The Experts below are selected from a list of 618 Experts worldwide ranked by ideXlab platform
James Anthony St John - One of the best experts on this subject based on the ideXlab platform.
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Olfactory Ensheathing Glia are required for embryonic Olfactory axon targeting and the migration of gonadotropin releasing hormone neurons
Biology Open, 2013Co-Authors: Perrine Barraud, James Anthony St John, Claus C Stolt, Michael Wegner, Clare V H BakerAbstract:Kallmann's syndrome is caused by the failure of Olfactory axons and gonadotropin-releasing hormone (GnRH) neurons to enter the embryonic forebrain, resulting in anosmia and sterility. Sox10 mutations have been associated with Kallmann's syndrome phenotypes, but their effect on Olfactory system development is unknown. We recently showed that Sox10 is expressed by neural crest-derived Olfactory Ensheathing cells (OECs). Here, we demonstrate that in homozygous Sox10lacZ/lacZ mouse embryos, OEC differentiation is disrupted; Olfactory axons accumulate in the ventromedial Olfactory nerve layer and fewer Olfactory receptor neurons express the maturation marker OMP (most likely owing to the failure of axonal targeting). Furthermore, GnRH neurons clump together in the periphery and a smaller proportion enters the forebrain. Our data suggest that human Sox10 mutations cause Kallmann's syndrome by disrupting the differentiation of OECs, which promote embryonic Olfactory axon targeting and hence Olfactory receptor neuron maturation, and GnRH neuron migration to the forebrain.
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Olfactory Ensheathing cells from the nose clinical application in human spinal cord injuries
Experimental Neurology, 2011Co-Authors: Alan Mackaysim, James Anthony St JohnAbstract:Olfactory mucosa, the sense organ of smell, is an adult tissue that is regenerated and repaired throughout life to maintain the integrity of the sense of smell. When the sensory neurons of the Olfactory epithelium die they are replaced by proliferation of stem cells and their axons grow from the nose to brain assisted by Olfactory Ensheathing cells located in the lamina propria beneath the sensory epithelium. When transplanted into the site of traumatic spinal cord injury in rat, Olfactory lamina propria or purified Olfactory Ensheathing cells promote behavioural recovery and assist regrowth of some nerves in the spinal cord. A Phase I clinical trial demonstrated that autologous Olfactory Ensheathing cell transplantation is safe, with no adverse outcomes recorded for three years following transplantation. Autologous Olfactory mucosa transplantation is also being investigated in traumatic spinal cord injury although this whole tissue contains many cells in addition to Olfactory Ensheathing cells, including stem cells. If Olfactory Ensheathing cells are proven therapeutic for human spinal cord injury there are several important practical issues that will need to be solved before they reach general clinical application. This article is part of a Special Issue entitled: Understanding Olfactory Ensheathing Glia and their prospect for nervous system repair.
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motile membrane protrusions regulate cell cell adhesion and migration of Olfactory Ensheathing Glia
Glia, 2007Co-Authors: Louisa Windus, Christina Claxton, Chelsea L Allen, Brian Key, James Anthony St JohnAbstract:Olfactory Ensheathing cells (OECs) are candidates for therapeutic approaches for neural regeneration due to their ability to assist axon regrowth in central nervous system lesion models. However, little is understood about the processes and mechanisms underlying migration of these cells. We report here that novel lamellipodial protrusions, termed lamellipodial waves, are integral to OEC migration. Time-lapse imaging of migrating OECs revealed that these highly dynamic waves progress along the shaft of the cells and are crucial for mediating cell-cell adhesion. Without these waves, cell-cell adhesion does not occur and migrational rates decline. The activity of waves is modulated by both Glial cell line-derived neurotrophic factor and inhibitors of the JNK and SRC kinases. Furthermore, the activity of lamellipodial waves can be modulated by Mek1, independently of leading edge activity. The ability to selectively regulate cell migration via lamellipodial waves has implications for manipulating the migratory behavior of OECs during neural repair. (C) 2007 Wiley-Liss, Inc.
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motile membrane protrusions regulate cell cell adhesion and migration of Olfactory Ensheathing Glia
Glia, 2007Co-Authors: Louisa Windus, Christina Claxton, Chelsea L Allen, Brian Key, James Anthony St JohnAbstract:Olfactory Ensheathing cells (OECs) are candidates for therapeutic approaches for neural regeneration due to their ability to assist axon regrowth in central nervous system lesion models. However, little is understood about the processes and mechanisms underlying migration of these cells. We report here that novel lamellipodial protrusions, termed lamellipodial waves, are integral to OEC migration. Time-lapse imaging of migrating OECs revealed that these highly dynamic waves progress along the shaft of the cells and are crucial for mediating cell-cell adhesion. Without these waves, cell-cell adhesion does not occur and migrational rates decline. The activity of waves is modulated by both Glial cell line-derived neurotrophic factor and inhibitors of the JNK and SRC kinases. Furthermore, the activity of lamellipodial waves can be modulated by Mek1, independently of leading edge activity. The ability to selectively regulate cell migration via lamellipodial waves has implications for manipulating the migratory behavior of OECs during neural repair.
Giles W. Plant - One of the best experts on this subject based on the ideXlab platform.
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tissue sparing behavioral recovery supraspinal axonal sparing regeneration following sub acute Glial transplantation in a model of spinal cord contusion
BMC Neuroscience, 2013Co-Authors: Helen R Barbour, Giles W. Plant, Alan R Harvey, Christine D PlantAbstract:Background It has been shown that Olfactory Ensheathing Glia (OEG) and Schwann cell (SCs) transplantation are beneficial as cellular treatments for spinal cord injury (SCI), especially acute and sub-acute time points. In this study, we transplanted DsRED transduced adult OEG and SCs sub-acutely (14 days) following a T10 moderate spinal cord contusion injury in the rat. Behaviour was measured by open field (BBB) and horizontal ladder walking tests to ascertain improvements in locomotor function. Fluorogold staining was injected into the distal spinal cord to determine the extent of supraspinal and propriospinal axonal sparing/regeneration at 4 months post injection time point. The purpose of this study was to investigate if OEG and SCs cells injected sub acutely (14 days after injury) could: (i) improve behavioral outcomes, (ii) induce sparing/regeneration of propriospinal and supraspinal projections, and (iii) reduce tissue loss.
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Transfer to Olfactory Ensheathing Glia: Effects on Rubrospinal Tract Regeneration, Lesion Size, and Functional Recovery after Implantation in the Injured Rat Spinal Cord
2013Co-Authors: M J Ruitenberg, Joost Verhaagen, B Blits, G J Boer, Giles W. Plant, Frank P. T. Hamers, Joke Wortel, Paul A. Dijkhuizen, Willem Hendrik Gispen, Red’s Spinal CordAbstract:The present study uniquely combines Olfactory Ensheathing Glia (OEG) implantation with ex vivo adenoviral (AdV) vector-based neurotrophin gene therapy in an attempt to enhance regeneration after cervical spinal cord injury. Primary OEG were transduced with AdV vectors encoding rat brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or bacterial marker protein �-galactosidase (LacZ) and subsequently implanted into adult Fischer rats directly after unilateral transection of the dorsolateral funiculus. Implanted animals received a total of 2 � 10 5 OEG that were subjected to transduction with neurotrophin-encoding AdV vector, AdV-LacZ, or no vector, respectively. At 4 months after injury, lesion volumes were smaller in all OEG implanted rats and significantly reduced in size after implantation of neurotrophin-encoding AdV vector-transduced OEG. All OEG grafts were filled with neurofilament-positive axons, and AdV vector-mediated expression of BDNF by implanted cells significantly enhanced regenerative sprouting of the rubrospinal tract. Behavioral analysis revealed that OEG-implanted rats displayed better locomotion during horizontal rope walking than unimplanted lesioned controls. Recovery of hind limb function was also improved after implantation of OEG that were transduced with a BDNF- or NT-3-encoding AdV vector. Hind limb performance during horizontal rope locomotion did directly correlate with lesion size, suggestin
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Neurological Surgery and
2013Co-Authors: Giles W. Plant, Mary Bartlett Bunge, Yelena Pressman, Margaret L Bates, Paul F. Currier, Ernesto P. Cuervo, Patrick M WoodAbstract:Several studies have suggested that Olfactory Ensheathing Glia (EG) can form Schwann cell (SC)-like myelin. Because of possible misinterpretation attributable to contaminating SCs, the capacity of EG to produce myelin needs to be explored further. Therefore, we compared the abilities of adult EG, purified by immunopanning with p75 antibody, and adult SCs to produce myelin when cocultured with purified dorsal root ganglion neurons (DRGNs) in serum-free and serum-containing media. In both media formulations, the number of myelin sheaths in SC/DRGN cultures was far higher than in EG/DRGN cultures; the number of sheaths in EG/DRGN cultures was equal to that in purified DRGN cultures without added cells. The latter result demonstrates that myelination by a few SCs remaining in purified DRGN cultures may occur, suggesting that myelin in EG/DRGN cultures could be SC myelin. Striking differences i
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Olfactory Ensheathing Glia repairing injury to the mammalian visual system
Experimental Neurology, 2011Co-Authors: Giles W. Plant, Seok Voon Lee, Alan R Harvey, Simone G LeaverAbstract:The visual system is widely used as a model in which to study neurotrauma of the central nervous system and to assess the effects of experimental therapies. Adult mammalian retinal ganglion cell axons do not normally regenerate their axons for long distances following injury. Trauma to the visual system, particularly damage to the optic nerve or central visual tracts, causes loss of electrical communication between the retina and visual processing areas in the brain. After optic nerve crush or transection, axons degenerate and retinal ganglion cells (RGCs) are lost over a period of days. To promote and maintain axonal growth and connectivity, strategies must be developed to limit RGC death and provide regenerating axons with permissive substrates and a sustainable growth milieu that will ultimately provide long term visual function. This review explores the role Olfactory Glia can play in this repair. We describe the isolation of these cells from the Olfactory system, transplantation to the brain, gene therapy and the possible benefits that these cells may have over other cellular therapies to initiate repair, in particular the stimulation of axonal regeneration in visual pathways. This article is part of a Special Issue entitled: Understanding Olfactory Ensheathing Glia and their prospect for nervous system repair.
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culture conditions affect proliferative responsiveness of Olfactory Ensheathing Glia to neuregulins
Glia, 2007Co-Authors: T R De Mello, Samantha J Busfield, Sarah A Dunlop, Giles W. PlantAbstract:Olfactory Ensheathing Glia (OEG) have been used to improve outcome after experimental spinal cord injury and are being trialed clinically. Their rapid proliferation in vitro is essential to optimize clinical application, with neuregulins (NRG) being potential mitogens. We examined the effects of NRG-1beta, NRG-2alpha, and NRG3 on proliferation of p75-immunopurified adult OEG. OEG were grown in serum-containing medium with added bovine pituitary extract and forskolin (added mitogens) or in serum-containing medium (no added mitogens). Cultures were switched to chemically defined medium (no added mitogens or serum), NRG added and OEG proliferation assayed using BrdU. OEG grown initially with added mitogens were not responsive to added NRGs and pre-exposure to forskolin and pituitary extract increased basal proliferation rates so that OEG no longer responded to added NRG. However, NRG promoted proliferation but only if cells were initially grown in mitogen-free medium. Primary OEG express ErbB2, ErbB3, and small levels of ErbB4 receptors; functional blocking indicates that ErbB2 and ErbB3 are the main NRG receptors utilized in the presence of NRG-1beta. The long-term stimulation of OEG proliferation by initial culture conditions raises the possibility of manipulating OEG before therapeutic transplantation.
Joost Verhaagen - One of the best experts on this subject based on the ideXlab platform.
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Transfer to Olfactory Ensheathing Glia: Effects on Rubrospinal Tract Regeneration, Lesion Size, and Functional Recovery after Implantation in the Injured Rat Spinal Cord
2013Co-Authors: M J Ruitenberg, Joost Verhaagen, B Blits, G J Boer, Giles W. Plant, Frank P. T. Hamers, Joke Wortel, Paul A. Dijkhuizen, Willem Hendrik Gispen, Red’s Spinal CordAbstract:The present study uniquely combines Olfactory Ensheathing Glia (OEG) implantation with ex vivo adenoviral (AdV) vector-based neurotrophin gene therapy in an attempt to enhance regeneration after cervical spinal cord injury. Primary OEG were transduced with AdV vectors encoding rat brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or bacterial marker protein �-galactosidase (LacZ) and subsequently implanted into adult Fischer rats directly after unilateral transection of the dorsolateral funiculus. Implanted animals received a total of 2 � 10 5 OEG that were subjected to transduction with neurotrophin-encoding AdV vector, AdV-LacZ, or no vector, respectively. At 4 months after injury, lesion volumes were smaller in all OEG implanted rats and significantly reduced in size after implantation of neurotrophin-encoding AdV vector-transduced OEG. All OEG grafts were filled with neurofilament-positive axons, and AdV vector-mediated expression of BDNF by implanted cells significantly enhanced regenerative sprouting of the rubrospinal tract. Behavioral analysis revealed that OEG-implanted rats displayed better locomotion during horizontal rope walking than unimplanted lesioned controls. Recovery of hind limb function was also improved after implantation of OEG that were transduced with a BDNF- or NT-3-encoding AdV vector. Hind limb performance during horizontal rope locomotion did directly correlate with lesion size, suggestin
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noninvasive bioluminescence imaging of Olfactory Ensheathing Glia and schwann cells following transplantation into the lesioned rat spinal cord
Cell Transplantation, 2012Co-Authors: Kasper C D Roet, Joost Verhaagen, Ruben EggersAbstract:In this study, we assess the feasibility of bioluminescence imaging to monitor the survival of Schwann cells (SCs) and Olfactory Ensheathing Glia cells (OECs) after implantation in the lesioned spinal cord of adult rats. To this end, purified SCs and OECs were genetically modified with lentiviral vectors encoding luciferase-2 and GFP and implanted in the lesioned dorsal column. The bioluminescent signal was monitored for over 3 months, and at 7 and 98 days postsurgery, the signal was compared to standard histological analysis of GFP expression in the spinal cords. The temporal profile of the bioluminescent signal showed three distinct phases for both cell types. (I) A relatively stable signal in the first week. (II) A progressive decline in signal strength in the second and third week. (III) After the third week, the average bioluminescent signal stabilized for both cell types. Interestingly, in the first week, the peak of the bioluminescent signal after luciferin injection was delayed when compared to later time points. Similar to in vitro, our data indicated a linear relationship between the in vivo bioluminescent signal and the GFP signal of the SCs and OECs in the spinal cords when the results of both the 7 and 98 day time points are combined. This is the first report of the use of in vivo bioluminescence to monitor cell survival in the lesioned rat spinal cord. Bioluminescence could be a potentially powerful, noninvasive strategy to examine the efficacy of treatments that aim to improve the survival of proregenerative cells transplanted in the injured rat spinal cord.
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Olfactory Ensheathing Glia and schwann cells exhibit a distinct interaction behavior with meningeal cells
Journal of Neuroscience Research, 2009Co-Authors: Elske H P Franssen, Freddy M De Bree, Kasper C D Roet, Joost VerhaagenAbstract:Schwann cells (SCs) and Olfactory Ensheathing Glia (OEG) have both been used as cellular transplants to promote spinal cord repair. Both cell types support axonal regeneration and have beneficial effects on functional recovery. A significant difference between SCs and OEG is the effect of these cell types on astrocytes (ACs) present in the neural scar. In contrast to OEG, which associate and intermingle with ACs, SCs and ACs form separate cellular territories. Here, we show that OEG and SCs also interact differently with meningeal cells (MCs), another major cellular component of the neural scar. Whereas OEG intermingle with MCs in cocultures, SCs aggregate into well-defined cell clusters. Our data suggest that (a) soluble factor(s) as well as direct cellular contact are involved in the MC-induced SC clustering. Furthermore, the cluster formation of SCs in coculture with MCs is different from the previously reported segregation of SCs and ACs in coculture. The present results help to understand the differential behavior of both cell types after transplantation in the injured spinal cord and will be important to either determine which cell has optimal capacities to render the scar more permissive for regeneration, or to exploit the transplantation of both cell types in combination.
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comparative gene expression profiling of Olfactory Ensheathing Glia and schwann cells indicates distinct tissue repair characteristics of Olfactory Ensheathing Glia
Glia, 2008Co-Authors: Elske H P Franssen, Almudena Ramoncueto, Freddy M De Bree, Anke H W Essing, Joost VerhaagenAbstract:Olfactory Ensheathing Glia (OEG) are a specialized type of Glia that support the growth of primary Olfactory axons from the neuroepithelium in the nasal cavity to the brain. Transplantation of OEG in the injured spinal cord promotes sprouting of injured axons and results in reduced cavity formation, enhanced axonal and tissue sparing, remyelination, and angiogenesis. Gene expression analysis may help to identify the molecular mechanisms underlying the ability of OEG to recreate an environment that supports regeneration in the central nervous system. Here, we compared the transcriptome of cultured OEG (cOEG) with the transcriptomes of cultured Schwann cells (cSCs) and of OEG directly obtained from their natural environment (nOEG), the Olfactory nerve layer of adult rats. Functional data mining by Gene Ontology (GO)-analysis revealed a number of overrepresented GO-classes associated with tissue repair. These classes include “response to wounding,” “blood vessel development,” “cell adhesion,” and GO-classes related to the extracellular matrix and were overrepresented in the set of differentially expressed genes between both comparisons. The current screening approach combined with GO-analysis has identified distinct molecular properties of OEG that may underlie their efficacy and interaction with host tissue after implantation in the injured spinal cord. These observations can form the basis for studies on the function of novel target molecules for therapeutic intervention after neurotrauma. © 2008 Wiley-Liss, Inc.
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Olfactory Ensheathing Glia their contribution to primary Olfactory nervous system regeneration and their regenerative potential following transplantation into the injured spinal cord
Brain Research Reviews, 2007Co-Authors: Elske H P Franssen, Freddy M De Bree, Joost VerhaagenAbstract:Olfactory Ensheathing Glia (OEG) are a specialized type of Glia that guide primary Olfactory axons from the neuroepithelium in the nasal cavity to the brain. The primary Olfactory system is able to regenerate after a lesion and OEG contribute to this process by providing a growth-supportive environment for newly formed axons. In the spinal cord, axons are not able to restore connections after an injury. The effects of OEG transplants on the regeneration of the injured spinal cord have been studied for over a decade. To date, of all the studies using only OEG as a transplant, 41 showed positive effects, while 13 studies showed limited or no effects. There are several contradictory reports on the migratory and axon growth-supporting properties of transplanted OEG. Hence, the regenerative potential of OEG has become the subject of intense discussion. In this review, we first provide an overview of the molecular and cellular characteristics of OEG in their natural environment, the primary Olfactory nervous system. Second, their potential to stimulate regeneration in the injured spinal cord is discussed. OEG influence scar formation by their ability to interact with astrocytes, they are able to remyelinate axons and promote angiogenesis. The ability of OEG to interact with scar tissue cells is an important difference with Schwann cells and may be a unique characteristic of OEG. Because of these effects after transplantation and because of their role in primary Olfactory system regeneration, the OEG can be considered as a source of neuroregeneration-promoting molecules. To identify these molecules, more insight into the molecular biology of OEG is required. We believe that genome-wide gene expression studies of OEG in their native environment, in culture and after transplantation will ultimately reveal unique combinations of molecules involved in the regeneration-promoting potential of OEG.
Jesús Avila - One of the best experts on this subject based on the ideXlab platform.
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Regeneration in the Central Nervous System?
2013Co-Authors: Olfactory Ensheathing, Javier Díaz-nido, Glia Drivers Axonal, Teresa M. Moreno-flores, Francisco W, Jesús AvilaAbstract:Olfactory Ensheathing Glia (OEG) accompany Olfactory growing axons in their entry to the adult mammalian central nervous system (CNS). Due to this special characteristic, considerable attention has been focused on the possibility of using OEG for CNS regeneration. OEG present a large heterogeneity in culture with respect to their cellular morphology and expressed molecules. The specific characteristics of OEG responsible for their regenerative properties have to be defined. These properties probably result from the combination of several factors: molecular composition of the membrane (expressing adhesion molecules as PSA-NCAM, L1 and/or others) combined with their ability to reduce Glial scarring and to accompany new growing axons into the host CNS. Their capacity to produce some neurotrophic factors might also account for their ability to produce CNS regeneration
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expression of plasminogen activator inhibitor 1 by Olfactory Ensheathing Glia promotes axonal regeneration
Glia, 2011Co-Authors: Diana Simon, Filip Lim, Erika Pastrana, Javier Diaznido, Maria Jesus Martinbermejo, Maria Teresa Gallegohernandez, Vega Garciaescudero, Ana Garciagomez, Jesús AvilaAbstract:Olfactory Ensheathing Glia (OEG) cells are known to facilitate repair following axotomy of adult neurons, although the molecular mechanisms involved are not fully understood. We previously identified plasminogen activator inhibitor-1 (PAI-1), proteinase-activated receptor-1 (PAR-1), and thrombomodulin (TM) as candidates to regulate rat OEG-dependent axonal regeneration. In this study, we have validated the involvement of these proteins in promoting axonal regeneration by immortalized human OEGs. We studied the effect of silencing these proteins in OEGs on their capacity to promote the regeneration of severed adult retinal ganglion cells (RGCs) axons. Our results support the role of Glial PAI-1 as a downstream effector of PAR-1 in promoting axon regeneration. In contrast, we found that TM inhibits OEG induced-axonal regeneration. We also assessed the signaling pathways downstream of PAR-1 that might modulate PAI-1 expression, observing that specifically inhibiting Gα(i), Rho kinase, or PLC and PKC downregulated the expression of PAI-1 in OEGs, with a concomitant reduction in OEG-dependent axon regeneration in adult RGCs. Our findings support an important role for the thrombin system in regulating adult axonal regeneration by OEGs.
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reversibly immortalized human Olfactory Ensheathing Glia from an elderly donor maintain neuroregenerative capacity
Glia, 2010Co-Authors: Filip Lim, Javier Diaznido, Vega Garciaescudero, Ana Garciagomez, Jesus M Martinbermejo, Teresa M Gallegohernandez, Alberto Rabano, Jesús AvilaAbstract:Grant sponsors: Noscira; The Fundacion M. Botin; Fundacion Ramon Areces; Spanish Ministry of Science (Programs Ramon y Cajal and I3; FPI Fellowships); CSIC (Program I3P).
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A clonal cell line from immortalized Olfactory Ensheathing Glia promotes functional recovery in the injured spinal cord.
Molecular Therapy, 2006Co-Authors: M. Teresa Moreno-flores, Elizabeth J. Bradbury, M. Jesús Martín-bermejo, Marta Agudo, Filip Lim, Erika Pastrana, Jesús Avila, Javier Díaz-nido, Stephen B. Mcmahon, Francisco WandosellAbstract:Immortalized cell lines of Olfactory Ensheathing Glia (OEG) that maintain the proregenerative properties of primary cultures provide an unlimited source of OEG for both basic and applied studies. Indeed, one specific immortalized rat OEG clonal line (TEG3) proved to be as good as primary OEG in promoting neuritogenesis and axon regeneration in culture models. Thus, we examined the capacity of TEG3 to promote axonal repair in an animal model of spinal cord injury, dorsal column crush. TEG3 cells can acquire astrocyte-like or Schwann cell-like morphology depending on the conditions under which they are cultured. In the injured spinal cord, prelabeled TEG3 survived for at least 10 weeks after grafting and they integrated into the spinal cord, adopting Schwann cell-like, astrocyte-like, or intermediate morphologies. In TEG3-transplanted animals, sensory projection axons grow into the lesion site and there was robust sprouting/axonal growth of the corticospinal tract, both into and beyond the lesion site, after crushing of the spinal cord–dorsal columns. TEG3-transplanted animals also recovered sensory and motor function in tape removal and beam walking behavioral tests. These data indicate that certain immortalized cell lines derived from a single cell can maintain the regenerative properties of primary OEG.
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immortalized Olfactory Ensheathing Glia promote axonal regeneration of rat retinal ganglion neurons
Journal of Neurochemistry, 2003Co-Authors: Teresa M Morenoflores, Filip Lim, Jesús Avila, Javier Diaznido, Jesus M Martinbermejo, Francisco WandosellAbstract:Olfactory bulb Ensheathing Glia (OEG) have attracted special attention during the last few years because of their unique properties in promoting regeneration of adult mammalian central nervous system (CNS) components. However the molecular and cellular characteristics responsible for this capacity remain to be revealed. Such studies are presently hindered by the lack of a plentiful source of homogenous OEG. Thus the availability of immortalized OEG lines maintaining the regenerative characteristics of the primary cultures would represent an unlimited source of OEG for use not only in biochemical analyses of neuroregenerative mechanisms but also to characterize their regenerative properties in models in culture and in vivo. We have immortalized primary rat OEG using the SV40 large T antigen expressed from a constitutive cellular promotor, and report here the isolation and characterization of clonal lines. These OEG clonal lines were comparable to primary OEG and Schwann cells in the promotion of axonal regeneration of mature rat retinal ganglion neurons (RGN) but, significantly, this culture assay system more closely reflects the in vivo reparative properties of OEG on transected nerves than other assays of neuritogenesis in that it revealed OEG cells to promote the growth of a larger number of long axons than Schwann cells. Using this assay we were able to grade our OEG lines for their neuroregenerative capacity, opening the possibility of identifying molecules with correlative expression levels in these cells. Our preliminary characterization revealed that the expression level of a classical OEG marker, the p75-NGF receptor, does not correlate with neuroregenerative capacity.
Mary Bartlett Bunge - One of the best experts on this subject based on the ideXlab platform.
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REVIEW Bridging Areas of Injury in the Spinal Cord
2016Co-Authors: Mary Bartlett BungeAbstract:There is a devastating loss of function when substantial numbers of axons are interrupted by injury to the spinal cord. This loss may be eventually reversed by providing bridging prostheses that will enable axons to regrow across the injury site and enter the spinal cord beyond. This review addresses the bridging strate-gies that are being developed in a number of spinal cord lesion models: complete and partial transection and cavities arising from contusion. Bridges containing peripheral nerve, Schwann cells, Olfactory Ensheathing Glia, fetal tissue, stem cells/neuronal precursor cells, and macrophages are being evaluated as is the administration of neurotrophic factors, administered by infusion or secreted by genetically engineered cells. Biomaterials may be an important factor in developing successful strategies. Due to the complexity of the sequelae following spinal cord injury, no one strategy will be effective. The compelling question today is: What combinations of the strategies discussed, or new ones, along with an initial neuroprotective treatment, will substantially improve outcome after spinal cord injury? NEUROSCIENTIST 7(4):325–339, 2001 KEY WORDS Cellular bridges, CNS regeneration, CNS injury, Neurotrophins, Transplantation Laceration injuries or those that lead to cavitation in the spinal cord interrupt descending and ascending axons. Whereas loss of gray matter may be small, it is the in
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Pages?–? Transplantation strategies to promote repair of the
2015Co-Authors: Mary Bartlett Bunge, Phd Damien, D. PearseAbstract:Abstract—This review describes the results of the transplanta-tion of Schwann cells and Olfactory Ensheathing Glia in combi-nation with other interventions. The complete transection injury model was used to test the combination of Schwann cell bridges with methylprednisolone, neurotrophins, or Olfactory Ensheathing Glia. The contusion injury model was used to com-pare Schwann cell and Olfactory Ensheathing Glia transplanta-tion and to examine the results of combining Schwann cell transplants with elevated levels of cyclic adenosine monophos-phate. The combination strategies were more effective than cell transplantation alone. The improved regeneration response usu-ally involved a reduction in secondary tissue loss, axonal regen-eration from brainstem neurons, an increase in myelinated fibers in the transplant, the exit of regenerated fibers from the transplant into the contiguous cord, and an improvement i
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Neurological Surgery and
2013Co-Authors: Giles W. Plant, Mary Bartlett Bunge, Yelena Pressman, Margaret L Bates, Paul F. Currier, Ernesto P. Cuervo, Patrick M WoodAbstract:Several studies have suggested that Olfactory Ensheathing Glia (EG) can form Schwann cell (SC)-like myelin. Because of possible misinterpretation attributable to contaminating SCs, the capacity of EG to produce myelin needs to be explored further. Therefore, we compared the abilities of adult EG, purified by immunopanning with p75 antibody, and adult SCs to produce myelin when cocultured with purified dorsal root ganglion neurons (DRGNs) in serum-free and serum-containing media. In both media formulations, the number of myelin sheaths in SC/DRGN cultures was far higher than in EG/DRGN cultures; the number of sheaths in EG/DRGN cultures was equal to that in purified DRGN cultures without added cells. The latter result demonstrates that myelination by a few SCs remaining in purified DRGN cultures may occur, suggesting that myelin in EG/DRGN cultures could be SC myelin. Striking differences i
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survival integration and axon growth support of Glia transplanted into the chronically contused spinal cord
Cell Transplantation, 2005Co-Authors: David J Barakat, Mary Bartlett Bunge, Christian M Andrade, Raisa Puzis, Yelena Pressman, S M Gaglani, S R Neravetla, Arnaldo Sanchez, Maneesh Sen Garg, Damien D PearseAbstract:Due to an ever-growing population of individuals with chronic spinal cord injury, there is a need for experimental models to translate efficacious regenerative and reparative acute therapies to chronic injury application. The present study assessed the ability of fluid grafts of either Schwann cells (SCs) or Olfactory Ensheathing Glia (OEG) to facilitate the growth of supraspinal and afferent axons and promote restitution of hind limb function after transplantation into a 2-month-old, moderate, thoracic (T8) contusion in the rat. The use of cultured Glial cells, transduced with lentiviral vectors encoding enhanced green fluorescent protein (EGFP), permitted long-term tracking of the cells following spinal cord transplantation to examine their survival, migration, and axonal association. At 3 months following grafting of 2 million SCs or OEG in 6 µl of DMEM/F12 medium into the injury site, stereological quantification of the three-dimensional reconstructed spinal cords revealed that an average of 17.1 ± 6.8% of the SCs and 2.3 ± 1.4% of the OEG survived from the number transplanted. In the OEG grafted spinal cord, a limited number of Glia were unable to prevent central cavitation and were found in patches around the cavity rim. The transplanted SCs, however, formed a substantive graft within the injury site capable of supporting the ingrowth of numerous, densely packed neurofilament-positive axons. The SC grafts were able to support growth of both ascending calcitonin gene-related peptide (CGRP)-positive and supraspinal serotonergic axons and, although no biotinylated dextran amine (BDA)-traced corticospinal axons were present within the center of the grafts, the SC transplants significantly increased corticospinal axon numbers immediately rostral to the injury–graft site compared with injury-only controls. Moreover, SC grafted animals demonstrated modest, though significant, improvements in open field locomotion and exhibited less foot position errors (base of support and foot rotation). Whereas these results demonstrate that SC grafts survive, support axon growth, and can improve functional outcome after chronic contusive spinal cord injury, further development of OEG grafting procedures in this model and putative combination strategies with SC grafts need to be further explored to produce substantial improvements in axon growth and function.
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combining schwann cell bridges and Olfactory Ensheathing Glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord
The Journal of Neuroscience, 2005Co-Authors: Karim Fouad, Mary Bartlett Bunge, Lisa Schnell, Martin E Schwab, Thomas Liebscher, Damien D PearseAbstract:Numerous obstacles to successful regeneration of injured axons in the adult mammalian spinal cord exist. Consequently, a treatment strategy inducing axonal regeneration and significant functional recovery after spinal cord injury has to overcome these obstacles. The current study attempted to address multiple impediments to regeneration by using a combinatory strategy after complete spinal cord transection in adult rats: (1) to reduce inhibitory cues in the Glial scar (chondroitinase ABC), (2) to provide a growth-supportive substrate for axonal regeneration [Schwann cells (SCs)], and (3) to enable regenerated axons to exit the bridge to re-enter the spinal cord (Olfactory Ensheathing Glia). The combination of SC bridge, Olfactory Ensheathing Glia, and chondroitinase ABC provided significant benefit compared with grafts only or the untreated group. Significant improvements were observed in the Basso, Beattie, and Bresnahan score and in forelimb/hindlimb coupling. This recovery was accompanied by increased numbers of both myelinated axons in the SC bridge and serotonergic fibers that grew through the bridge and into the caudal spinal cord. Although prominent descending tracts such as the corticospinal and reticulospinal tracts did not successfully regenerate through the bridge, it appeared that other populations of regenerated fibers were the driving force for the observed recovery; there was a significant correlation between numbers of myelinated fibers in the bridge and improved coupling of forelimb and hindlimb as well as open-field locomotion. Our study tests how proven experimental treatments interact in a well-established animal model, thus providing needed direction for the development of future combinatory treatment regimens.
