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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
MEDICAL ACADEMY
FACULTY OF MEDICINE
INSTITUTE OF ANATOMY
Satellite glial cells of stellate ganglion and their clinical
significance in nociception (scientific literature review)
Žvaigždinio mazgo gliocitai ir jų klinikinė reikšmė skausmo
perdavime (mokslinės literatūros apžvalga)
Siman Lazauskas
Thesis supervisor: Dr. Anita Dabužinskiene Kaunas 2019
2 TABLE OF CONTENTS 1. Summary……….3 2. Acknowledgment………4 3. Conflict of interest………..………5
4. Ethics committee approval………..6
5. Abbreviations………..7
6. Introduction……….8
7. Aim and objective………9
8. Literature review………10
8.1 Structure and function of the satellite glial cells……….………….10
8.2 SGC proliferation, inflammation and central pain sensitization………..11
8.3 Different types of communications and transmission in sensory ganglions………….15
8.4 Expression on satellite glial cells……….….18
8.5 Development of SGC……….……19
8.6 Role of satellite glial cells in nociception and pain………...20
8.7 Stellate ganglia gender differences………24
9. Methods and material………...25
9.1 Material………...25
9.2 Microscopic examination………...25
9.3 Statistical Analysis ………....26
10. Results and discussion ………..……….………...….27
11. Conclusions………...31
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1. SUMMARY
Author: Siman Lazauskas
Title: Satellite glial cells of stellate ganglion and their clinical significance in nociception (scientific literature review)
BACKROUND: stellate ganglion is responsible to regulate involuntary sympathetic nervous functions. Beside the neurons ganglion is composed of satellite glial cells surrounding the neurons. These satellite cells are responsible for neurotransmission of the neurons and their metabolic changes. In the scientific literature were not plenty information about clinical significance of the satellite glial cells of human stellate ganglion in the nociception.
AIM AND OBJECTIVE: to review clinical significance of satellite glial cells of stellate ganglia in
nociception from scientific literature and evaluate the gender differences in number of satellite glial cells, and size of neurons of the stellate ganglia.
MATERIAL AND METHODS: in research were used histological slides of 17 human stellate
ganglions of both genders between ages 38- 95. They were stored in the Institute of Anatomy. The slides were immunostained for neurofilament protein and examined by microscope LSM (Carl Zeiss, Jena, Germany). In the ganglions were examined the size of neurons and calculated the number of the satellite glial cells surrounding the neurons.
RESULTS: average of square area of the female neurons was 632.5000 µm², average of satellite glial
cells number surrounding one neuron was 2.4. Average of square area of the male neurons was 613.3208 µm², average of the number of satellite glial cells surrounding one neuron was 1.5.
CONCLUSIONS: 1. Difference in amount of SGCs surrounding the neurons of males and females was
statistically significant. Female neurons were enveloped by larger number of SGCs. 2. Difference in average of neuronal cross area (µm²) between males and females was not statistically significant. 3. Our findings do not show correlation between neuronal cross area and the number of SGCs in human stellate ganglia.
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2. ACKNOWLEDGMENT
I would like to thank the Anatomy institute and my supervisor.
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2. CONFLICT OF INTEREST
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4. ETHICS COMMITEE APPROVAL
Lithuanian University of Health Sciences ethics committee approval number BEC MF 328, certified in 5 March, 2019 by the State Service for Food and Veterinary.
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5. ABBREVATIONS
SG- stellate ganglion SGCs- satellite glial cells NF- neurofilament protein ATP- adenosine triphosphate GABA- gamma aminobutyric acid DRG- dorsal root ganglion
TG- trigeminal ganglia FA- Friedrich ataxia
mGluR - metabotropic glutamate receptors GFAP-glial fibrillary acidic protein
Brdu- Bromodeoxyuridine
NMDARs-N-methyl-D-aspartate receptors Ach-acetylcholine
CMY-cardiomyopathy LQTS-long QT syndrome
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6. INTRODUCTION
Stellate ganglion is part of the sympathetic nervous system. It is responsible to regulate involuntary sympathetic nervous functions and is composed of different type neurons and non-neuronal satellite glial cells, which surround the neurons. These cells are important components of either sensory or autonomic ganglia.
It is known that satellite glial cells are responsible for neurotransmission of the neurons and participated in their metabolic changes [1, 2]. According different scientific studies satellite glial cells undergo proliferation and inflammatory process after nerve injury [7, 8, 10, 2, 16, 17, 30-34]. Some scientists considered that these cells are taking part in nociception, but in the scientific literature were not plenty information about clinical significance of that.
This study was done in order to determine the clinical importance of non-neuronal satellite glial cells of human stellate ganglion in nociception from scientific literature. Either were to determine the gender differences in number of cells surrounding the neuron of the human stellate ganglion and size of the neurons.
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7. AIM AND OBJECTIVES
Aim of this study is to review clinical significance of satellite glial cells of stellate ganglion in
nociception from scientific literature and evaluate the gender differences of satellite glial cells and neurons size.
Objectives:
1. To review in the scientificliterature the clinical significance of the satellite glial cells in nociception 2. To investigate the gender differences of the number of satellite glial cells surrounding a neuron 3. To determine the size of neurons of stellate ganglion
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8. LITERATURE REVIEW
8.1 Structure and function of the satellite glial cells
Glial cells are important for many functions of CNS and PNS, their main type in sensory, sympathetic and parasympathetic ganglions is satellite cells, these cells usually surround a single neuron, which create a distinct functional unit. According to Hanani SGCs carry receptors for ATP neurotransmitter and that they also have an uptake mechanism for GABA, and possibly other neurotransmitters, which allows them to control the neuronal microenvironment. Damage to post- or preganglionic nerve fibers has an influence both the ganglionic neurons and the SGCs. One major consequence of postganglionic nerve section is preganglionic nerve terminals detachment, which results in decreased synaptic transmission. It appears that, at least in sympathetic ganglia, SGCs participate in the detachment process, and possibly in the subsequent recovery of the synaptic connections. Different to sensory neurons, neurons in autonomic ganglia receive synaptic inputs, and SGCs are in very close contact with synaptic boutons. This places the SGCs in a position to influence synaptic transmission and information processing in autonomic ganglia, but this topic requires much further work [1].
In sensory ganglia each nerve cell body is usually surrounded by a satellite glial cell (SGC) sheath, sharply separated by connective tissue from sheaths surrounding nearby neurons. However during Panesse study it was found that, after axon injury SGCs can make bridges connecting previously separate perineuronal sheaths. Each sheath is of made of one or several layers of cells that overlap in a more or less complex fashion; sometimes SGCs make a perineuronal myelin sheath. SGCs are flattened cells with one nucleus 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. Pannese study also showed that after an 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
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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 [2].
8.2 SGC proliferation, inflammation and central pain sensitization
Cairns et al investigated the potential role of SGC in the process of neuro-inflammation, suggesting these cells to take part (e.g. by cytokine secretion in the dorsal root ganglia of the spinal column) in the important transition from acute to chronic pain. They suggest that better understanding and characterization of SGCcould, in the future, better our therapeutic means for acute pain reduction and diminishing the risks of acute pain transforming into chronic pain [4].
Activation of SGC has been implicated to take an active role in the central sensitization towards pain sensations delivered by peripheral nerves: Hossain and co-authors suggest that pro-inflammatory cytokines expressed by SGC, sensitizing the neurons, described as “Neuro-Glia Crosstalk” to be responsible for modulation of motor activity in the orofacial region [5].
According to Koeppen et al who investigated DRG in Friedrich ataxia (FA) and the proliferation and inflammation of satellite cells by immunohistochemical and immunofluorescence methods and use panel of antibodies, FA causes satellite cells proliferation and inflammatory destruction of neurons.
In conclusion to their study, FA differentially affects the key cellular elements of DRG, and that the disease induces loss of bidirectional trophic support between satellite cells and neurons [7].
Donegan et al investigated SGC proliferation in trigeminal ganglia after chronic constriction injury of the infraorbital nerve by the use of bromodeoxyuridine (BrdU) labeling combined with immunohistochemistry for SGC specific proteins they positively confirmed their proliferation, they found that the proliferation peaks at approximately 4 days after injury and dividing SGCs are preferentially located around immunopositive neurons for ATF-3, which is a marker of nerve injury. Following nerve injury there is an increase GFAP expression in SGCs associated with both ATF-3 immunopositive and immunonegative neurons throughout the ganglia. SGCs also express the non-glial proteins, CD45 and CD163, which label resident macrophages and circulating leukocytes, respectively.
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In addition to SGCs, they found some Schwann cells, endothelial cells, resident macrophages, and circulating leukocytes were BrdU immunopositive [8].
Gap junctions intercellular coupling is one of the main features of glial cells, but very little is known about this aspect of satellite glial cells (SGCs) in sympathetic ganglia. Hanani and co used the dye coupling method to investigate this question in both prevertebral ganglion (superior mesenteric) and a paravertebral ganglion (superior cervical) of mice. Their findings show that in control ganglia, the incidence of dye coupling among SGCs that form the envelope around a given neuron was 10-20%, and coupling between SGCs around different envelopes was rare (1.5-3%). The dye injections also gave novel information on SGCs structure. After peripheral inflammation, both types of coupling were increased, but most striking was the augmentation of coupling between SGCs forming envelopes around different neurons, which rose by 8-14.6-fold. This effect appeared to be non-systemic, and was blocked by the gap junction blocker carbenoxolone. According to these changes in SGCs it is possible to assume that signal transmission and processing in sympathetic ganglia may be affected [12].
MicroRNAs (miRNAs) has significant roles in regulation of numerous cellular processes. Harding and Velerman investigated the two genes which are important to satellite cell function syndecan-4 and glypican-1, and in order to determine if miRNAs influences myogenic satellite cell function, they were inhibited in vitro by transfection of inhibitors targeting each miRNA. Their inhibition differentially affected these genes expression, and myogenic regulatory factors myoD and myogenin. Inhibition of miR-16 decreased proliferation of satellite cells at 72 h. Inhibition of miR-128 and miR-24 had no effect on proliferation. Inhibition of miRNAs caused reduction in differentiation of satellite cells into myotubes at 48 and 72 h except for miR-16, which only affected differentiation at 72 h. Inhibition of all three miRNAs decreased myotube width at 24 h of differentiation and increased myotube width at 48 h of differentiation. Inhibition of these miRNAs also increases the number of nuclei per myotube at 72 h of differentiation. According to these data it possible to assume that individual miRNAs are regulators of genes which have importance for proliferation and differentiation of myogenic satellite cell [10]. Ferrari et al investigated the role N-methyl-D-aspartate receptors (NMDARs) expressed in the DRG in the inflammatory sensitization of peripheral nociceptor terminals to mechanical stimulation. Injection of NMDA into the fifth lumbar (L5)-DRG generated hyperalgesia in the rat hind paw with a profile similar to that of intraplantar injection of prostaglandin E2 (PGE2), which was significantly attenuated by injection of the NMDAR antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5) in the
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DRG. Moreover, blockade of DRG AMPA receptors by the antagonist 6.7-dinitroquinoxaline-2.3-dione had no effect in the PGE2-induced hyperalgesia in the paw, showing specific involvement of NMDARs in this modulatory effect and suggesting that activation of NMDAR in the DRG have an important role in the peripheral inflammatory hyperalgesia. In following experiments was observed attenuation of PGE2-induced hyperalgesia in the paw by the knockdown of NMDAR subunitsNR1, NR2B, NR2D, and NR3A with antisense-oligodeoxynucleotide treatment in the DRG. Also, in vitro experiments demonstrated that the NMDA-induced sensitization of cultured DRG neurons depends on satellite cell activation and on those same NMDAR subunits, suggesting they are important for the PGE2-induced hyperalgesia. In addition, fluorescent calcium imaging experiments in cultures of DRG cells demonstrated induction of calcium transients by glutamate or NMDA only in satellite cells, but not in neurons. Together, these results propose that the mechanical inflammatory nociceptor sensitization is glutamate release dependent at the DRG and subsequent NMDAR activation in satellite glial cells, supporting the idea that the peripheral hyperalgesia is an event modulated by a glutamatergic system in the DRG [16].
Feldman-Goriachnik et al investigated changes in SGCs in mouse nerve ganglia (NG) after the intraperitoneal administration of lipopolysaccharide (LPS), which promotes systemic inflammation. Using calcium imaging it was found that SGCs in intact, freshly isolated NG are sensitive to ATP, acting largely via purinergic P2 receptors (mixed P2X and P2Y). They suggested ATP has a role in the LPS-induced changes. In conclusion inflammation causes prominent changes in SGCs of NG, which might be involved in vagal afferent functions, such as the inflammatory reflex [17].
The aim of Takeda et al in their study was to investigate whether peripheral inflammation in anesthetized rats can alter the SGC Killer cell Immunoglobulin-like Receptor (Kir 4.1) current using in vivo patch clamp and immunohistochemical techniques. Inflammation induction by injection of complete Freund’s adjuvant into the whisker pad. The threshold of escape from mechanical stimulation applied to the orofacial area in inflamed rats was significantly lower than in naïve rats. The mean percentage of small/medium diameter trigeminal ganglion neurons encircled by Kir4.1-immunoreactive SGCs in inflamed rats was also significantly lower than in naïve rats. In vivo whole-cell recordings were made using SGCs in the trigeminal ganglia (TRGs). Increasing extracellular K+ concentrations resulted in significantly smaller potentiation of the mean peak amplitude of the Kir current in inflamed compared with naïve rats. In addition, the density of the Ba2+-sensitive Kir current associated with small-diameter
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TRG neurons was significantly lower in inflamed rats compared with naïve rats. Mean membrane potential in inflamed rats was more depolarized than in naïve rats. These results suggest that inflammation could suppress Kir4.1 currents of SGCs in the TRGs and that this impairment of glial potassium homeostasis in the TRGs causes trigeminal pain. Therefore, the Kir4.1 channel in SGCs may serve as a new molecular target for the treatment of trigeminal inflammatory pain [30].
Ajijola at al focused in their study on how severe cardiac pathology can cause alterations in SGN neurochemistry as well as SGC distribution and functional state, by doing comparison with stellate ganglia from patients with cardiomyopathy (CMY) and arrhythmias undergoing cardiac sympathetic denervation, and with control subjects who serve as heart and/or lung donors. They conclude that stellate ganglia from patients with CMY and arrhythmias show inflammation, neurochemical remodeling, oxidative stress, and satellite glial cell activation. According to them these changes have contribution to excessive and dysfunctional efferent sympathetic tone, and provide sympathectomy as a treatment for arrhythmias in this population [31].
In their study, Krishnan et al show that adult DRG contain populations of self-renewing cells, collectively referred as DRG, DRCCs, and suggest that they are active not only in “quiescent” ganglia but also cause acceleration to their turnover in response to distal axotomy. An unexpected proportion of DRCCs were resident macrophages. These cells closely accompanied, and aligned with recycling SGCs that were juxtaposed to sensory neurons and possessed stem cell-like properties. By selective inhibition of colony stimulating factor 1 receptor they prevented local proliferation of macrophages. Interestingly, DRCC turnover was accompanied by apoptosis at later intervals indicating a balanced cellular milieu in the DRGs. These findings identify a complex interactive multicellular DRG microenvironment s which supports self-renewal of both macrophages and SGCs and their potential implications in the overall response of adult DRGs to injury [32].
SGCs activation seems to be involved in pathological pain. Souza at al suggested that fractalkine, which is constitutively expressed by primary nociceptive neurons, is the link between peripheral inflammation and the activation of SGCs and is the origin of the inflammatory pain. The injection of carrageenin into the rat hind paw induced a decrease in the mechanical nociceptive threshold (hypernociception), which has association with an increase in mRNA and GFAP protein expression in the DRG. Both events were inhibited by direct administration of anti-fractalkine antibody into the DRG (L5) which caused production of mechanical hypernociception in a dose-, time-, and CX3C receptor-1
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dependent manner. Fractalkine's hypernociceptive effect appears to be indirect, as it reduction occurred by local treatment with anti-TNF-α antibody, IL-1-receptor antagonist, or indomethacin. Accordingly, in vitro incubation of isolated and cultured SGC with fractalkine provoked the production/release of TNF-α, IL-1β, and prostaglandin E2. Finally, treatment with i.gl. fluorocitrate blocked fractalkine (i.gl.) - and carrageenin (paw)- caused hypernociception. To summarize, these results confirms the hypothesis of this study and that it leads to TNFα, IL-1β, and prostanoids production, which are likely to have responsibility for the maintenance of inflammatory pain. Thus, these results indicate that the inhibiting fractalkine/CX3CR1 signaling in SGCs may serve as a target for control of inflammatory pain [33]. Migraine is a complex, chronic, painful, neurovascular disorder characterized by episode of trigeminal system activation. Increased levels of CGRP are found in different levels during migraine attacks and is also released within the trigeminal ganglia proposing possible local effects on satellite cells.
CGRP was shown an increase of interleukin 1β (IL-1β) in satellite cells, while trigeminal neurons express an activity-dependent production of nitric oxide (NO). Capuano and co, suggested in the their study that IL-1β and NO cause activation of trigeminal satellite cell, and that once active they can influence neuronal responses and as such serve as targets for therapeutic intervention in migraine [34]. Rizzo and co-authors proposed on their study that T-cell–mediated cytotoxicity toward ganglion cells may rise adrenergic activity as being trigger or intensify electric instability inLong QT syndrome/ Catecholaminergic polymorphic ventricular tachycardia (LQTS/CPVT) patients who are already have genetic predisposition to arrhythmias [39].
8.3 Different types of communications and transmission in sensory ganglions
While metabotropic glutamate receptors (mGluR) expression has been investigated largely in the DRG, Larsen and coauthors focused on mGluR expression on neurons and satellite glial cells (SGCs) of the trigeminal ganglion (TG) and according the results of their study they suggested mGluR has a role in relation to trigeminal pain transmission within the craniofacial region [6].
Retamal et al suggested SGCs establish bidirectional paracrine communication with sensory neurons in the central nervous system (CNS), astrocytes present connexin43 (Cx43) hemichannels and pannexin1 (Panx1) channels, and the opening of these channels allows the release of signal molecules, such as ATP and glutamate. They suggest that these channels could play a role in glia-neuron communication in sensory ganglia. Therefore, they studied the expression and function of Cx43 and Panx1 in rat and mouse
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nodose-petrosal-jugular complexes (NPJCs) using confocal immunofluorescence, molecular and electrophysiological techniques [9].
Studies of the structural organization and functions of the neuronal body and its surrounding SGCs in sensory ganglia have led to the realization that SGCs is an active participant in processing information of sensory signals from afferent terminals to the spinal cord. SGCs use a variety ways of communication between each other and with their enwrapped soma. Changes in this communication under conditions of injury often lead to abnormal pain conditions. Huang and co focused on the mechanisms underlying the neuronal soma and SGC communication in sensory ganglia and how do tissue or nerve injuries affect the communication?” as the main questions of their review [11].
Stimulation of peripheral nociception from orofacial structures are largely transmitted by the trigeminal nerve. Goto et al suggest that according to the peripheral noxious stimuli, neurons in the TG produce neuropeptides such as substance P, and calcitonin-gene-related peptide, etc. and that, there exists unique non-synaptic interaction system between maxillary and mandibular neurons in the TG. TG neurons are enveloped by SGCs and also send signal to them.
The SGCs secrete a transmitter to activate adjacent SGCs or TG neurons, thereby increasing the signal, for example, from mandibular neurons to maxillary neurons in the TG. Similar to the DRG, in the TG, microglia/macrophage-like cells (MLCs) are activated by uptake of a transmitter from TG neurons or SGCs. This communication between neurons, SGCs, and MLCs results in responses such as ectopic pain, hyperesthesia, or allodynia. In this review they focused on the cooperative interaction of the maxillary and mandibular nerves in the TG by neuropeptides, and adenosine 3-phosphate (ATP) signaling from neurons to SGCs and MLCs.
Stimulated neurons either secrete ATP by means of vesicular nucleotide transporters, or secrete neuropeptides from the neuronal cell body to mediate signal transmission [13].
SGCs are believed to make important contributions to the function of the ganglia under normal and pathological conditions. It has been proposed that SGCs communicate chemically with the neurons. Feldman-Goriachnik et al investigated if they respond to ACh by using calcium imaging. In summary they suggest according results that SGCs in the superior cervical ganglia show muscarinic ACh receptors, which allows them to communicate chemically with the sympathetic neurons [18].
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Perineuronal satellite cells have an intimate anatomical relationship with sensory neurons that suggests close functional collaboration and mutual support. Christie et al examined several facets of this relationship in adult sensory dorsal root ganglia (DRG). Collaboration included the support of process outgrowth by clustering of satellite cells, induction of distal branching behavior by soma signaling, the capacity of satellite cells to respond to distal axon injury of its neighboring neurons, and evidence of direct neuron-satellite cell exchange. In vitro, closely adherent coharvested satellite cells routinely clustered around new outgrowing processes and groups of satellite cells attracted neurite processes. Similar clustering was encountered in the pseudounipolar processes of intact sensory neurons within intact DRG in vivo. While short term exposure of distal growth cones of unselected adult sensory neurons to transient gradients of a PTEN inhibitor had negligible impacts on their behavior, exposure of the soma induced early and substantial growth of their distant neurites and branches, an example of local soma signaling. In turn, satellite cells sensed when distal neuronal axons were injured by enlarging and proliferating. We also observed that satellite cells were capable of internalizing and expressing a neuron fluorochrome label, diamidinoyellow, applied remotely to distal injured axons of the neuron and retrograde transported to dorsal root ganglia sensory neurons. The findings illustrate a robust interaction between intraganglionic neurons and glial cells that involve two way signals, features that may be critical for both regenerative responses and ongoing maintenance [26].
Satellite glial cells (SGCs) in sensory ganglia share some properties with astrocytes, in this review Suadicani et al usedcultured neurons and SGCs from mouse trigeminal ganglia to investigate whether SGC’s share the same way of communication as astrocytes through transmission of intercellular calcium signals. Focal electrical or mechanical stimulation of single neurons in trigeminal ganglion cultures increased intracellular calcium concentration in these cells and triggered calcium elevations in adjacent glial cells. Similar to neurons, SGCs responded to mechanical stimulation with increase in cytosolic calcium that spread to the adjacent neuron and neighboring glial cells. According to these it is indicated that for the first time the presence of bidirectional calcium signaling between neurons and SGCs in sensory ganglia cultures, which is mediated by the activation of purinergic P2 receptors, and to some extent by gap junctions. Furthermore, the results show that both sensory neurons, and SGCs release ATP. This form of intercellular calcium signaling is likely to have key roles in the modulation of neuronal activity within sensory ganglia in normal and pathological states [35].
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While investigating and measuring cell cycle dynamics in the embryonic mouse sympathetic stellate ganglion, where neuroblasts continue to proliferate following neuronal differentiation Gonsalvez et al proposed that there is relative change in neuroblasts and non-neuroblasts propotions in wild-type mice. And according their results same as other neurons, sympathetic neuron differentiation is associated with exit from the cell cycle; sympathetic neurons are unusual in that they then re-enter the cell cycle before later permanently exiting [36].
Zhang et al proposed in their study that several chemokines are upregulated after peripheral nerve injury and contribute to the pathogenesis of neuropathic pain via different forms of neuron-glia interaction in the spinal cord. They found that, first chemokine CX3CL1 is expressed in primary afferents and spinal neurons and induces microglial activation via its microglial receptor CX3CR1 (neuron-to-microglia signaling). Second, CCL2 and CXCL1 are expressed in spinal astrocytes and act on CCR2 and CXCR2 in spinal neurons to increase excitatory synaptic transmission (astrocyte-to-neuron signaling). Third, it was recently identified that CXCL13 is highly upregulated in spinal neurons after spinal nerve ligation and induces spinal astrocyte activation via receptor CXCR5 (neuron-to-astrocyte signaling). Strategies that target chemokine-mediated neuron-glia interactions may lead to novel therapies for the treatment of neuropathic pain [38].
8.4 Expression on Satellite glial cells
Dogs can be used as a translational animal model to close the gap between basic discoveries in rodents and clinical trials in humans. Tongtako et al investigated and compared the species-specific properties of SGCs of canine and murine DRG in situ and in vitro using light microscopy, electron microscopy, and immunostainings. The in situ expression of CNPase, GFAP, and glutamine synthetase (GS) has also been investigated in simian SGCs. In situ, most canine SGCs (>80%) expressed the neural progenitor cell markers nestin and Sox2. CNPase and GFAP were found in most canine and simian but not murine SGCs. GS was detected in 94% of simian and 71% of murine SGCs, whereas only 44% of canine SGCs expressed GS. In vitro, most canine (>84%) and murine (>96%) SGCs expressed CNPase, whereas GFAP expression was differentially affected by culture conditions and varied between 10% and 40%. However, GFAP expression was caused by bone morphogenetic protein 4 in SGCs of both species. Interestingly, canine SGCs also stimulated neurite formation of DRG neurons. These findings indicate that SGCs represent an exceptional, intermediate glial cell population with phenotypical characteristics of oligodendrocytes and astrocytes and might possess intrinsic regenerative capabilities in vivo [44].
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Aberrant sympathetic sprouting is seen in the uninjured trigeminal ganglia of transgenic mice that ectopically express nerve growth factor under the control of the glial fibrillary acidic protein promoter. These sympathetic axons form perineuronal plexuses around a subset of sensory somata in 2- to 3-month-old transgenic mice. Smithson and co suggest that aged transgenic mice (i.e., 11–14 and 16–18 months old) have dystrophic sympathetic plexuses (i.e., increased densities of swollen axons), and that satellite glial cells, specifically those in contact with dystrophic plexuses in the aged mice demonstrate strong immunostaining for tumor necrosis factor alpha. The colocalization of dystrophic plexuses and reactive satellite glial cells in the aged mice corresponds with degeneration in the enveloped sensory somata. Collectively, these novel results show that, with advancing age, sympathetic plexuses go through dystrophic changes that enhance satellite glial cell reactivity and that this correspond with neuronal degenerative processes [15].
TLRs orchestrate immune responses to a wide variety of danger- and pathogen-associated molecular patterns. Compared to the CNS, expression profile and function of TLRs in the human PNS are ill-defined. We analyzed TLR expression of SGCs and microglia, glial cells predominantly involved in local immune responses in ganglia of the human PNS and NAWM of the CNS, respectively. Ex vivo flow cytometry analysis of cell suspensions obtained from human cadaveric TG and NAWM showed that both SGCs and microglia expressed TLR1-5, TLR7, and TLR9, although expression levels varied between these cell types. Immunohistochemistry confirmed expression of TLR1-TLR4 and TLR9 by SGCs in situ. Stimulation of TG- and NAWM-derived cell suspensions with ligands of TLR1-TLR6, but not TLR7 and TLR9, induced interleukin 6 (IL-6) secretion. We identified CD45LOW CD14POS SGCs and microglia, but not CD45HIGH leukocytes and CD45NEG cells as the main source of IL-6 and TNF-α upon stimulation with TLR3 and TLR5 ligands. In conclusion, human TG-resident SGCs express a broad panel of functional TLRs, suggesting their role in initiating and orchestrating inflammation to pathogens in human sensory ganglia [23].
8.5 Development of SGC
The aim of Wang et al in their study was to establish a novel primary culture method for satellite glial cells derived from dorsal root ganglia. Neonatal rat spine was collected and an incision made to expose the transverse protrusion and remove dorsal root ganglia. Dorsal root ganglia were freed from nerve fibers, connective tissue, and capsule membranes, then rinsed and transferred to 6-well plates, and cultured in a humidified 5% CO2 incubator at 37°C. After 3 days in culture, some cells had migrated
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from dorsal root ganglia. After subculture, cells were identified by immunofluorescence labeling for three satellite glial cell-specific markers: glutamine synthetase, glial fibrillary acidic protein, and S100β. Cultured cells expressed glutamine synthetase, glial fibrillary acidic protein, and S100β, suggesting they are satellite glial cells with a purity of > 95%. Thus, they have successfully established a novel primary culture method for obtaining high-purity satellite glial cells from rat dorsal root ganglia without digestion [24].
Callahan et al examined satellite cells phenotypic development in mouse sympathetic ganglia by localizing the transcription factors, Sox10 and Phox2b, the neuronal marker, tyrosine hydroxylase (TH), and brain‐derived fatty acid binding protein (B‐FABP), which identifies glial precursors and mature glia. In their investigation they found that neither GDNF nor GFRα1 are essential for the development of satellite glia in sympathetic ganglia [40].
8.6 Role of satellite glial cells in nociception and pain
The aim of Costa et al in their study was to summarize some of the important physiological and morphological characteristics of these cells and gather the most relevant scientific evidence about their possible involvement in the chronic pain development.
They suggest that bidirectional communication via a paracrine signaling between neurons and SGC is enabled by the functional unit they form. There is a growing body of evidence that glial satellite cells undergo structural and biochemical changes after nerve injury, which influence neuronal excitability and consequently the development and/or maintenance of pain in different animal models of chronic pain. In conclusion SGC are important in the establishment of physiological pain, in addition to being a potential target for the development of new pain treatments [3].
SGCs envelop neurons in sensory ganglia that perform similar functions to the glia found in the CNS. During primary sensory neurons injury, the surrounding SGCs go through characteristic changes. There is good evidence that the SGCs are not just bystanders to the injury but they have an active role in the initiation and maintenance of neuronal changes that underlie neuropathic pain. Feldman- Goriachnik et al review the literature on the relationship between SGCs and nociception and present evidence that changes in SGC potassium ion buffering capacity and glutamate recycling can lead to neuropathic
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like behavior in animal models. The role that SGCs play in the immune responses to injury is also considered. They suggest the term gliopathic pain to describe those conditions in which central or peripheral glia are thought to be the principal generators of principal pain generators [27].
Gastrointestinal (GI) pain is a common clinical problem, with limited effective therapy. Sensations from the GI tract, including pain, are mediated largely by neurons in the dorsal root ganglia (DRG), and to a smaller extent by vagal afferents emerging from neurons in the nodose/jugular ganglia. Hanani proposes that neurons in rodent DRG become hyperexcitable in models of GI pain (e.g., gastric or colonic inflammation), and can serve as a source for chronic pain [20].
Chemotherapy with Oxaliplatin and Taxol is known to induce peripheral neuropathy as a serious side effect in cancer treatment, a major manifestation being neuropathic pain that can be debilitating and can reduce the quality of life of the patient. Warwick and Hanani proposed that satellite glial cells in DRGs are altered in chemotherapy‐induced peripheral neuropathy models and contribute to neuropathic pain [21].
Blum and co-authors investigated LPS long term effects on SGC, and tested pain behavior, assessed SGCs activation in DRG using glial GFAP immunostaining, and injected a fluorescent dye intracellularly to study intercellular coupling. Electron microscopy was used for quantitative changes in gap junctions. They conclude that a single LPS injection have long-term behavioral and cellular changes. And that this is consistent with the idea that SGC activation contributes to hyperalgesia [22].
At DRG, neurons and SGC can communicate through ATP release and P2X7 receptor activation and they also interconnect by gap junctions and have been previously implicated in modulating inflammatory and chronic pain. Lemes et al show evidence in their investigation that SGCs are also involved in processing acute nociception in rat dorsal root ganglia. By use of primary dorsal root ganglia cultures they observed that calcium transients induced in neurons by capsaicin administration were followed by activation of satellite glial cells. Only satellite glial cells response was reduced by administration of the P2X7 receptor antagonist A740003. In vivo, acute nociception induced by intraplantar injection of capsaicin in rats was inhibited by A740003 or by the gap junction blocker carbenoxolone administered at the dorsal root ganglia (L5 level). Both drugs also reduced the second phase of the formalin test. These results suggest that communication between neurons and satellite glial cells is not only involved in inflammatory or pathological pain, but also in the transmission of the nociceptive signal, possibly in situations involving C-fiber activation [25].
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Neuropathic pain is a very common complication in diabetes mellitus, and its treatment is limited. As this disease is becoming a global epidemic it is important to understand and treat this problem. The mechanisms of diabetic neuropathic pain are largely obscure. Recent studies have shown that glial cells are important for a variety of neuropathic pain types, and we investigated what are the changes that satellite glial cells (SGCs) in dorsal root ganglia undergo in a DM type 1 model, induced by streptozotocin (STZ) in mice and rats. We carried out immunohistochemical studies to learn about changes in the activation marker glial fibrillary acidic protein (GFAP) in SGCs. We found that after STZ‐treatment the number of neurons surrounded with GFAP‐positive SGCs in dorsal root ganglia increased 4‐fold in mice and 5‐fold in rats. Western blotting for GFAP, which was done only on rats because of the larger size of the ganglia, showed an increase of about 2‐fold in STZ‐treated rats, supporting the immunohistochemical results. These results indicate for the first time that SGCs are activated in rodent models of DM1. As SGC activation appears to contribute to chronic pain, these results suggest that SGCs may participate in the generation and maintenance of diabetic neuropathic pain, and can serve as a potential therapeutic target [28].
SGCs go through phenotypic changes and divide the following injury into a peripheral nerve. Nerve injury, also promotes an immune response and several antigen-presenting cells are found in close proximity to SGCs. Jasmin and co suggest that silencing SCG-specific molecules involved in intercellular transport (Connexin 43) or glutamate recycling (glutamine synthase) can dramatically cause alteration in nociceptive responses of normal and nerve-injured rats. Transduction of SGCs with glutamic acid decarboxylase can produce analgesia in models of trigeminal pain. According to these data they also suggest that SGCs may be involved in the genesis or maintenance of pain and open a variety of new possibilities to cure neuropathic pain [29].
Chronic pain is one of the most prevalent chronic diseases in the world. The plastic changes of sensory neurons in dorsal root ganglia (DRG) have been extensively studied as the underlying periphery mechanism. Recent studies revealed that satellite cells, the major glial cells in DRG, also played important roles in the development/modulation of chronic pain. Whether DRG satellite glial cells generate new neurons as their counterparts in enteric nerve ganglia and carotid body do under pathological conditions remains poorly investigated. In their study Zhang and co-authors propose that chronic pain induces proliferation and upregulation of progenitor markers in the sex‐determining region Y‐box 2 (Sox2) ‐ and platelet‐derived growth factor receptor alpha (PDGFRα) ‐positive satellite glial
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cells. By BrdU incorporation assay was revealed the generation of IB4‐ and CGRP‐positive neurons, but not NF200‐positive neurons in DRG ipsilateral to injury. Genetic fate tracings showed that PDGFRα‐ positive cells did not generate neurons, whereas Sox2‐positive cells indicated production of both IB4‐ and CGRP‐positive neurons. Interestingly, glial fibrillary acidic protein‐positive cells, a subpopulation of Sox2‐positive satellites, only gave birth to IB4‐positive neurons. Local persistent delivery of tetrodotoxin to the sciatic nerve trunk significantly reduced the pain‐induced neurogenesis. Furthermore, patch‐clamp studies showed that these glia‐derived new neurons could fire action potentials and have response to capsaicin. Taken together, these data showed a chronic pain‐induced nociceptive neurogenesis in DRG from Sox2‐positive satellite cells, indicating a possible contribution of DRG neurogenesis to the pathology of chronic pain [19].
Watkins and Maier suggest is their study the possibility that the reason for drugs failure to manage chronic pain lies in the fact that they were designed to target neurons rather than immune or glial cells. It describes how immune cells are a natural and inextricable part of skin, peripheral nerves, dorsal root ganglia, and spinal cord. It then examines how immune and glial activation may participate in the etiology and symptomatology of diverse pathological pain states in both humans and laboratory animals. Of the variety of substances released by activated immune and glial cells, pro inflammatory cytokines (tumor necrosis factor, interleukin-1, interleukin- 6) appear to be of special importance in the creation of peripheral nerve and neuronal hyperexcitability. Although this review focuses on immune modulation of pain, the implications are pervasive. Indeed, all nerves and neurons regardless of modality or function are likely affected by immune and glial activation in the ways described for pain [42].
Stellate ganglion blocks are used as treatment for pain in different medical conditions, for example, in the case of complex regional pain [43].
8.7 Stellate ganglia gender differences
Bayels et al investigated the gender differences in transcriptometric and neurochemical analysis between genders and they generated a dataset of baseline measurements of mouse stellate ganglia using RNA seq, HPLC and mass spectrometry. Expression differences between male and female mice were identified including physiologically important genes for growth factors, receptors and ion channels. While the neurochemical profiles of male and female stellate ganglia did not show difference, minor differences in neurotransmitter content were identified in heart tissue [37].
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9. MATERIALS AND METHODS
9.1 Material
17 human stellate ganglions of both genders between ages 38-95 were used for investigation. The microscope preparations were made earlier and were stored in the Institute of Anatomy. We examined and measured the neurons squared meter and calculated amount of glial satellite cells (SGCs) surrounding single neuron.
4 females and 13 males SG were investigated under microscope to see if there is any difference between the genders in size and SGCs amount was investigated also. Sections of ganglions were used to determinate immunoreactivity. They were immunostained for neurofilament protein (NF) as a marker. Antibody – NF- DAKO, NR M0726 (dilution 1:50).
Preparation of the ganglions. Sections were fixed in the 4% 0.1 M phosphate buffer paraformaldehyde solution (PBS) (pH 7.4) 3-4 days. Afterwards the specimens were embedded in the paraffin and blocks were cutted for sections of 5 µm thickness. Sections were deparaffined and rehydrated. Next step was immunohistochemistry. Sections were washed in distillate water, then were incubated in the citrate buffer (10 mM, pH 6.0) 5 min in microwave oven. Afterwards 15-20 min refresh and then 5 min wash in PBS.
The next step is 5 min 3% peroxide solution and afterwards 2 times washed in PBS. Additional incubation for 30 min in primary antibody solution- mouse monoclonal antibody. Then sections were washed 10 min in phosphate buffer then further incubation for 10 min in biotinylated secondary antibody, washed 10 min, further 10 min. incubation with streptavidin. Then were washed 10 min in PBS and 5 min with 3.3-diaminobenzidine- DAB. Again 5 min were washed and at the end sections were stained with haematoxylin or hemalum solution.
Expression of immunohistochemistry reaction: neurons cytoplasm- brown, nucleus light, nucleolus light blue, neurons processes (fibers, bundles, nerves) - brown. Satellite glial cells - light blue.
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9.2 Microscopic examination
Microphotographs of 17 histological slides of neural structures were examined and their digital images were taken by a camera on a microscope LSM (Carl Zeiss, Jena, Germany). In taken stellate ganglions digital images were uploaded to Axiovision software 4.8 where the neurons with nucleus and nucleolus were marked and were measured cross area (µm²) of the neural somata. The number of the surrounding satellite glial cells which surround the single neuron were calculated.
9.3 Statistical analysis
Data were processed using MS Excel 2010 and analyzed using IBM SPSS Statistics, version 20.
The descriptive analysis included the calculation of the prevalence of minimum and maximum of the neurons size and quantity of SGCs surrounding each neuron. Continuous variables were presented as mean ± standard deviation (SD). Comparisons were done using the Mann- Whitney U Test.
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10. RESULTS AND DISCUSSION
In the human stellate ganglions each neuron was wreathed by its glial cover. For each neuron this complex was distinct. We found that glial satellite cells were covered not only neurons somata, but they were also close to neurons processes, which were adjacent to neurons body. Number of these cells was variable: from 1 to 5. These cells may be grouped around the circumference of neuron or may be located in the rows. There were some neurons without SCGs.
Fig 1. Neuron and satellite glial cells surrounding it, male 65 year old. Immunohistochemistry NF- DAKO, NR M0726
Neuron
Satellite glial cell
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Fig 2. Neurons size (µm²) of the different gender human stellate ganglion
Average size of neurons in female was 632.5 (µm²) and in male 613.32 (µm²). We found, that size of the female neurons was larger than male, but this difference was not statistically significant (Fig 2.).
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Fig 3. Gender differences of the number of the satellite glial cells of human stellate ganglion
Average of satellite glial cells number in female was 2.4 and in male 1.4 (Fig. 3), this result was statistically significant.
This study was demonstrated related gender differences in SGCs of human stellate ganglion. While measuring the stellate ganglia neurons was found the variety of neuron size however findings show there was no significant statistical difference in size of neurons between both genders. These results were similar to results of Bayels et al (37, Fig. 2). During the calculation of the quantity of the SGCs surrounding each neuron we found appropriate results that there were more SGCs surrounding female neurons (Fig. 3).
Paneese’s study mentioned in the literature review suggests that 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 [2].
However during the SGCs calculation in our examination it was found that some neurons were not surrounded at all by satellite glial cells and that different size neurons were surrounded by different quantity of SGCs, it may be related to age, according Liutkiene et al study on superior cervical ganglia it is shown that there are age related morphological changes that may influence neurons: decline of neuronal functional capacity, plasticity and regeneration [44].
According literature review communication and transmission between neurons to their surrounding SGCs happens in different ways [6, 9, 11, 8, 26, 35, 36, 38].
Different scientific studies were suggested that SGCs undergo proliferation and inflammatory processes [7, 8, 10, 2, 16, 17, 30-34].
Most of the articles in this literature review were suggested that SGCs have an important role in nociception and pain [3-5, 19-22, 25, 27-29, 42, 43].
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11. CONCLUSIONS
1. The difference in amount of SGCs surrounding the human stellate ganglion neurons of male and female was statistically significant. Female neurons were enveloped by the larger number of SGCs. 2. Difference in average of neuronal cross area (µm²) between male and female was not statistically significant.
3. Our findings do not show correlation between neuronal cross area and the number of SGCs in human stellate ganglia.
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