Figure 6 - uploaded by Wesley J Thompson
Content may be subject to copyright.
Schwann cells associated with Pacinian corpuscles are immunopositive for the neuregulin receptor erbB3. A–C , Confocal images of a whole mount of P5 Pacinian corpuscles triple-labeled with anti-S-100 for Schwann cells ( A ), anti-erbB3 ( B ), and anti-synaptophysin to show the nerve terminal ( C ). ErbB3 immunoreactivity co-localizes with Schwann cells. Because the antibodies to S-100 and erbB3 are both rabbit polyclonals, the tissue was stained using the technique of dilutional neglect for these two antibodies (see Materials and Methods). Scale bar, 20 m.
Source publication
Golgi tendon organs and Pacinian corpuscles are peripheral mechanoreceptors that disappear after denervation during a critical period in early postnatal development. Even if regeneration is allowed to occur, Golgi tendon organs do not reform, and the reformation of Pacinian corpuscles is greatly impaired. The sensory nerve terminals of both types o...
Context in source publication
Context 1
... of the S-100- positive inner core, suggesting that these were actually inner core cells rather than Schwann cells that contributed to the developing myelin sheath of the sensory axon. In addition, confocal images taken through the inner core region identified these cells as apoptotic (not shown). Terminal Schwann cells at the developing neuromuscular junction and premyelinating Schwann cells associated with developing motor nerves seem to be trophically dependent on motor axon- derived neuregulin (Grinspan et al., 1996; Trachtenberg and Thompson, 1996). We investigated whether Schwann cells associated with mechanoreceptive afferents may also be trophically dependent on neuregulin by applying recombinant human GGF2 in an attempt to rescue mechanoreceptor-associated Schwann cells from denervation-induced apoptosis. For an examination of Golgi tendon organs, a BSA-containing vehicle solution with or without GGF2 was injected subcutane- ously for 1–2 d into the hindlimbs of animals denervated at P4. Innervated, noninjected muscles contralateral to the GGF- treated muscles were used as controls, because preliminary experiments showed that GGF2 does not seem to have systemic effects in a contralateral hindlimb when injected into the other limb (i.e., the number of tendon organs in a normally innervated soleus located contralateral to a denervated soleus treated with or without GGF2 is the same as the number of tendon organs in a soleus of an untreated littermate) (data not shown). Preparations were double-labeled with anti-S-100 and TUNEL and examined at P5 and P6. GGF2 rescued the Schwann cells in tendon organs from denervation-induced apoptosis (Fig. 3 A,B ). A summary of quantitative data is presented in Figure 5. At P5 and P6, control soleus muscles, denervated muscles treated with vehicle, and denervated muscles treated with GGF2 all had similar numbers of tendon organs (13–15). However, the denervated muscles receiving vehicle had many more apoptotic cells per tendon organ than did the denervated muscles receiving GGF2. In fact, the numbers of apoptotic cells in the denervated, GGF2-treated muscles were similar to those of contralateral control muscles. Similar to Golgi tendon organs, GGF2 rescued the Schwann, or inner core, cells of denervated Pacinian corpuscles (Figs. 3 C,D , 5). Pacinian corpuscles denervated at P2 were given GGF2 for 3 d and examined at P5, a time when previous examinations revealed that their normal complement of corpuscles is greatly reduced, and all of the remaining corpuscles are small and dispersed in morphology compared with controls (see above). Preparations were labeled with anti-S-100 and the TUNEL method. Denervated animals treated with vehicle alone had many fewer Pacinian corpuscles compared with denervated, GGF2-treated animals or controls. Furthermore, the number of apoptotic cells per receptor was much higher in the denervated preparations that received vehicle compared with denervated GGF2-treated animals or controls. The effect of GGF2 administration was also examined on Golgi tendon organs and Pacinian corpuscles at a time after denerva- tion when, in the absence of GGF2, all of these structures have disappeared. By late P7, when all tendon organs have normally disappeared after denervation at P4, labeling with S-100 revealed that all tendon organs were preserved (as identified by staining for their Schwann cells) after the exogenous administration of GGF2 (Figs. 4 A , 5). The morphology of these structures looked strik- ingly normal. Similar to tendon organs, by late P6 when Pacinian corpuscles have normally disappeared after denervation at P2, S-100 labeling revealed that Pacinian corpuscles remained in animals receiving GGF2 during this time (Figs. 4 B , 5). All denervated Pacinian corpuscles that were preserved by GGF were smaller than age-matched controls. Although approximately one- fourth of these Pacinian corpuscles appeared elongated in morphology (similar to age-matched controls), most were rounder. For Golgi tendon organs and Pacinian corpuscles, double-labeling with antibodies to Schwann cells and neurofilament and synaptophysin confirmed that none of the rescued Schwann cells were associated with axons (data not shown). If a neuregulin such as GGF2 is an axon-derived trophic factor that functions in vivo to maintain directly the Schwann cells associated with mechanosensory end organs, then the sensory nerve terminals should contain neuregulin protein, and the Schwann cells should express the appropriate neuregulin receptors. Antibodies to neuregulin and the three neuregulin receptors erbB2, erbB3, and erbB4 were used to examine this possibility. Whole mounts of Golgi tendon organs and Pacinian corpuscles at P5 were labeled with anti-S-100 to identif y Schwann cells, anti- erbB3 to localize this receptor, and anti-synaptophysin to identify the nerve terminal. In whole mounts, Schwann cells of both types of mechanoreceptors were immunopositive for erbB3 (Fig. 6 for Pacinian corpuscles; Golgi tendon organ not shown). The erbB3 staining appeared absent from the nucleus of inner core Schwann cells. Confocal images revealed that there was often a high immunoreactivity for erbB3 surrounding the nerve terminal (i.e., in the Schwann cells wrapping the axon as it entered the corpuscle) (data not shown). The specificity of erbB3 immunostaining was confirmed by its elimination after preincubation of the erbB3 antibody with the peptide it was raised against. Whole-mount preparations of P5 Pacinian corpuscles and Golgi tendon organs did not stain for erbB2, erbB4, or neuregulin; however, each of these probes revealed positive immunoreactivity in cryostat sections made of Pacinian corpuscles in interosseus membranes (Fig. 7). In sections, the inner core region of Pacinian corpuscles stained with anti-S-100 (Fig. 7 A ), anti-erbB2 (Fig. 7 B ), anti-erbB3 (result not shown), and anti-erbB4 (Fig. 7 C ). The specificity of staining for each antibody was confirmed by its elimination after incubation with the appropriate control peptide. Interestingly, erbB4 has not been detected in Schwann cells that are not associated with mechanoreceptors (Grinspan et al., 1996; Carroll et al., 1997), except in one recent study (Vartanian et al., 1997) in which trace amounts of erbB4 were detected in cultured rat Schwann cells by Western blotting. In addition, message to erbB4 was detected in human Schwann cells (Levi et al., 1995). Finally, Pacinian corpuscles were repeatedly identifiable by Nomarski optics (Fig. 7 D ), and their sensory nerve terminal could ...
Citations
... Wang et al. have demonstrated that RPNI, in comparison with regular burial of neuroma in innervated muscle as well as controls, decreases the extent of (symptomatic) neuroma development regarding (1) scarring and connective tissue proliferation, (2) degree of irregular axonal regeneration, (3) expression levels of various markers of neuroinflammation and mechanosensitivity (eg, a-SMA, sigma-1 receptor, c-fos, substance P, increased GDNF), and (4) decreased levels of autotomy behavior in rats (25% vs 70% and 90%, respectively). 186 In addition, these denervated targets exhibit Schwann cells that undergo induced apoptotic death 84 which recruit macrophages 175 that may produce a focused gradient of new neurotrophic factors or hypoxic conditions to promote new nerve ingrowth and reactivation of developmental nerve programs. Despite these clinical observations and tangential studies, the literature directly interrogating symptomatic neuromas and the mechanisms behind the therapeutic benefit of TMR/RPNI remain incompletely understood. ...
Neuromas are a substantial cause of morbidity and reduction in quality of life. This is not only caused by a disruption in motor and sensory function from the underlying nerve injury but also by the debilitating effects of neuropathic pain resulting from symptomatic neuromas. A wide range of surgical and therapeutic modalities have been introduced to mitigate this pain. Nevertheless, no single treatment option has been successful in completely resolving the associated constellation of symptoms. While certain novel surgical techniques have shown promising results in reducing neuroma-derived and phantom limb pain, their effectiveness and the exact mechanism behind their pain-relieving capacities have not yet been defined. Furthermore, surgery has inherent risks, may not be suitable for many patients, and may yet still fail to relieve pain. Therefore, there remains a great clinical need for additional therapeutic modalities to further improve treatment for patients with devastating injuries that lead to symptomatic neuromas. However, the molecular mechanisms and genetic contributions behind the regulatory programs that drive neuroma formation—as well as the resulting neuropathic pain—remain incompletely understood. Here, we review the histopathological features of symptomatic neuromas, our current understanding of the mechanisms that favor neuroma formation, and the putative contributory signals and regulatory programs that facilitate somatic pain, including neurotrophic factors, neuroinflammatory peptides, cytokines, along with transient receptor potential, and ionotropic channels that suggest possible approaches and innovations to identify novel clinical therapeutics.
... The presence of motor neurons affects Schwann cell viability. Motor neurons secret neuregulins, which are glial growth factors that promote survival and proliferation of Schwann cells [83,84]. ...
PURPOSE: Minor skeletal muscle injuries can be repaired, but more extensive volumetric muscle loss (VML) leads to a permanent functional disability with ambiguous therapeutic outcomes, and reconstructive surgical procedures are constrained by donor tissue scarcity. This review assessed the considerable attention paid to biomaterials in healing damaged skeletal muscle.METHODS: A comprehensive search in PubMed, Web of Science, Google Scholar, and Wiley Online Library was conducted to obtain previous studies exploring the state of biocompatible tissue scaffolds for VML recovery.RESULTS: By regenerating the function of damaged skeletal muscle, tissue-engineered skeletal muscle construction could revolutionize the treatment of VML. However, transporting cells into the wounded muscle location presents a significant challenge because it may result in unfavorable immunological reactions. The development and validation of several biomaterials with varying physical and chemical natures to treat various muscle injuries have recently been undertaken to overcome this problem. This review discusses the relative benefits of satellite cells (SC), the most prevalent skeletal muscle stem cells employed to seed scaffolds.CONCLUSIONS: Biomaterials can be used with skeletal muscle stem cells and growth factors to repair VML because of their customizable and desirable physicochemical qualities. Owing to the capacity of SCs for self-renewal and their undifferentiated state, these cells are excellent candidates for cell therapy. A large gap exists between understanding SC behavior and how it can be used to repair and regenerate human skeletal muscle tissue. Thus, this review sought to portray the current knowledge on the lifespan of SCs and their involvement in exercise-induced muscle regeneration and hypertrophy.
... The treatment of bFGF could up-regulate the transcription of brain-derived neurotrophic factors within axons, which promote axonal regeneration (Soto et al., 2006). GGF-2 is axon-derived neuregulin which has trophic effects on Schwann cells in terms of proliferation, migration, myelination and neuron-glia interactions (Mahanthappa et al., 1996;Kopp et al., 1997). The combined application of these growth factors orchestrates the differentiation and proliferation of Schwann cells (Jessen and Mirsky, 1999). ...
Peripheral nerve injuries (PNIs) are frequent traumatic injuries across the globe. Severe PNIs result in irreversible loss of axons and myelin sheaths and disability of motor and sensory function. Schwann cells can secrete neurotrophic factors and myelinate the injured axons to repair PNIs. However, Schwann cells are hard to harvest and expand in vitro, which limit their clinical use. Adipose-derived stem cells (ADSCs) are easily accessible and have the potential to acquire neurotrophic phenotype under the induction of an established protocol. It has been noticed that Tacrolimus/FK506 promotes peripheral nerve regeneration, despite the mechanism of its pro-neurogenic capacity remains undefined. Herein, we investigated the neurotrophic capacity of ADSCs under the stimulation of tacrolimus. ADSCs were cultured in the induction medium for 18 days to differentiate along the glial lineage and were subjected to FK506 stimulation for the last 3 days. We discovered that FK506 greatly enhanced the neurotrophic phenotype of ADSCs which potentiated the nerve regeneration in a crush injury model. This work explored the novel application of FK506 synergized with ADSCs and thus shed promising light on the treatment of severe PNIs.
... Consistently, exogenous delivery of Neuregulin 1 prevents endorgan Schwann cell apoptosis of Pacinian corpuscles during development. 20 Remak Schwann cells also rely on Neuregulin 1; consequently, nociceptive nerves lacking Neuregulin 1 have defective Remak Schwann cell ensheathment, 12 and this deficit is not compensated by any other mechanism. 11 Thus, if nociceptive Schwann cells share mechanisms with Pacinian sensory endorgan Schwann cells and Remak Schwann cells, the severe consequences observed in this study on nociceptive Schwann cells by chemical ablation of nerves could indicate a continuous dependence of nociceptive Schwann cells on Neuregulin 1 supplied by nociceptive nerves. ...
Recent findings indicate that nociceptive nerves are not "free", but similar to touch and pressure sensitive nerves, terminate in an end-organ in mice. This sensory structure consists of the nociceptive nerves and specialized nociceptive Schwann cells forming a mesh-like organ in subepidermis with pain transduction initiated at both these cellular constituents. The intimate relation of nociceptive nerves with nociceptive Schwann cells in mice raises the question whether defects in nociceptive Schwann cells can by itself contribute to pain hyperalgesia, nerve retraction, and peripheral neuropathy. We therefore examined the existence of nociceptive Schwann cells in human skin and their possible contribution to neuropathy and pain hyperalgesia in mouse models. Similar to mouse, human skin contains SOX10+/S100B+/AQP1+ Schwann cells in the subepidermal border that have extensive processes, which are intimately associated with nociceptive nerves projecting into epidermis. The ablation of nociceptive Schwann cells in mice resulted in nerve retraction and mechanical, cold, and heat hyperalgesia. Conversely, ablating the nociceptive nerves led to a retraction of epidermal Schwann cell processes, changes in nociceptive Schwann cell soma morphology, heat analgesia, and mechanical hyperalgesia. Our results provide evidence for a nociceptive sensory end-organ in the human skin and using animal models highlight the interdependence of the nerve and the nociceptive Schwann cell. Finally, we show that demise of nociceptive Schwann cells is sufficient to cause neuropathic-like pain in the mouse.
... Nevertheless, the neuroglial relationships support the viability of neurons, maintain the nerve tissue integrity and its resistance to damaging insults (Aldskogius and Kozlova, 1998;Whiteside et al., 1998). Nerve and glial cells are known to exchange ions, metabolites, and neurotrophic factors, which support mutual survival (Barres and Barde, 2000;Kopp et al., 1997). Neuron damage causes death of surrounding glial cells (Kolosov and Uzdensky, https://doi. ...
... Ultrastructural studies of axotomized neurons from rat hippocampus Spaeth et al., 2012;Yoo et al., 2003), or dorsal root ganglia (Spaeth et al., 2012), as well as from invertebrates including Aplysia (Ashery et al., 1996;Spira et al., 1993Spira et al., , 2003), earthworm, squid, or crayfish (Eddleman et al., 1998;Godell et al., 2006;Kopp et al., 1997). In turn, glia dysfunction suppresses neuronal functions and induces neuronal death (Egawa et al., 2017;Largo et al., 1996). ...
Neurotrauma is among main causes of human disability and death. We studied effects of axotomy on ultrastructure and neuronal activity of a simple model object – an isolated crayfish stretch receptor that consists of single mechanoreceptor neurons (MRN) enwrapped by multilayer glial envelope. After isolation, MRN regularly fired until spontaneous activity cessation. Axotomy did not change significantly MRN spike amplitude and firing rate. However, the duration of neuron activity from MRN isolation to its spontaneous cessation decreased in axotomized MRN relative to intact neuron. [Ca²⁺] in MRN axon and soma increased 3–10 min after axotomy. Ca²⁺ entry through ion channels in the axolemma accelerated axotomy-stimulated firing cessation. MRN incubation with Ca²⁺ionophore ionomycin accelerated MRN inactivation, whereas Ca²⁺-channel blocker Cd²⁺ prolonged firing. Activity duration of either intact, or axotomized MRN did not change in the presence of ryanodine or dantrolene, inhibitors of ryanodin-sensitive Ca²⁺ channels in endoplasmic reticulum. Thapsigargin, inhibitor of endoplasmic reticulum Ca²⁺-ATPase, or its activator ochratoxin were ineffective. Ultrastructural study showed that the defect in the axon transected by thin scissors is sealed by fused axolemma, glial and collagen layers. Only the 30–50 μm long segment completely lost microtubules and contained swelled mitochondria. The microtubular bundle remained undamaged at 300 μm away from the axotomy site. However, mitochondria within the 200–300 μm segment were strongly condensed and lost matrix and cristae. Glial and collagen layers exhibited greater damage. Swelling and edema of glial layers, collagen disorganization and rupture occurred within this segment. Thus, axotomy stronger damages glia/collagen envelope, axonal microtubules and mitochondria.
... Interestingly, the dependence of the corpuscular glial cells from the axons continues during adult life at least for the expression of some antigens. After denervation, glial cells of Meissner-like corpuscles lack some specific markers [44,45] and strongly decrease the expression of TrkA [46], and the glial cells forming the inner core of Pacinian corpuscles undergo apoptotic death that can be prevented by administration of glial growth factor 2 [47]. ...
... Interestingly, the dependence of the corpuscular glial cells from the axons continues during adult life at least for the expression of some antigens. After denervation, glial cells of Meissner-like corpuscles lack some specific markers [44,45] and strongly decrease the expression of TrkA [46], and the glial cells forming the inner core of Pacinian corpuscles undergo apoptotic death that can be prevented by administration of glial growth factor 2 [47]. ...
Sensory corpuscles of human skin are structures located at the peripheral end of the mechanoreceptive neurons and function as low-threshold mechanoreceptors (LTMRs). In its structure, in addition to the axon, there are glial cells, not myelinat-ing, that are organized in different ways according to the morphotype of sensitive corpuscle, forming the so-called laminar cells of Meissner's corpuscles, the laminar cells of the inner core of Pacinian corpuscles, or cells of the inner core in Ruffini's corpuscles. Classically the glial cells of sensory corpuscles have been considered support cells and passive in the process of mechanotransduction. However, the presence of ion channels and synapses-like systems between them and the axon suggests that corpuscular glial cells are actively involved in the transformation of mechanical into electrical impulses. This chapter is an update on the origin, development , cytoarchitecture, and protein profile of glial cells of sensitive corpuscles especially those of human glabrous skin.
... Following loading, it was apparent that the cell's nucleus was deformed, along with the cytoskeleton. (Kopp, Trachtenberg, & Thompson, 1997), which also have the same receptors that activate various signalling pathways such as G protein, MAPK's, cAMP pathways, and Ca 2+ influx on loading (M. Liu, Xu, Tanswell, & Post, 1994). ...
Tendon mechanobiology plays a vital role in tendon repair and regeneration; however, this mechanism is currently poorly understood. We tested the role of different mechanical loads on extra-cellular matrix (ECM) remodelling gene expression and the morphology of tendon fibroblasts in collagen hydrogels, designed to mimic native tissue. Hydrogels were subjected to precise static or uniaxial loading patterns of known magnitudes and sampled to analyse gene expression of known mechano-responsive ECM-associated genes (COL I, COL III, Tenomodulin and TGF-β). Tendon fibroblast cytomechanics was studied under load by using a tension culture force monitor (t-CFM), with immunofluorescence and immunohistological staining used to examine cell morphology. Tendon fibroblasts subjected to cyclic load showed endogenous matrix tension was maintained, with significant concomitant upregulation of ECM remodelling genes, COL I, COL III, Tenomodulin, and TGF-b when compared to static load and control samples. These data indicate that tendon fibroblasts acutely adapt to the mechanical forces placed upon them, transmitting forces across the ECM without losing mechanical dynamism. This model demonstrates cell-material (ECM) interaction and remodelling in pre-clinical a platform, which can be used as a screening tool to understand tendon regeneration.
... Study of neuroglial interactions under nerve tissue injury needs adequate models and instruments. Neuroglial interactions may affect the survival of neurons and glial cells [1,2]. So, cell survival rate could be used as an indicator of cytoprotective interactions between neuronal and glial cells. ...
... Therefore the observed effect of increased survival of the glial cells as one approached to the giant axons, could be consequence of glia protective neuroglial interactions in the crayfish VNC. Obtained results seem us of special importance because existing literature on support of survival between neural and glial cells relate mainly to embryonic and neonatal periods of individual development, when nerve tissue are under formation [2,14]. Before, we have already report on neuron-dependent survival of glial cells in stretch receptor of adult crayfish [15]. ...
... In recent years, the molecular profiles of the mechanosensory neurons that form Meissner (Ichikawa et al., 2000;González-Martínez et al., 2004Pérez-Piñera et al., 2008;Bourane et al., 2009;Abdo et al., 2011;Roudaut et al., 2012;Fleming and Luo, 2013) and Pacinian corpuscles (Kopp et al., 1997;Sedý et al., 2004Sedý et al., , 2006Luo et al., 2009;Hu et al., 2012;Fleming et al., 2016) have been established and are now rather well known. Conversely, information is limited regarding the interactions between the growing mechanosensory axons and the surrounding cells. ...
... Conversely, information is limited regarding the interactions between the growing mechanosensory axons and the surrounding cells. Nevertheless, the available data strongly suggest that local growth factors (Schecterson and Bothwell, 1992;Kopp et al., 1997;Dontchev Fig. 18. Schematic diagram showing the main stages in development of human Meissner corpuscles. ...
Meissner's and Pacinian corpuscles are cutaneous mechanoreceptors responsible for different modalities of touch. The development of these sensory formations in humans is poorly known, especially regarding the acquisition of the typical immunohistochemical profile related to their full functional maturity. Here we used a panel of antibodies (to specifically label the main corpuscular components: axon, Schwann-related cells and endoneurial-perineurial-related cells) to investigate the development of digital Meissner's and Pacinian corpuscles in a representative sample covering from 11 weeks of estimated gestational age (wega) to adulthood. Development of Pacinian corpuscles starts at 13 wega, and it is completed at 4 months of life, although their basic structure and immunohistochemical characteristics are reached at 36 wega. During development, around the axon, a complex network of S100 positive Schwann-related processes is progressively compacted to form the inner core, while the surrounding mesenchyme is organized and forms the outer core and the capsule. Meissner's corpuscles start to develop at 22 wega and complete their typical morphology and immunohistochemical profile at 8 months of life. In developing Meissner's corpuscles, the axons establish complex relationships with the epidermis and are progressively covered by Schwann-like cells until they complete the mature arrangement late in postnatal life. The present results demonstrate an asynchronous development of the Meissner's and Pacini's corpuscles and show that there is not a total correlation between morphological and immunohistochemical maturation. The correlation of the present results with touch-induced cortical activity in developing humans is discussed.
