradiculoneuropathy. Cranial nerve involvement was observed in 18/25 patients (72%). All patients except one had an associated CNS involvement. The first manifestation of the disease concerned the PNS in three patients. First-line immunotherapy was administered to 18/24 patients (75%). The last follow-up modified Rankin Scale was ≤ 2 in 19/23 patients (83%). Patients with PNS involvement had significantly more bladder dysfunction than patients with isolated CNS involvement (68 vs 40.3%, p = 0.031). CONCLUSIONS PNS involvement in GFAP-Abs autoimmunity is heterogeneous but not rare and is mostly represented by acute or subacute cranial nerve injury and/or lower limb radiculopathy. Rarely, PNS involvement can be the first manifestation revealing the disease.
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Affiliation(s)
- Julian Theuriet
- Service d'electroneuromyographie et de pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Groupement Est, 59 boulevard Pinel, Bron, France
| | - Florent Cluse
- Service d'electroneuromyographie et de pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Groupement Est, 59 boulevard Pinel, Bron, France
- Service de Neurologie C, troubles du mouvement et pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Groupement Est, Bron, France
| | - Alice Gravier-Dumonceau
- Service de Neurologie C, troubles du mouvement et pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Groupement Est, Bron, France
| | - Géraldine Picard
- French Reference Centre on Paraneoplastic Neurological Syndrome, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
| | - Sterenn Closs
- French Reference Centre on Paraneoplastic Neurological Syndrome, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
| | - Véronique Rogemond
- French Reference Centre on Paraneoplastic Neurological Syndrome, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
| | - Noémie Timestit
- Service de biostatistique, Hospices Civils de Lyon, Lyon, France
| | - Françoise Bouhour
- Service d'electroneuromyographie et de pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Groupement Est, 59 boulevard Pinel, Bron, France
| | - Philippe Petiot
- Service d'electroneuromyographie et de pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Groupement Est, 59 boulevard Pinel, Bron, France
| | - Vincent Davy
- Service de neurologie, Hôpital Pitié Salpétrière, Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Eve Chanson
- Service de neurologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France
| | - Joaquín Arzalluz-Luque
- Service de Neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon, Bron, France
| | - Romain Marignier
- Service de Neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon, Bron, France
- Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (MIRCEM), Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon, Bron, France
| | - Jerome Honnorat
- French Reference Centre on Paraneoplastic Neurological Syndrome, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
- MeLiS-UCBL-CNRS UMR 5284-INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France
| | - Antoine Pegat
- Service d'electroneuromyographie et de pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Groupement Est, 59 boulevard Pinel, Bron, France.
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Sanchini G, Vaes N, Boesmans W. Mini-review: Enteric glial cell heterogeneity: Is it all about the niche? Neurosci Lett 2023; 812:137396. [PMID: 37442521 DOI: 10.1016/j.neulet.2023.137396] [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: 04/01/2023] [Revised: 06/28/2023] [Accepted: 07/10/2023] [Indexed: 07/15/2023]
Abstract
Enteric glial cells represent the enteric population of peripheral glia. According to their 'glial' nature, their principal function is to support enteric neurons in both structural and functional ways. Mounting evidence however demonstrates that enteric glial cells crucially contribute to the majority of enteric nervous system functions, thus acting as pivotal players in the maintenance of gut homeostasis. Various types of enteric glia are present within the gut wall, creating an intricate interaction network with other gastrointestinal cell types. Their distribution throughout the different layers of the gut wall translates in characteristic phenotypes that are tailored to the local tissue requirements of the digestive tract. This heterogeneity is assumed to be mirrored by functional specialization, but the extensive plasticity and versatility of enteric glial cells complicates a one on one phenotype/function definition. Moreover, the relative contribution of niche-specific signals versus lineage determinants for driving enteric glial heterogeneity is still uncertain. In this review we focus on the current understanding of phenotypic and functional enteric glial cell heterogeneity, from a microenvironmental and developmental perspective.
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Affiliation(s)
- Gabriele Sanchini
- Enteric Neurobiology Lab, Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
| | - Nathalie Vaes
- Enteric Neurobiology Lab, Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
| | - Werend Boesmans
- Enteric Neurobiology Lab, Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium; Department of Pathology, GROW-School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, the Netherlands.
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Patani R, Hardingham GE, Liddelow SA. Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration. Nat Rev Neurol 2023; 19:395-409. [PMID: 37308616 DOI: 10.1038/s41582-023-00822-1] [Citation(s) in RCA: 192] [Impact Index Per Article: 96.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2023] [Indexed: 06/14/2023]
Abstract
Despite advances in uncovering the mechanisms that underlie neuroinflammation and neurodegenerative disease, therapies that prevent neuronal loss remain elusive. Targeting of disease-defining markers in conditions such as Alzheimer disease (amyloid-β and tau) or Parkinson disease (α-synuclein) has been met with limited success, suggesting that these proteins do not act in isolation but form part of a pathological network. This network could involve phenotypic alteration of multiple cell types in the CNS, including astrocytes, which have a major neurosupportive, homeostatic role in the healthy CNS but adopt reactive states under acute or chronic adverse conditions. Transcriptomic studies in human patients and disease models have revealed the co-existence of many putative reactive sub-states of astrocytes. Inter-disease and even intra-disease heterogeneity of reactive astrocytic sub-states are well established, but the extent to which specific sub-states are shared across different diseases is unclear. In this Review, we highlight how single-cell and single-nuclei RNA sequencing and other 'omics' technologies can enable the functional characterization of defined reactive astrocyte states in various pathological scenarios. We provide an integrated perspective, advocating cross-modal validation of key findings to define functionally important sub-states of astrocytes and their triggers as tractable therapeutic targets with cross-disease relevance.
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Affiliation(s)
- Rickie Patani
- Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, UK
- The Francis Crick Institute, Human Stem Cells and Neurodegeneration Laboratory, London, UK
| | - Giles E Hardingham
- Euan MacDonald Centre for MND, University of Edinburgh, Edinburgh, UK
- UK Dementia Research Institute at the University of Edinburgh, University of Edinburgh, Edinburgh, UK
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Shane A Liddelow
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA.
- Department of Neuroscience & Physiology, NYU Grossman School of Medicine, New York, NY, USA.
- Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA.
- Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, USA.
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McGinnis A, Ji RR. The Similar and Distinct Roles of Satellite Glial Cells and Spinal Astrocytes in Neuropathic Pain. Cells 2023; 12:965. [PMID: 36980304 PMCID: PMC10047571 DOI: 10.3390/cells12060965] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/19/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Preclinical studies have identified glial cells as pivotal players in the genesis and maintenance of neuropathic pain after nerve injury associated with diabetes, chemotherapy, major surgeries, and virus infections. Satellite glial cells (SGCs) in the dorsal root and trigeminal ganglia of the peripheral nervous system (PNS) and astrocytes in the central nervous system (CNS) express similar molecular markers and are protective under physiological conditions. They also serve similar functions in the genesis and maintenance of neuropathic pain, downregulating some of their homeostatic functions and driving pro-inflammatory neuro-glial interactions in the PNS and CNS, i.e., "gliopathy". However, the role of SGCs in neuropathic pain is not simply as "peripheral astrocytes". We delineate how these peripheral and central glia participate in neuropathic pain by producing different mediators, engaging different parts of neurons, and becoming active at different stages following nerve injury. Finally, we highlight the recent findings that SGCs are enriched with proteins related to fatty acid metabolism and signaling such as Apo-E, FABP7, and LPAR1. Targeting SGCs and astrocytes may lead to novel therapeutics for the treatment of neuropathic pain.
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Affiliation(s)
- Aidan McGinnis
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Ru-Rong Ji
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA
- Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
- Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA
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Janigro D, Mondello S, Posti JP, Unden J. GFAP and S100B: What You Always Wanted to Know and Never Dared to Ask. Front Neurol 2022; 13:835597. [PMID: 35386417 PMCID: PMC8977512 DOI: 10.3389/fneur.2022.835597] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/03/2022] [Indexed: 12/19/2022] Open
Abstract
Traumatic brain injury (TBI) is a major global health issue, with outcomes spanning from intracranial bleeding, debilitating sequelae, and invalidity with consequences for individuals, families, and healthcare systems. Early diagnosis of TBI by testing peripheral fluids such as blood or saliva has been the focus of many research efforts, leading to FDA approval for a bench-top assay for blood GFAP and UCH-L1 and a plasma point-of-care test for GFAP. The biomarker S100B has been included in clinical guidelines for mTBI (mTBI) in Europe. Despite these successes, several unresolved issues have been recognized, including the robustness of prior data, the presence of biomarkers in tissues beyond the central nervous system, and the time course of biomarkers in peripheral body fluids. In this review article, we present some of these issues and provide a viewpoint derived from an analysis of existing literature. We focus on two astrocytic proteins, S100B and GFAP, the most commonly employed biomarkers used in mTBI. We also offer recommendations that may translate into a broader acceptance of these clinical tools.
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Affiliation(s)
- Damir Janigro
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, United States.,FloTBI, Cleveland, OH, United States
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Jussi P Posti
- Department of Neurosurgery, Neurocenter, Turku Brain Injury Center, Turku University Hospital, University of Turku, Turku, Finland
| | - Johan Unden
- Department of Operation and Intensive Care, Hallands Hospital Halmstad, Lund University, Lund, Sweden
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Iruzubieta P, Cantarero I, Monzón M, Lahoz M, Junquera C. Supporting Evidence of Human Enteric Nervous System Adult Neurogenesis: Presence of Primary Cilia and Adult Neurogenesis Markers. Cell Mol Neurobiol 2022; 42:473-481. [PMID: 33237455 PMCID: PMC11441200 DOI: 10.1007/s10571-020-01017-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 11/18/2020] [Indexed: 11/26/2022]
Abstract
Adult neurogenesis has been profusely studied in central nervous system. However, its presence in enteric nervous system remains elusive although it has been recently demonstrated in mice and intimately linked to glial cells. Moreover, primary cilium is an important organelle in central adult neurogenesis. In the present study, we analysed some parallelisms between central and enteric nervous system (ENS) in humans based on ultrastructural and immunohistochemical techniques. Thus, we described the presence of primary cilia in some subtypes of glial cells and Interstitial Cells of Cajal (ICCs) and we performed 3-D reconstructions to better characterise their features. Besides, we studied the expression of several adult neurogenesis-related proteins. Immature neuron markers were found in human ENS, supporting the existence of adult neurogenesis. However, only ICCs showed proliferation markers. Hence, we propose a new paradigm where ICCs would constitute the original neural stem cells which, through asymmetrical cell division, would generate the new-born neurons.
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Affiliation(s)
- Pablo Iruzubieta
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain.
- Institute for Health Research Aragón (IIS), Domingo Miral s/n, 50009, Zaragoza, Spain.
| | - Irene Cantarero
- Dpto. Biología Celular, Fisiología e Inmunología. Facultad de Medicina, Instituto Maimonides de Investigación Biomédica (IMIBIC), Universidad de Córdoba, Córdoba, Spain
| | - Marta Monzón
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain
- Institute for Health Research Aragón (IIS), Domingo Miral s/n, 50009, Zaragoza, Spain
| | - Manuel Lahoz
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain
| | - Concepción Junquera
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain
- Institute for Health Research Aragón (IIS), Domingo Miral s/n, 50009, Zaragoza, Spain
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Blood Biomarkers in Brain Injury Medicine. CURRENT PHYSICAL MEDICINE AND REHABILITATION REPORTS 2022; 2022:10.1007/s40141-022-00343-w. [PMID: 35433117 PMCID: PMC9009302 DOI: 10.1007/s40141-022-00343-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Purpose of Review This review seeks to explore blood-based biomarkers with the potential for clinical implementation. Recent Findings Emerging non-proteomic biomarkers hold promise for more accurate diagnostic and prognostic capabilities, especially in the subacute to chronic phase of TBI recovery. Further, there is a growing understanding of the overlap between TBI-related and Dementia-related blood biomarkers. Summary Given the significant heterogeneity inherent in the clinical diagnosis of Traumatic Brain Injury (TBI), there has been an exponential increase in TBI-related biomarker research over the past two decades. While TBI-related biomarker assessments include both cerebrospinal fluid analysis and advanced neuroimaging modalities, blood-based biomarkers hold the most promise to be non-invasive biomarkers widely available to Brain Injury Medicine clinicians in diverse practice settings. In this article, we review the most relevant blood biomarkers for the field of Brain Injury Medicine, including both proteomic and non-proteomic blood biomarkers, biomarkers of cerebral microvascular injury, and biomarkers that overlap between TBI and Dementia.
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Seguella L, Gulbransen BD. Enteric glial biology, intercellular signalling and roles in gastrointestinal disease. Nat Rev Gastroenterol Hepatol 2021; 18:571-587. [PMID: 33731961 PMCID: PMC8324524 DOI: 10.1038/s41575-021-00423-7] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/28/2021] [Indexed: 02/07/2023]
Abstract
One of the most transformative developments in neurogastroenterology is the realization that many functions normally attributed to enteric neurons involve interactions with enteric glial cells: a large population of peripheral neuroglia associated with enteric neurons throughout the gastrointestinal tract. The notion that glial cells function solely as passive support cells has been refuted by compelling evidence that demonstrates that enteric glia are important homeostatic cells of the intestine. Active signalling mechanisms between enteric glia and neurons modulate gastrointestinal reflexes and, in certain circumstances, function to drive neuroinflammatory processes that lead to long-term dysfunction. Bidirectional communication between enteric glia and immune cells contributes to gastrointestinal immune homeostasis, and crosstalk between enteric glia and cancer stem cells regulates tumorigenesis. These neuromodulatory and immunomodulatory roles place enteric glia in a unique position to regulate diverse gastrointestinal disease processes. In this Review, we discuss current concepts regarding enteric glial development, heterogeneity and functional roles in gastrointestinal pathophysiology and pathophysiology, with a focus on interactions with neurons and immune cells. We also present a working model to differentiate glial states based on normal function and disease-induced dysfunctions.
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Affiliation(s)
- Luisa Seguella
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy
- Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI, USA
| | - Brian D Gulbransen
- Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI, USA.
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15
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Bozic I, Savic D, Lavrnja I. Astrocyte phenotypes: Emphasis on potential markers in neuroinflammation. Histol Histopathol 2020; 36:267-290. [PMID: 33226087 DOI: 10.14670/hh-18-284] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Astrocytes, the most abundant glial cells in the central nervous system (CNS), have numerous integral roles in all CNS functions. They are essential for synaptic transmission and support neurons by providing metabolic substrates, secreting growth factors and regulating extracellular concentrations of ions and neurotransmitters. Astrocytes respond to CNS insults through reactive astrogliosis, in which they go through many functional and molecular changes. In neuroinflammatory conditions reactive astrocytes exert both beneficial and detrimental functions, depending on the context and heterogeneity of astrocytic populations. In this review we profile astrocytic diversity in the context of neuroinflammation; with a specific focus on multiple sclerosis (MS) and its best-described animal model experimental autoimmune encephalomyelitis (EAE). We characterize two main subtypes, protoplasmic and fibrous astrocytes and describe the role of intermediate filaments in the physiology and pathology of these cells. Additionally, we outline a variety of markers that are emerging as important in investigating astrocytic biology in both physiological conditions and neuroinflammation.
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Affiliation(s)
- Iva Bozic
- Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Danijela Savic
- Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Irena Lavrnja
- Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia.
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16
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Abstract
Surgical pathology for Hirschsprung disease (HSCR) occasionally is difficult, especially for those who encounter the disorder infrequently. This article reviews pathologic features of HSCR, considers various specimens the pathologist is required to evaluate, and discusses useful ancillary tests. Potential diagnostic pitfalls are highlighted, and helpful hints are provided to successfully navigate challenging situations. Finally, the article looks forward to new ancillary tests on the horizon and future topics for HSCR research.
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Affiliation(s)
- Samuel Hwang
- Department of Pathology, University of Utah, Salt Lake City, UT, USA; Seattle Children's Hospital, University of Washington, OC.8.720 4800, Sand Point Way Northeast, Seattle, WA 98105, USA
| | - Raj P Kapur
- Department of Pathology, Seattle Children's Hospital, University of Washington, OC.8.720 4800, Sand Point Way Northeast, Seattle, WA 98105, USA.
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17
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Fleming MA, Ehsan L, Moore SR, Levin DE. The Enteric Nervous System and Its Emerging Role as a Therapeutic Target. Gastroenterol Res Pract 2020; 2020:8024171. [PMID: 32963521 PMCID: PMC7495222 DOI: 10.1155/2020/8024171] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/03/2020] [Accepted: 08/24/2020] [Indexed: 02/08/2023] Open
Abstract
The gastrointestinal (GI) tract is innervated by the enteric nervous system (ENS), an extensive neuronal network that traverses along its walls. Due to local reflex circuits, the ENS is capable of functioning with and without input from the central nervous system. The functions of the ENS range from the propulsion of food to nutrient handling, blood flow regulation, and immunological defense. Records of it first being studied emerged in the early 19th century when the submucosal and myenteric plexuses were discovered. This was followed by extensive research and further delineation of its development, anatomy, and function during the next two centuries. The morbidity and mortality associated with the underdevelopment, infection, or inflammation of the ENS highlight its importance and the need for us to completely understand its normal function. This review will provide a general overview of the ENS to date and connect specific GI diseases including short bowel syndrome with neuronal pathophysiology and current therapies. Exciting opportunities in which the ENS could be used as a therapeutic target for common GI diseases will also be highlighted, as the further unlocking of such mechanisms could open the door to more therapy-related advances and ultimately change our treatment approach.
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Affiliation(s)
- Mark A. Fleming
- Department of Surgery, Division of Pediatric Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Lubaina Ehsan
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Sean R. Moore
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Daniel E. Levin
- Department of Surgery, Division of Pediatric Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
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18
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King AC, Wood TE, Rodriguez E, Parpura V, Gray M. Differential effects of SNARE-dependent gliotransmission on behavioral phenotypes in a mouse model of Huntington's disease. Exp Neurol 2020; 330:113358. [PMID: 32387649 PMCID: PMC7313419 DOI: 10.1016/j.expneurol.2020.113358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 04/14/2020] [Accepted: 05/05/2020] [Indexed: 01/31/2023]
Abstract
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine expansion in the widely expressed huntingtin protein. Multiple studies have indicated the importance of mutant huntingtin (mHTT) in astrocytes to HD pathogenesis. Astrocytes exhibit SNARE-dependent exocytosis and gliotransmission, which can be hampered by transgenic expression of dominant negative SNARE (dnSNARE) in these glial cells. We used BACHD mice and crossed them with the dnSNARE model to determine if pan-astrocytic SNARE-dependent exocytosis plays an important role in vivo in the progression of HD behavioral phenotypes. We assessed motor and neuropsychiatric behaviors in these mice. At 12 months of age there was a significant improvement in motor coordination (rotarod test) in BACHD/dnSNARE mice when compared to BACHD mice. Analyses of open field performance revealed significant worsening of center entry (at 9 and 12 months), but not distance traveled in BACHD/dnSNARE when compared to BACHD mice, and variable/inconclusive results on vertical plane entry. While no differences between BACHD and BACHD/dnSNARE mice at 12 months of age in the forced swim test were found, we did observe a significant decrease in performance of BACHD/dnSNARE mice in the light-dark box paradigm. Thus, reduction of astrocytic SNARE-dependent exocytosis has differential effects on the psychiatric-like and motor phenotypes observed in BACHD mice. These data suggest broadly targeting SNARE-dependent exocytosis in astrocytes throughout the brain as a means to modulate gliotransmission in HD may contribute to worsening of specific behavioral deficits and perhaps a brain-region specific approach would be required.
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Affiliation(s)
- Annesha C King
- Graduate Biomedical Sciences Neuroscience Theme, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, AL, USA
| | - Tara E Wood
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, AL, USA
| | - Efrain Rodriguez
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, AL, USA
| | - Vladimir Parpura
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Michelle Gray
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, AL, USA; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Prognostic Value of Glial Fibrillary Acidic Protein in Patients With Moderate and Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis. Crit Care Med 2020; 47:e522-e529. [PMID: 30889029 DOI: 10.1097/ccm.0000000000003728] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Biomarkers have been suggested as potential prognostic predictors following a moderate or severe traumatic brain injury but their prognostic accuracy is still uncertain. The objective of this systematic review is to assess the ability of the glial fibrillary acidic protein to predict prognosis in patients with moderate or severe traumatic brain injury. DATA SOURCES MEDLINE, Embase, CENTRAL, and BIOSIS electronic databases and conference abstracts, bibliographies of selected studies, and narrative reviews were searched. STUDY SELECTION Pairs of reviewers identified eligible studies. Cohort studies including greater than or equal to four patients with moderate or severe traumatic brain injury and reporting glial fibrillary acidic protein levels according to the outcomes of interest, namely Glasgow Outcome Scale or Extended Glasgow Outcome Scale, and mortality, were eligible. DATA EXTRACTION Pairs of reviewers independently extracted data from the selected studies using a standardized case report form. Mean levels were log-transformed, and their differences were pooled with random effect models. Results are presented as geometric mean ratios. Methodologic quality, risk of bias, and applicability concerns of the included studies were assessed. DATA SYNTHESIS Seven-thousand seven-hundred sixty-five citations were retrieved of which 15 studies were included in the systematic review (n = 1,070), and nine were included in the meta-analysis (n = 701). We found significant associations between glial fibrillary acidic protein serum levels and Glasgow Outcome Scale score less than or equal to 3 or Extended Glasgow Outcome Scale score less than or equal to 4 (six studies: geometric mean ratio 4.98 [95% CI, 2.19-11.13]; I = 94%) and between mortality (seven studies: geometric mean ratio 8.13 [95% CI, 3.89-17.00]; I = 99%). CONCLUSIONS Serum glial fibrillary acidic protein levels were significantly higher in patients with an unfavorable prognosis. Glial fibrillary acidic protein has a potential for clinical bedside use in helping for prognostic assessment. Further research should focus on multimodal approaches including tissue biomarkers for prognostic evaluation in critically ill patients with traumatic brain injury.
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20
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Zupin L, Ottaviani G, Rupel K, Biasotto M, Zacchigna S, Crovella S, Celsi F. Analgesic effect of Photobiomodulation Therapy: An in vitro and in vivo study. JOURNAL OF BIOPHOTONICS 2019; 12:e201900043. [PMID: 31219220 DOI: 10.1002/jbio.201900043] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 06/18/2019] [Accepted: 06/19/2019] [Indexed: 06/09/2023]
Abstract
Laser therapy, also known as Photobiomodulation (PBM) is indicated to reduce pain associated with different pathologies and applied using protocols that vary in wavelength, irradiance and fluence. Its mechanisms of action are still unclear and possibly able to directly impact on pain transmission, reducing nociceptor response. In our study, we examined the effect of two specific laser wavelengths, 800 and 970 nm, extensively applied in the clinical context and known to exert important analgesic effects. Our results point to mitochondria as the primary target of laser light in isolated dorsal root ganglion (DRG) neurons, reducing adenosine triphosphate content and increasing reactive oxygen species levels. Specifically, the 800 nm laser wavelength induced mitochondrial dysregulation, that is, increased superoxide generation and mitochondrial membrane potential. When DRG neurons were firstly illuminated by the different laser protocols and then stimulated with the natural transient receptor potential cation channel subfamily V member 1 (TRPV1) ligand capsaicin, only the 970 nm wavelength reduced the calcium response, in both amplitude and frequency. Consistent results were obtained in vivo in mice, by subcutaneous injection of capsaicin. Our findings demonstrate that the effect of PBM depends on the wavelength used, with 800 nm light mainly acting on mitochondrial metabolism and 970 nm light on nociceptive signal transmission.
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Affiliation(s)
- Luisa Zupin
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Giulia Ottaviani
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Katia Rupel
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Matteo Biasotto
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Serena Zacchigna
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
- Cardiovascular Biology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Sergio Crovella
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
- Institute for Maternal and Child Health, IRCCS Materno Infantile Burlo Garofolo, Trieste, Italy
| | - Fulvio Celsi
- Institute for Maternal and Child Health, IRCCS Materno Infantile Burlo Garofolo, Trieste, Italy
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21
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Kapur RP, Arnold MA, Conces MR, Ambartsumyan L, Avansino J, Levitt M, Wood R, Mast KJ. Remodeling of Rectal Innervation After Pullthrough Surgery for Hirschsprung Disease: Relevance to Criteria for the Determination of Retained Transition Zone. Pediatr Dev Pathol 2019; 22:292-303. [PMID: 30541422 DOI: 10.1177/1093526618817658] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND After pullthrough surgery for Hirschsprung disease (HSCR), Glut1-positive submucosal nerve hypertrophy is used to diagnose retained transition zone in the neorectum. We hypothesized that pelvic nerves, severed during pullthrough surgery, sprout into the neorectum to mimic transition zone. METHODS The density (nerves/100x field) and maximum diameter of Glut1-positive submucosal nerves were measured in biopsies and redo resections from 20 patients with post-pullthrough obstructive symptoms. Their original and/or redo resections excluded unequivocal features of transition zone (myenteric hypoganglionosis or partial circumferential aganglionosis) in 17. Postoperative values were compared with control data from 28 cadaveric and 6 surgical non-HSCR specimens, and 14 primary HSCR resections. When possible, nerves were tracked from attached native pelvic soft tissue or aganglionic rectal cuff into the pulled-through colon. RESULTS Glut1-positive submucosal nerves were not present in the 11 colons of non-HSCR infants less than 1 year of age, except sparsely in the rectum. In 17 older non-HSCR controls, occasional Glut1-positive nerves were observed in prerectal colon and were larger and more numerous in the rectum. In redo resections, Glut1-positive submucosal innervation in post-pullthrough specimens did not differ significantly from age-appropriate non-HSCR rectal controls and pelvic Glut1-positive nerves were never observed to penetrate the pulled-through colon. However, the density and caliber of Glut1-positive nerves in the neorectums were significantly greater than expected based on the prerectal location from which the pulled-through bowel originated. CONCLUSIONS Submucosal innervation in post-pullthrough specimens does not support the hypothesis that native pelvic nerves innervate the neorectum, but suggests remodeling occurs to establish the age-appropriate density and caliber of rectal Glut1-positive innervation. The latter should not be interpreted as transition zone pullthrough in a rectal biopsy from a previously done pullthrough.
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Affiliation(s)
- Raj P Kapur
- 1 Department of Pathology, Seattle Children's Hospital and University of Washington, Seattle, Washington
| | - Michael A Arnold
- 2 Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio
- 3 Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Miriam R Conces
- 2 Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio
- 3 Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Lusine Ambartsumyan
- 4 Department of Gastroenterology, Seattle Children's Hospital and University of Washington, Seattle, Washington
| | - Jeffrey Avansino
- 5 Department of Pediatric Surgery, Seattle Children's Hospital and University of Washington, Seattle, Washington
| | - Marc Levitt
- 6 Center for Colorectal and Pelvic Reconstruction, Nationwide Children's Hospital, Columbus, Ohio
| | - Richard Wood
- 6 Center for Colorectal and Pelvic Reconstruction, Nationwide Children's Hospital, Columbus, Ohio
| | - Kelley J Mast
- 7 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
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22
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Vergnolle N, Cirillo C. Neurons and Glia in the Enteric Nervous System and Epithelial Barrier Function. Physiology (Bethesda) 2019; 33:269-280. [PMID: 29897300 DOI: 10.1152/physiol.00009.2018] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The intestinal epithelial barrier is the largest exchange surface between the body and the external environment. Its functions are regulated by luminal, and also internal, components including the enteric nervous system. This review summarizes current knowledge about the role of the digestive "neuronal-glial-epithelial unit" on epithelial barrier function.
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Affiliation(s)
- Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse , France.,Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary , Calgary, Alberta , Canada
| | - Carla Cirillo
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse , France.,Laboratory for Enteric Neuroscience, TARGID, University of Leuven , Leuven , Belgium
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23
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Zhang L, Xie R, Yang J, Zhao Y, Qi C, Bian G, Wang M, Shan J, Wang C, Wang D, Luo C, Wang Y, Wu S. Chronic pain induces nociceptive neurogenesis in dorsal root ganglia from Sox2‐positive satellite cells. Glia 2019; 67:1062-1075. [DOI: 10.1002/glia.23588] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 11/15/2018] [Accepted: 12/21/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Li Zhang
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
- Department of Anatomy, Institute of Basic Medical Science Xi'an Medical University Xi'an Shaanxi China
| | - Rougang Xie
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Jiping Yang
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
- Department of Anatomy, Institute of Basic Medical Science Xi'an Medical University Xi'an Shaanxi China
| | - Youyi Zhao
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Chuchu Qi
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Ganlan Bian
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Mengmeng Wang
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Junjia Shan
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Chen Wang
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Dong Wang
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Ceng Luo
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Yazhou Wang
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
| | - Shengxi Wu
- Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine Fourth Military Medical University Xi'an Shaanxi China
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Xie YK, Zhou X, Yuan HT, Qiu J, Xin DQ, Chu XL, Wang DC, Wang Z. Resveratrol reduces brain injury after subarachnoid hemorrhage by inhibiting oxidative stress and endoplasmic reticulum stress. Neural Regen Res 2019; 14:1734-1742. [PMID: 31169191 PMCID: PMC6585540 DOI: 10.4103/1673-5374.257529] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Previous studies have shown that resveratrol, a bioactive substance found in many plants, can reduce early brain injury after subarachnoid hemorrhage, but how it acts is still unclear. This study explored the mechanism using the experimental subarachnoid hemorrhage rat model established by injecting autologous blood into the cerebellomedullary cistern. Rat models were treated with an intraperitoneal injection of 60 mg/kg resveratrol 2, 6, 24 and 46 hours after injury. At 48 hours after injury, their neurological function was assessed using a modified Garcia score. Brain edema was measured by the wet-dry method. Neuronal apoptosis in the prefrontal cortex was detected by terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Levels of reactive oxygen species and malondialdehyde in the prefrontal cortex were determined by colorimetry. CHOP, glucose-regulated protein 78, nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1 mRNA expression levels in the prefrontal cortex were measured by reverse transcription polymerase chain reaction. Tumor necrosis factor-alpha content in the prefrontal cortex was detected by enzyme linked immunosorbent assay. Immunohistochemical staining was used to detect the number of positive cells of nuclear factor-erythroid 2-related factor 2, heme oxygenase 1, glucose-regulated protein 78, CHOP and glial fibrillary acidic protein. Western blot assay was utilized to analyze the expression levels of nuclear factor-erythroid 2-related factor 2, heme oxygenase 1, glucose-regulated protein 78 and CHOP protein expression levels in the prefrontal cortex. The results showed that resveratrol treatment markedly alleviated neurological deficits and brain edema in experimental subarachnoid hemorrhage rats, and reduced neuronal apoptosis in the prefrontal cortex. Resveratrol reduced the levels of reactive oxygen species and malondialdehyde, and increased the expression of nuclear factor-erythroid 2-related factor 2, heme oxygenase-1 mRNA and protein in the prefrontal cortex. Resveratrol decreased glucose-regulated protein 78, CHOP mRNA and protein expression and tumor necrosis factor-alpha level. It also activated astrocytes. The results suggest that resveratrol exerted neuroprotective effect on subarachnoid hemorrhage by reducing oxidative damage, endoplasmic reticulum stress and neuroinflammation. The study was approved by the Animals Ethics Committee of Shandong University, China on February 22, 2016 (approval No. LL-201602022).
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Affiliation(s)
- Yun-Kai Xie
- Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong Province, China
| | - Xin Zhou
- Department of Physiology, School of Basic Medical Sciences, Shandong University; Department of Spinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China
| | - Hong-Tao Yuan
- Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong Province, China
| | - Jie Qiu
- Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong Province, China
| | - Dan-Qing Xin
- Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong Province, China
| | - Xi-Li Chu
- Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong Province, China
| | - Da-Chuan Wang
- Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong Province, China
| | - Zhen Wang
- Department of Spinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China
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25
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Pharmacodynamic Effect of Luteolin Micelles on Alleviating Cerebral Ischemia Reperfusion Injury. Pharmaceutics 2018; 10:pharmaceutics10040248. [PMID: 30501051 PMCID: PMC6320772 DOI: 10.3390/pharmaceutics10040248] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/13/2018] [Accepted: 11/14/2018] [Indexed: 12/15/2022] Open
Abstract
Oxidative stress and inflammation are important mechanisms of cerebral ischemia reperfusion (IR) injury. Luteolin (Lu), one of the major active components in the classical Tibetan prescription, which has been used in the treatment of cardiovascular diseases since 700 BC, has potential for IR injury therapy. Its hydrophobicity has impeded its further applications. In this study, we first prepared Lu micelles (M-Lu) by self-assembling with an amphiphilic copolymer via the thin film hydration method to improve the dispersion of Lu in water. The obtained M-Lu was about 30 nm, with a narrow particle size distribution, and a 5% (w/w) of Lu. The bioavailability of the micelles was further evaluated in vitro and in vivo. Compared to free Lu, M-Lu had a better penetration efficiency, which enhanced its therapeutic effect in IR injury restoration. M-Lu further strengthened the protection of nerve cells through the nuclear factor-κ-gene binding κ (NF-κB) and mitogen-activated protein kinases (MAPK) pathways and inhibited the apoptosis of cells by adjusting the expression of B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in the case of oxidative stress damage. M-Lu induced stem cells to differentiate into neuron-like cells to promote the repair and regeneration of neurons. The results of in vivo pharmacodynamics of Lu on occlusion of the middle cerebral artery model further demonstrated that M-Lu better inhibited inflammation and the oxidative stress response by the down-regulation of the inflammatory cytokine, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, and the up-regulation of the activity of anti-oxidant kinase, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), which further ameliorated the degree of IR injury. The M-Lu could be a new strategy for IR injury therapy.
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26
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Linker KE, Cross SJ, Leslie FM. Glial mechanisms underlying substance use disorders. Eur J Neurosci 2018; 50:2574-2589. [PMID: 30240518 DOI: 10.1111/ejn.14163] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 08/23/2018] [Accepted: 08/28/2018] [Indexed: 12/28/2022]
Abstract
Addiction is a devastating disorder that produces persistent maladaptive changes to the central nervous system, including glial cells. Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive. Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of processes beyond inflammation and immune surveillance, and may represent a promising therapeutic target. Indeed, glia actively modulate neurotransmission, synaptic connectivity and neural circuit function, and are critically poised to contribute to addictive-like brain states and behaviors. In this review, we argue that glia influence the cellular, molecular, and synaptic changes that occur in neurons following drug exposure, and that this cellular relationship is critically modified following drug exposure. We discuss direct actions of abused drugs on glial function through immune receptors, such as Toll-like receptor 4, as well as other mechanisms. We highlight how drugs of abuse affect glia-neural communication, and the profound effects that glial-derived factors have on neuronal excitability, structure, and function. Recent research demonstrates that glia have brain region-specific functions, and glia in different brain regions have distinct contributions to drug-associated behaviors. We will also evaluate the evidence demonstrating that glial activation is essential for drug reward and drug-induced dopamine release, and highlight clinical evidence showing that glial mechanisms contribute to drug abuse liability. In this review, we synthesize the extensive evidence that glia have a unique, pivotal, and underappreciated role in the development and maintenance of addiction.
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Affiliation(s)
- K E Linker
- Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, USA
| | - S J Cross
- Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, USA
| | - F M Leslie
- Department of Pharmacology, University of California Irvine, Irvine, CA, USA
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27
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SheikhBahaei S, Morris B, Collina J, Anjum S, Znati S, Gamarra J, Zhang R, Gourine AV, Smith JC. Morphometric analysis of astrocytes in brainstem respiratory regions. J Comp Neurol 2018; 526:2032-2047. [PMID: 29888789 PMCID: PMC6158060 DOI: 10.1002/cne.24472] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 05/07/2018] [Accepted: 05/13/2018] [Indexed: 12/30/2022]
Abstract
Astrocytes, the most abundant and structurally complex glial cells of the central nervous system, are proposed to play an important role in modulating the activities of neuronal networks, including respiratory rhythm‐generating circuits of the preBötzinger complex (preBötC) located in the ventrolateral medulla of the brainstem. However, structural properties of astrocytes residing within different brainstem regions are unknown. In this study astrocytes in the preBötC, an intermediate reticular formation (IRF) region with respiratory‐related function, and a region of the nucleus tractus solitarius (NTS) in adult rats were reconstructed and their morphological features were compared. Detailed morphological analysis revealed that preBötC astrocytes are structurally more complex than those residing within the functionally distinct neighboring IRF region, or the NTS, located at the dorsal aspect of the medulla oblongata. Structural analyses of the brainstem microvasculature indicated no significant regional differences in vascular properties. We hypothesize that high morphological complexity of preBötC astrocytes reflects their functional role in providing structural/metabolic support and modulation of the key neuronal circuits essential for breathing, as well as constraints imposed by arrangements of associated neurons and/or other local structural features of the brainstem parenchyma.
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Affiliation(s)
- Shahriar SheikhBahaei
- Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH), Bethesda, Maryland.,Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Brian Morris
- Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH), Bethesda, Maryland
| | - Jared Collina
- Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH), Bethesda, Maryland
| | - Sommer Anjum
- Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH), Bethesda, Maryland
| | - Sami Znati
- Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH), Bethesda, Maryland
| | - Julio Gamarra
- Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH), Bethesda, Maryland
| | - Ruli Zhang
- Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH), Bethesda, Maryland
| | - Alexander V Gourine
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Jeffrey C Smith
- Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH), Bethesda, Maryland
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28
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Pannese E. Biology and Pathology of Perineuronal Satellite Cells in Sensory Ganglia. BIOLOGY AND PATHOLOGY OF PERINEURONAL SATELLITE CELLS IN SENSORY GANGLIA 2018. [DOI: 10.1007/978-3-319-60140-3_1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Kastriti ME, Adameyko I. Specification, plasticity and evolutionary origin of peripheral glial cells. Curr Opin Neurobiol 2017; 47:196-202. [DOI: 10.1016/j.conb.2017.11.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 08/30/2017] [Accepted: 11/03/2017] [Indexed: 12/31/2022]
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30
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Xiang H, Xu H, Fan F, Shin SM, Hogan QH, Yu H. Glial fibrillary acidic protein promoter determines transgene expression in satellite glial cells following intraganglionic adeno-associated virus delivery in adult rats. J Neurosci Res 2017; 96:436-448. [PMID: 28941260 DOI: 10.1002/jnr.24183] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 08/25/2017] [Accepted: 09/05/2017] [Indexed: 12/24/2022]
Abstract
Recombinant adeno-associated viral (AAV)-mediated therapeutic gene transfer to dorsal root ganglia (DRG) is an effective and safe tool for treating chronic pain. However, AAV with various constitutively active promoters leads to transgene expression predominantly to neurons, while glial cells are refractory to AAV transduction in the peripheral nervous system. The present study evaluated whether in vivo satellite glial cell (SGC) transduction in the DRG can be enhanced by the SGC-specific GFAP promoter and by using shH10 and shH19, which are engineered capsid variants with Müller glia-prone transduction. Titer-matched AAV6 (as control), AAVshH10, and AAVshH19, all encoding the EGFP driven by the constitutively active CMV promoter, as well as AAV6-EGFP and AAVshH10-EGFP driven by a GFAP promoter (AAV6-GFAP-EGFP and AAVshH10-GFAP-EGFP), were injected into DRG of adult male rats. Neurotropism of gene expression was determined and compared by immunohistochemistry. Results showed that injection of AAV6- and AAVshH10-GFAP-EGFP induces robust EGFP expression selectively in SGCs, whereas injection of either AAVshH10-CMV-EGFP or AAVshH19-CMV-EGFP into DRG resulted in a similar in vivo transduction profile to AAV6-CMV-EGFP, all showing efficient transduction of sensory neurons without significant transduction of glial cell populations. Coinjection of AAV6-CMV-mCherry and AAV6-GFAP-EGFP induces transgene expression in neurons and SGCs separately. This report, together with our prior studies, demonstrates that the GFAP promoter rather than capsid tropism determines selective gene expression in SGCs following intraganglionic AAV delivery in adult rats. A dual AAV system, one with GFAP promoter and the other with CMV promoter, can efficiently express transgenes selectively in neurons versus SGCs.
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Affiliation(s)
- Hongfei Xiang
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.,Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Hao Xu
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.,Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Fan Fan
- Department of Pharmacology and Toxicology, Mississippi University Medical Center, Jackson, Mississippi
| | - Seung-Min Shin
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Quinn H Hogan
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.,Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin
| | - Hongwei Yu
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.,Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin
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31
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Posti JP, Hossain I, Takala RSK, Liedes H, Newcombe V, Outtrim J, Katila AJ, Frantzén J, Ala-Seppälä H, Coles JP, Kyllönen A, Maanpää HR, Tallus J, Hutchinson PJ, van Gils M, Menon DK, Tenovuo O. Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 Are Not Specific Biomarkers for Mild CT-Negative Traumatic Brain Injury. J Neurotrauma 2017; 34:1427-1438. [PMID: 27841729 DOI: 10.1089/neu.2016.4442] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) have been studied as potential biomarkers of mild traumatic brain injury (mTBI). We report the levels of GFAP and UCH-L1 in patients with acute orthopedic injuries without central nervous system involvement, and relate them to the type of extracranial injury, head magnetic resonance imaging (MRI) findings, and levels of GFAP and UCH-L1 in patients with CT-negative mTBI. Serum UCH-L1 and GFAP were longitudinally measured from 73 patients with acute orthopedic injury on arrival and on days 1, 2, 3, 7 after admission, and on the follow-up visit 3-10 months after the injury. The injury types were recorded, and 71% patients underwent also head MRI. The results were compared with those found in patients with CT-negative mTBI (n = 93). The levels of GFAP were higher in patients with acute orthopedic trauma than in patients with CT-negative mTBI (p = 0.026) on arrival; however, no differences were found on the following days. The levels of UCH-L1 were not significantly different between these two groups at any measured point of time. Levels of GFAP and UCH-L1 were not able to distinguish patients with CT-negative mTBI from patients with orthopedic trauma. Patients with orthopedic trauma and high levels of UCH-L1 or GFAP values may be falsely diagnosed as having a concomitant mTBI, predisposing them to unwarranted diagnostics and unnecessary brain imaging. This casts a significant doubt on the diagnostic value of GFAP and UCH-L1 in cases with mTBI.
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Affiliation(s)
- Jussi P Posti
- 1 Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital , Turku, Finland
- 2 Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital , Turku, Finland
- 3 Department of Neurology, University of Turku , Turku, Finland
| | | | - Riikka S K Takala
- 4 Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital and University of Turku , Turku, Finland
| | - Hilkka Liedes
- 5 Systems Medicine, VTT Technical Research Centre of Finland Ltd , Tampere, Finland
| | - Virginia Newcombe
- 6 Division of Anaesthesia, Department of Medicine, University of Cambridge , Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Joanne Outtrim
- 6 Division of Anaesthesia, Department of Medicine, University of Cambridge , Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Ari J Katila
- 4 Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital and University of Turku , Turku, Finland
| | - Janek Frantzén
- 1 Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital , Turku, Finland
- 2 Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital , Turku, Finland
| | | | - Jonathan P Coles
- 7 Department of Clinical Neurosciences, Neurosurgery Unit, University of Cambridge , Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Anna Kyllönen
- 3 Department of Neurology, University of Turku , Turku, Finland
| | | | - Jussi Tallus
- 3 Department of Neurology, University of Turku , Turku, Finland
| | - Peter J Hutchinson
- 7 Department of Clinical Neurosciences, Neurosurgery Unit, University of Cambridge , Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Mark van Gils
- 5 Systems Medicine, VTT Technical Research Centre of Finland Ltd , Tampere, Finland
| | - David K Menon
- 6 Division of Anaesthesia, Department of Medicine, University of Cambridge , Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Olli Tenovuo
- 2 Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital , Turku, Finland
- 3 Department of Neurology, University of Turku , Turku, Finland
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32
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Sirri R, Sabattini S, Bettini G, Mandrioli L. Reclassification of 21 Presumptive Canine Peripheral Nerve Sheath Tumors (PNST) Using a Literature-Based Immunohistochemical Panel. ACTA VET-BEOGRAD 2016. [DOI: 10.1515/acve-2016-0039] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Abstract
The aim of this study was to re-evaluate archived samples of canine soft tissue sarcomas (STSs) morphologically consistent with peripheral nerve sheath tumors (PNSTs). In each case, an immunohistochemical panel was applied, including α-SMA, calponin, desmin, S-100, GFAP, NSE and Olig2, in order to assess whether the phenotype was consistent with the tumor histological appearance. Additionally, the expression of EGFR, a marker with potential therapeutic implications in malignant PNSTs, was evaluated. Twenty-one tumors were included. Fourteen cases (66.7%) were positive for one or more muscular markers and were reclassified as perivascular tumors (PWTs). A positive labeling for S-100 was observed in one tumor (4.8%), thus classifi ed as PNST. The other 6 tumors were generically classified as poorly differentiated STSs. No unique histopathological feature was observed within the three groups. NSE and Olig2 labeling was aspecific and not useful for diagnostic purposes. GFAP was negative in all cases. Six cases (28.6%) were positive for EGFR, including the PNST. Even after the application of a wide immunohistochemical panel, distinguishing between PNSTs and PWTs remains a challenge. Finally, a subgroup of cases cannot be classified based on light microscopy alone.
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Affiliation(s)
- Rubina Sirri
- Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, Ozzano dell’Emilia, Bologna, Italy
| | - Silvia Sabattini
- Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, Ozzano dell’Emilia, Bologna, Italy
| | - Giuliano Bettini
- Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, Ozzano dell’Emilia, Bologna, Italy
| | - Luciana Mandrioli
- Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra 50, Ozzano dell’Emilia, Bologna, Italy
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33
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Combination of grafted Schwann cells and lentiviral-mediated prevention of glial scar formation improve recovery of spinal cord injured rats. J Chem Neuroanat 2016; 76:48-60. [DOI: 10.1016/j.jchemneu.2015.12.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 11/26/2015] [Accepted: 12/25/2015] [Indexed: 01/03/2023]
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34
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Abstract
Ganglioneuromas are complex tumors that arise in peripheral ganglia and are composed of well-differentiated neurons, nerve processes, Schwann cells, and enteric glial cells. The term ganglioneuromatosis (GN) denotes a regional or segmental proliferation of ganglioneuromatous tissue. This report describes an 8-year-old mixed breed horse with GN in a 25-cm segment of small colon. Grossly, the lesion consisted of numerous sessile to pedunculated nodules extending from the serosal surface. Histologic examination revealed the nodules to consist of fascicles of spindle-shaped cells consistent with Schwann cells, clusters of neurons, supporting enteric glial cells, and thick bands of perineurial collagen. Most of the nodules coincided with the location of the myenteric plexus and extended through the outer layer of the tunica muscularis to the serosal surface. Neuronal processes were demonstrated within the lesion with electron microscopy. With immunohistochemistry neurons were positive for neuron specific enolase (NSE) and S-100 and the Schwann cells and enteric glial cells were positive for S-100 and glial fibrillary acidic protein (GFAP). The pathogenesis of GN is poorly understood. GN, although rare, should be included in the differential diagnosis of gastrointestinal tumors in the horse.
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Affiliation(s)
- B F Porter
- Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA.
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35
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36
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Suarez-Mier GB, Buckwalter MS. Glial Fibrillary Acidic Protein-Expressing Glia in the Mouse Lung. ASN Neuro 2015; 7:7/5/1759091415601636. [PMID: 26442852 PMCID: PMC4601129 DOI: 10.1177/1759091415601636] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Autonomic nerves regulate important functions in visceral organs, including the lung. The postganglionic portion of these nerves is ensheathed by glial cells known as non-myelinating Schwann cells. In the brain, glia play important functional roles in neurotransmission, neuroinflammation, and maintenance of the blood brain barrier. Similarly, enteric glia are now known to have analogous roles in gastrointestinal neurotransmission, inflammatory response, and barrier formation. In contrast to this, very little is known about the function of glia in other visceral organs. Like the gut, the lung forms a barrier between airborne pathogens and the bloodstream, and autonomic lung innervation is known to affect pulmonary inflammation and lung function. Lung glia are described as non-myelinating Schwann cells but their function is not known, and indeed no transgenic tools have been validated to study them in vivo. The primary goal of this research was, therefore, to investigate the relationship between non-myelinating Schwann cells and pulmonary nerves in the airways and vasculature and to validate existing transgenic mouse tools that would be useful for studying their function. We focused on the glial fibrillary acidic protein promoter, which is a cognate marker of astrocytes that is expressed by enteric glia and non-myelinating Schwann cells. We describe the morphology of non-myelinating Schwann cells in the lung and verify that they express glial fibrillary acidic protein and S100, a classic glial marker. Furthermore, we characterize the relationship of non-myelinating Schwann cells to pulmonary nerves. Finally, we report tools for studying their function, including a commercially available transgenic mouse line.
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Affiliation(s)
- Gabriela B Suarez-Mier
- Department of Neurology and Neurological Sciences, Stanford Medical School, Stanford, CA, USA Stanford Neurosciences Institute, Stanford, CA, USA
| | - Marion S Buckwalter
- Department of Neurology and Neurological Sciences, Stanford Medical School, Stanford, CA, USA Department of Neurosurgery, Stanford Medical School, Stanford, CA, USA
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37
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Aqueous Extract of Agaricus blazei Murrill Prevents Age-Related Changes in the Myenteric Plexus of the Jejunum in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:287153. [PMID: 25960748 PMCID: PMC4415631 DOI: 10.1155/2015/287153] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 12/15/2014] [Accepted: 12/16/2014] [Indexed: 01/27/2023]
Abstract
This study evaluated the effects of the supplementation with aqueous extract of Agaricus blazei Murrill (ABM) on biometric and blood parameters and quantitative morphology of the myenteric plexus and jejunal wall in aging Wistar rats. The animals were euthanized at 7 (C7), 12 (C12 and CA12), and 23 months of age (C23 and CA23). The CA12 and CA23 groups received a daily dose of ABM extract (26 mg/animal) via gavage, beginning at 7 months of age. A reduction in food intake was observed with aging, with increases in the Lee index, retroperitoneal fat, intestinal length, and levels of total cholesterol and total proteins. Aging led to a reduction of the total wall thickness, mucosa tunic, villus height, crypt depth, and number of goblet cells. In the myenteric plexus, aging quantitatively decreased the population of HuC/D(+) neuronal and S100(+) glial cells, with maintenance of the nNOS(+) nitrergic subpopulation and increase in the cell body area of these populations. Supplementation with the ABM extract preserved the myenteric plexus in old animals, in which no differences were detected in the density and cell body profile of neurons and glial cells in the CA12 and CA23 groups, compared with C7 group. The supplementation with the aqueous extract of ABM efficiently maintained myenteric plexus homeostasis, which positively influenced the physiology and prevented the death of the neurons and glial cells.
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38
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Hyperphosphorylation of tau protein in the ipsilateral thalamus after focal cortical infarction in rats. Brain Res 2014; 1543:280-9. [DOI: 10.1016/j.brainres.2013.11.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 10/29/2013] [Accepted: 11/01/2013] [Indexed: 11/24/2022]
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Davila D, Thibault K, Fiacco TA, Agulhon C. Recent molecular approaches to understanding astrocyte function in vivo. Front Cell Neurosci 2013; 7:272. [PMID: 24399932 PMCID: PMC3871966 DOI: 10.3389/fncel.2013.00272] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 12/06/2013] [Indexed: 12/11/2022] Open
Abstract
Astrocytes are a predominant glial cell type in the nervous systems, and are becoming recognized as important mediators of normal brain function as well as neurodevelopmental, neurological, and neurodegenerative brain diseases. Although numerous potential mechanisms have been proposed to explain the role of astrocytes in the normal and diseased brain, research into the physiological relevance of these mechanisms in vivo is just beginning. In this review, we will summarize recent developments in innovative and powerful molecular approaches, including knockout mouse models, transgenic mouse models, and astrocyte-targeted gene transfer/expression, which have led to advances in understanding astrocyte biology in vivo that were heretofore inaccessible to experimentation. We will examine the recently improved understanding of the roles of astrocytes – with an emphasis on astrocyte signaling – in the context of both the healthy and diseased brain, discuss areas where the role of astrocytes remains debated, and suggest new research directions.
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Affiliation(s)
- David Davila
- Glia-Glia and Glia-Neuron Interactions Group, National Center for Scientific Research, UFR Biomedicale, Paris Descartes University Paris, France
| | - Karine Thibault
- Glia-Glia and Glia-Neuron Interactions Group, National Center for Scientific Research, UFR Biomedicale, Paris Descartes University Paris, France
| | - Todd A Fiacco
- Department of Cell Biology and Neuroscience, and Center for Glial-Neuronal Interactions and Program in Cellular, Molecular and Developmental Biology, University of California at Riverside Riverside, CA, USA
| | - Cendra Agulhon
- Glia-Glia and Glia-Neuron Interactions Group, National Center for Scientific Research, UFR Biomedicale, Paris Descartes University Paris, France
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40
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Castillo C, Norcini M, Martin Hernandez L, Correa G, Blanck T, Recio-Pinto E. Satellite glia cells in dorsal root ganglia express functional NMDA receptors. Neuroscience 2013; 240:135-46. [DOI: 10.1016/j.neuroscience.2013.02.031] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 01/29/2013] [Accepted: 02/13/2013] [Indexed: 01/06/2023]
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41
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Merkwitz C, Lochhead P, Böttger J, Matz-Soja M, Sakurai M, Gebhardt R, Ricken AM. Dual origin, development, and fate of bovine pancreatic islets. J Anat 2013; 222:358-71. [PMID: 23171225 PMCID: PMC3582255 DOI: 10.1111/joa.12014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2012] [Indexed: 01/20/2023] Open
Abstract
Endocrine cells are evident at an early stage in bovine pancreatic development when the pancreas still consists of primitive epithelial cords. At this stage, the endocrine cells are interspersed between the precursor cells destined to form the ductulo-acinar trees of later exocrine lobules. We here demonstrate that, in bovine fetuses of crown rump length ≥ 11 cm, the endocrine cells become increasingly segregated from the developing exocrine pancreas by assembly into two units that differ in histogenesis, architecture, and fate. Small numbers of 'perilobular giant islets' are distinguishable from larger numbers of 'intralobular small islets'. The two types of islets arise in parallel from the ends of the ductal tree. Aside from differences in number, location, and size, the giant and small islets differ in cellular composition (predominantly insulin-synthesising cells vs. mixtures of endocrine cells), morphology (epithelial trabeculae with gyriform and rosette-like appearance vs. compact circular arrangements of endocrine cells), and in their relationships to intrapancreatic ganglia and nerves. A further difference becomes apparent during the antenatal period; while the 'interlobular small islets' persist in the pancreata of calves and adult cattle, the perilobular giant islets are subject to regression, characterised by involution of the parenchyma, extensive haemorrhage, leukocyte infiltration (myeloid and T-cells) and progressive fibrotic replacement. In conclusion, epithelial precursor cells of the ductolo-acinar tree may give rise to populations of pancreatic islets with different histomorphology, cellular composition and fates. This should be taken into account when using these cells for the generation of pancreatic islets for transplantation therapy.
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Affiliation(s)
- Claudia Merkwitz
- Institute of Anatomy, Faculty of Medicine, University of Leipzig, Leipzig, Germany
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EMSLEY JASONG, MACKLIS JEFFREYD. Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. ACTA ACUST UNITED AC 2012; 2:175-86. [PMID: 17356684 PMCID: PMC1820889 DOI: 10.1017/s1740925x06000202] [Citation(s) in RCA: 209] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Astroglia comprise an extremely morphologically diverse cell type that have crucial roles in neural development and function. Nonetheless, distinct regions of the CNS have traditionally been defined by the phenotypic characteristics and connectivity of neuros. In a complementary fashion, we present evidence that discrete regions of the adult CNS can be delineated based solely on the morphology, density and proliferation rates of astroglia. We used transgenic hGFAP-GFP mice in which robust expression of GFP in adult astroglia enables detailed morphological characterization of this diversely heterogeneous cell population with 3D confocal microscopy. By using three complementary methods for labeling adult astroglia (hGFAP-GFP expression, and GFAP and S100beta immunostaining), we find that there is a remarkably diverse, regionally stereotypical array of astroglial morphology throughout the CNS, and that discrete anatomical regions can be defined solely on the morphology of astroglia within that region. Second, we find that the density of astroglia varies dramatically across the CNS, and that astroglial density effectively delineates even the sub-regions of complex structures, such as the thalamus. We also find that regional astroglial density varies depending on how astroglia are labeled. To quantify and illustrate these broad differences in astroglial density, we generated an anatomical density atlas of the CNS. Third, the proliferation rate, or mitotic index, of astroglia in the adult CNS also effectively defines anatomical regions. These differences are present regardless of the astroglial-labeling method used. To supplement our atlas of astroglial density we generated an atlas of proliferation density for the adult CNS. Together, these studies demonstrate that the morphology, density and proliferation rate of astroglia can independently define the discrete cytoarchitecture of the adult mammalian CNS, and support the concept that regional astroglial heterogeneity reflects important molecular and functional differences between distinct classes of astroglia, much like the long-accepted heterogeneity of neuronal populations.
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Affiliation(s)
| | - JEFFREY D. MACKLIS
- Correspondence should be addressed to: Jeffrey D. Macklis, MGH-HMS Center for Nervous System Repair, Massachusetts General Hospital, Edwards 4 (EDR 410), 50 Blossom Street, Boston MA USA 02114, phone: +1 617 724 0678, fax: +1 617 726 2310,
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Serum biomarkers of neurologic injury in cardiac operations. Ann Thorac Surg 2012; 94:1026-33. [PMID: 22857981 DOI: 10.1016/j.athoracsur.2012.04.142] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2012] [Revised: 04/19/2012] [Accepted: 04/23/2012] [Indexed: 01/03/2023]
Abstract
Assessment of subtle neurocognitive decline after surgical procedures has been hampered by heterogeneous testing techniques and a lack of reproducibility. This review summarizes the sensitivity and specificity of biomarkers of neurologic injury to determine whether they can be applied in the postoperative period to accurately predict neurocognitive decline. Creatine kinase-brain type, neuron-specific enolase, and S100B can be released into serum during operations by extracranial sources. Glial fibrillary acidic protein is a sensitive marker, and there are extracranial sources that are antigenically different from the brain-derived form. Serum levels of tau protein after acute neurologic injury do not reliability correlate with incidence.
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Rozanski GM, Kim H, Li Q, Wong FK, Stanley EF. Slow chemical transmission between dorsal root ganglion neuron somata. Eur J Neurosci 2012; 36:3314-21. [PMID: 22845723 DOI: 10.1111/j.1460-9568.2012.08233.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Somatic sensory neuron somata are located within the dorsal root ganglia (DRG) and are mostly ensheathed by individual satellite glial cell sheets. It has been noted, however, that a subpopulation of these DRG somata are intimately associated, separated only by a single thin satellite glial cell membrane septum. We set out to test whether such neuron-glial cell-neuron trimers (NGlNs) are also linked functionally. The presence of NGlNs in chick DRGs was confirmed by electron microscopy. Selective satellite glial cell immunostains were identified and were used to image the inter-neuron septa in DRG frozen sections. We used a gentle, dispase-based enzymatic method to isolate chick and rat NGlNs in vitro for double patch clamp recordings. In the majority of pairs tested, an action potential-like stimulus train delivered to one soma resulted in a delayed, noisy and long-duration response in its idle partner. The response to a second stimulus train given minutes later was markedly facilitated. Both bidirectional and unidirectional transmission was observed between the paired neurons. Transmission was chemical and block by the general purinergic blocker suramin implicated ATP as a neurotransmitter. We conclude that the two neuronal somata in the NGlN can communicate by chemical transmission, which may involve a transglial, bi-synaptic pathway. This novel soma-to-soma transmission reflects a novel form of processing that may play a role in sensory disorders in the DRG and interneuron communication in the central nervous system.
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Affiliation(s)
- Gabriela M Rozanski
- Laboratory of Synaptic Transmission, Toronto Western Research Institute, Toronto, ON M5T 2S8, Canada
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Abstract
Astrocytes are possibly the most numerous cells of the vertebrate central nervous system, yet a detailed characterization of their functions is still missing. One potential reason for the obscurity of astrocytic function is that they represent a diverse population of cells that all share some critical characteristics. In the CNS, astrocytes have been proposed to perform many functions. For example, they are supportive cells that provide guidance to newly formed migrating neurons and axons. They regulate the functions of endothelial cells at the blood brain barrier, provide nutrients, and maintain homeostasis including ionic balance within the CNS. More recently, dissecting the central role of astrocytes in mediating injury responses in the CNS, particularly the spinal cord, has become an area of considerable importance. The ability to culture-enriched populations of astrocytes has facilitated a detailed dissection of their potential roles in the developing and adult, normal, and injured brain and spinal cord. Most importantly, in vitro models have defined molecular signals that may mediate or regulate astrocyte functions and the capacity to modulate these signals may provide new opportunities for therapeutic intervention after spinal cord injury and other neural insults.
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Affiliation(s)
- Amber E Kerstetter
- Department of Neurosurgery, Center for Translational Neurosciences, Case Western Reserve University, Cleveland, OH, USA
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Primary culture of glial cells from mouse sympathetic cervical ganglion: a valuable tool for studying glial cell biology. J Neurosci Methods 2010; 194:81-6. [PMID: 20888862 DOI: 10.1016/j.jneumeth.2010.09.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2010] [Revised: 08/12/2010] [Accepted: 09/22/2010] [Indexed: 11/22/2022]
Abstract
Central nervous system glial cells as astrocytes and microglia have been investigated in vitro and many intracellular pathways have been clarified upon various stimuli. Peripheral glial cells, however, are not as deeply investigated in vitro despite its importance role in inflammatory and neurodegenerative diseases. Based on our previous experience of culturing neuronal cells, our objective was to standardize and morphologically characterize a primary culture of mouse superior cervical ganglion glial cells in order to obtain a useful tool to study peripheral glial cell biology. Superior cervical ganglia from neonatal C57BL6 mice were enzymatically and mechanically dissociated and cells were plated on diluted Matrigel coated wells in a final concentration of 10,000cells/well. Five to 8 days post plating, glial cell cultures were fixed for morphological and immunocytochemical characterization. Glial cells showed a flat and irregular shape, two or three long cytoplasm processes, and round, oval or long shaped nuclei, with regular outline. Cell proliferation and mitosis were detected both qualitative and quantitatively. Glial cells were able to maintain their phenotype in our culture model including immunoreactivity against glial cell marker GFAP. This is the first description of immunocytochemical characterization of mouse sympathetic cervical ganglion glial cells in primary culture. This work discusses the uses and limitations of our model as a tool to study many aspects of peripheral glial cell biology.
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Schöniger S, Valentine BA, Fernandez CJ, Summers BA. Cutaneous Schwannomas in 22 Horses. Vet Pathol 2010; 48:433-42. [DOI: 10.1177/0300985810377072] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Schwannomas are uncommonly recognized in horses. This study describes cutaneous schwannomas in 22 horses aged 8 to 25 years: 12 male, 7 female, and 3 of unknown sex. The horses had solitary cutaneous masses: 9 on the head, 3 on the neck, and the others on the shoulder, hip, thorax, abdomen, rump, extremities, or tail. The location of 1 tumor was unknown. The dermal tumors were well demarcated and expansile. Twelve had a multinodular pattern, whereas 10 formed a single nodule. Antoni A areas were observed in all tumors, and 10 tumors contained Antoni B areas. In Antoni A areas, the densely packed spindle-shaped neoplastic cells were arranged in short fascicles with nuclear palisading. In the hypocellular Antoni B areas, neoplastic cells were separated by abundant myxomatous stroma. Tumors commonly had hyalinization of stroma and vessel walls and ancient change. Cellular vacuolation was observed in 18 tumors. In all 22 cases, neoplastic cells were immunopositive for S100 protein. Expression of laminin and glial fibrillary acidic protein was observed in all 6 tumors evaluated by immunohistochemistry for these markers. One tumor was examined ultrastructurally: Neoplastic cells had branched cytoplasmic processes and were surrounded by an external lamina. Follow-up information was available 8 months to 10 years postexcision for 9 horses, for which surgical excision of the tumor was curative. The equine cutaneous schwannomas in this study had microscopic features like those of human schwannoma and had benign clinical behavior. Correct classification of equine cutaneous schwannoma will facilitate accurate prognosis and appropriate treatment.
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Affiliation(s)
- S. Schöniger
- Department of Pathology and Infectious Disease, Royal Veterinary College, Hatfield, Hertfordshire, UK
| | - B. A. Valentine
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
- Current address: College of Veterinary Medicine, Oregon State University, Corvallis, Oregon
| | - C. J. Fernandez
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
- Current address: Animal and Plant Health Laboratories Division, Agri-Food and Veterinary Authority, Animal and Plant Health Center, Republic of Singapore
| | - B. A. Summers
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
- Current address: Department of Pathology and Infectious Diseases, Royal Veterinary College, Hatfield, Hertfordshire, UK
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The structure of the perineuronal sheath of satellite glial cells (SGCs) in sensory ganglia. ACTA ACUST UNITED AC 2010; 6:3-10. [DOI: 10.1017/s1740925x10000037] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
In sensory ganglia each nerve cell body is usually enveloped by a satellite glial cell (SGC) sheath, sharply separated from sheaths encircling adjacent neurons by connective tissue. However, following axon injury SGCs may form bridges connecting previously separate perineuronal sheaths. Each sheath consists of one or several layers of cells that overlap in a more or less complex fashion; sometimes SGCs form a perineuronal myelin sheath. SGCs are flattened mononucleate cells containing the usual cell organelles. Several ion channels, receptors and adhesion molecules have been identified in these cells. SGCs of the same sheath are usually linked by adherent and gap junctions, and are functionally coupled. Following axon injury, both the number of gap junctions and the coupling of SGCs increase markedly. The apposed plasma membranes of adjacent cells are separated by 15–20 nm gaps, which form a potential pathway, usually long and tortuous, between connective tissue and neuronal surface. The boundary between neuron and SGC sheath is usually complicated, mainly by many projections arising from the neuron. The outer surface of the SGC sheath is covered by a basal lamina. The number of SGCs enveloping a nerve cell body is proportional to the cell body volume; the volume of the SGC sheath is proportional to the volume and surface area of the nerve cell body. In old animals, both the number of SGCs and the mean volume of the SGC sheaths are significantly lower than in young adults. Furthermore, extensive portions of the neuronal surface are not covered by SGCs, exposing neurons of aged animals to damage by harmful substances.
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Enteric neural crest differentiation in ganglioneuromas implicates Hedgehog signaling in peripheral neuroblastic tumor pathogenesis. PLoS One 2009; 4:e7491. [PMID: 19834598 PMCID: PMC2759000 DOI: 10.1371/journal.pone.0007491] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2009] [Accepted: 08/18/2009] [Indexed: 01/11/2023] Open
Abstract
Peripheral neuroblastic tumors (PNTs) share a common origin in the sympathetic nervous system, but manifest variable differentiation and growth potential. Malignant neuroblastoma (NB) and benign ganglioneuroma (GN) stand at opposite ends of the clinical spectrum. We hypothesize that a common PNT progenitor is driven to variable differentiation by specific developmental signaling pathways. To elucidate developmental pathways that direct PNTs along the differentiation spectrum, we compared the expression of genes related to neural crest development in GN and NB. In GNs, we found relatively low expression of sympathetic markers including adrenergic biosynthesis enzymes, indicating divergence from sympathetic fate. In contrast, GNs expressed relatively high levels of enteric neuropeptides and key constituents of the Hedgehog (HH) signaling pathway, including Dhh, Gli1 and Gli3. Predicted HH targets were also differentially expressed in GN, consistent with transcriptional response to HH signaling. These findings indicate that HH signaling is specifically active in GN. Together with the known role of HH activity in enteric neural development, these findings further suggested a role for HH activity in directing PNTs away from the sympathetic lineage toward a benign GN phenotype resembling enteric ganglia. We tested the potential for HH signaling to advance differentiation in PNTs by transducing NB cell lines with Gli1 and determining phenotypic and transcriptional response. Gli1 inhibited proliferation of NB cells, and induced a pattern of gene expression that resembled the differential pattern of gene expression of GN, compared to NB (p<0.00001). Moreover, the transcriptional response of SY5Y cells to Gli1 transduction closely resembled the transcriptional response to the differentiation agent retinoic acid (p<0.00001). Notably, Gli1 did not induce N-MYC expression in neuroblastoma cells, but strongly induced RET, a known mediator of RA effect. The decrease in NB cell proliferation induced by Gli1, and the similarity in the patterns of gene expression induced by Gli1 and by RA, corroborated by closely matched gene sets in GN tumors, all support a model in which HH signaling suppresses PNT growth by promoting differentiation along alternative neural crest pathways.
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Canine Cutaneous Spindle Cell Tumours with Features of Peripheral Nerve Sheath Tumours: A Histopathological and Immunohistochemical Study. J Comp Pathol 2008; 139:16-23. [DOI: 10.1016/j.jcpa.2008.03.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2008] [Revised: 03/06/2008] [Accepted: 03/10/2008] [Indexed: 11/20/2022]
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