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ABSTRACT: So far, studies of the human autoimmune disease multiple sclerosis (MS) have largely been hampered by the absence of a pathogenic B cell component in its animal model, experimental autoimmune encephalomyelitis (EAE). To overcome this shortcoming, we have previously introduced the myelin basic protein (MBP)-proteolipid protein (PLP) MP4-induced EAE, which is B cell and autoantibody-dependent. Here we show that MP4-immunized wild-type C57BL/6 mice displayed a significantly lower disease incidence when their complement system was transiently depleted by a single injection of cobra venom factor (CVF) prior to immunization. Considering the underlying pathomechanism, our data suggest that the complement system is crucial for MP4-specific antibodies to trigger CNS pathology. Demyelinated lesions in the CNS were colocalized with complement depositions. In addition, B cell deficient J(H)T mice reconstituted with MP4-reactive serum showed significantly attenuated clinical and histological EAE after depletion of complement by CVF. The complement system was also critically involved in the generation of the MP4-specific T and B cell response: in MP4-immunized wild-type mice treated with CVF the MP4-specific cytokine and antibody response was significantly attenuated compared to untreated wild-type mice. Taken together, we propose two independent mechanisms by which the complement system can contribute to the pathology of autoimmune encephalomyelitis. Our data corroborate the role of complement in triggering antibody-dependent demyelination and antigen-specific T cell immunity and also provide first evidence that the complement system can modify the antigen-specific B cell response in EAE and possibly MS.
Clinical Immunology 12/2012; 146(3):155-164. · 4.05 Impact Factor
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ABSTRACT: While the role of T cells has been studied extensively in multiple sclerosis (MS), the pathogenic contribution of B cells has only recently attracted major attention, when it was shown that B cell aggregates can develop in the meninges of a subset of MS patients and were suggested to be correlates of late-stage and more aggressive disease in this patient population. However, whether these aggregates actually exist has subsequently been questioned and their functional significance has remained unclear. Here, we studied myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), which is one of the few animal models for MS that is dependent on B cells. We provide evidence that B cell aggregation is reflective of lymphoid neogenesis in the central nervous system (CNS) in MBP-PLP-elicited EAE. B cell aggregation was present already few days after disease onset. With disease progression CNS B cell aggregates increasingly displayed the phenotype of tertiary lymphoid organs (TLOs). Our results further imply that these TLOs were not merely epiphenomena of the disease, but functionally active, supporting intrathecal determinant spreading of the myelin-specific T cell response. Our data suggest that the CNS is not a passive "immune-privileged" target organ, but rather a compartment, in which highly active immune responses can perpetuate and amplify the autoimmune pathology and thereby autonomously contribute to disease progression.
Acta Neuropathologica 07/2012; · 9.32 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. The remitting-relapsing experimental autoimmune encephalomyelitis (EAE) in the SJL mouse strain is a common animal model for MS and similar to the human disease it is considered to be T helper cell mediated. Besides interferon-γ secreting T(H)1 cells in particular the T(H)17 subset is believed to be highly pathogenic. Spreading of the T(H)1 and T(H)17 response to newly emerging determinants has been used to explain clinical disease relapse, but if the magnitude of the T(H)1/T(H)17 response is linked to clinical relapse severity has remained unresolved. Here, we assessed clinical EAE severity, the extent of spinal cord histopathology and the magnitude of the antigen-specific T helper cell and autoantibody response in proteolipid protein peptide 139-151 (PLP:139-151)-immunized SJL mice in clinical remission and relapse. We demonstrate that spinal cord histopathology comprised inflammation, demyelination as well as axonal loss and correlated well with clinical disease severity. Although the degree of spinal cord histopathology and clinical severity was separated from the PLP:139-151-specific T(H)1/T(H)17 cell and antibody response, it was linked to the number of infiltrating macrophages and activated microglia. In particular, there was a correlation between their secretion product interleukin-1β and the degree of axonal loss. Although CD4(+) T cells seem to be mainly involved in disease initiation, we suggest that it is the downstream activation of the innate immune response that defines the magnitude of the disease outcome.
Glia 02/2012; 60(5):794-805. · 4.82 Impact Factor
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02/2012; , ISBN: 978-953-51-0038-6
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ABSTRACT: Multiple sclerosis (MS) is an autoimmune disorder of the CNS. Different subtypes of the disease have been noted, and characterized by distinct clinical courses and histopathologic manifestations. The most intensively studied animal model of MS, experimental autoimmune encephalomyelitis (EAE), classically leads to deficits in motor functions, and is mediated by T helper cells. Recently, T(H)17 cells were ascribed an even greater pathogenic impact than T(H)1 cells, but new findings render this view controversial. Although classic EAE has been an invaluable tool, it does not cover the entire pathogenic entity of MS. Especially B-cell contribution and autoantibody-dependence are not mirrored adequately: therefore, new B-cell-dependent models, such as MP4-induced EAE, have been introduced. Furthermore, certain symptoms and the spontaneous onset of MS are not featured in classic EAE. Herein, atypical and spontaneous EAE models can be used for investigation of common symptoms, such as tremor and ataxia, as well as spontaneous disease development. MS displays a marked inter-individual heterogeneity, and no single model will be able to cover all features. Thus, depending on the objective of one's study, the appropriate EAE model has to be carefully chosen. In addition, refined models should be designed to gain a more complete understanding of MS.
Apmis 12/2011; 119(12):819-30. · 1.99 Impact Factor
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ABSTRACT: Experimental autoimmune encephalomyelits (EAE) has been widely studied as a model for multiple sclerosis (MS). EAE also holds a special place in basic autoimmune research. It is induced by immunizing healthy, naïve mice with neuroantigen. Unlike in spontaneous autoimmune models, one can therefore clearly define the initiation time point, the inducing antigen, the circumstances of the immunization that elicit a pathogenic--or nonpathogenic--T cell response, and many other parameters that are required for the induction and perpetuation of autoimmune central nervous system pathology. In the following, we will provide an overview of our current understanding of the discrete steps that lead to the pathogenesis of EAE, and we will highlight several junctions at which the perpetuation or abortive course of the disease is defined. It has become abundantly clear that the induction of a pathogenic CD4+ T cell response is a necessary requirement for the induction of EAE. However, many downstream mechanisms need to be considered if we want to understand the pathomechanisms that define the variable outcomes of EAE, and by inference, of MS.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 09/2011; 31(12):907-16. · 1.63 Impact Factor
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ABSTRACT: The role of fibroblast growth factor-2 (FGF-2) in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis is discussed. This study is the first to use FGF-2(-/-) mice to further address the involvement of FGF-2 in the disease process. We demonstrate that immunization with myelin oligodendrocyte glycoprotein peptide 35-55 induces more severe experimental autoimmune encephalomyelitis in FGF-2(-/-) mice compared with FGF-2(+/+) mice. The antigen-specific cytokine response to myelin oligodendrocyte glycoprotein peptide and the degree of central nervous system inflammation was similar in both groups. However, FGF-2(-/-) mice displayed increased infiltration of CD8(+) T cells and macrophages/microglia. In addition, nerve fibre degeneration and axonal loss were augmented, whereas the extent of remyelination in central nervous system lesions was reduced. FGF-2 has been associated with the induction of demyelination and the inhibition of myelin production by oligodendrocytes. Our study supports the opposing notion that FGF-2 can also assert a neuroprotective function. This may be particularly appealing when it comes to targeting the neurodegenerative aspect of multiple sclerosis.
Immunology 07/2011; 133(3):370-8. · 3.32 Impact Factor
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ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is frequently used for studies of multiple sclerosis (MS). Because in most EAE models T cells mediate the pathology in the absence of B cells/autoantibodies, the notion has evolved that also MS may be a primarily T cell-mediated disease. We have previously introduced MBP-PLP fusion protein (MP4)-induced EAE in C57BL/6 mice. Here we show that the disease in this model is antibody-dependent. Immunization of B cell-deficient mice did not induce EAE. When such B cell-deficient mice were, however, injected with MBP/PLP-specific antibodies in addition to the immunization with MP4, they developed disease of a severity and course that was similar to the wild-type mice. The deposition of antibodies in demyelinated lesions provided further evidence for the contribution of MBP/PLP-specific antibodies to CNS lesion formation. Based upon these data we suggest a two-stage model for the involvement of MBP/PLP-specific antibodies in autoimmune CNS pathology.
Clinical Immunology 07/2011; 140(1):54-62. · 4.05 Impact Factor
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ABSTRACT: In this study we demonstrate that experimental autoimmune encephalomyelitis (EAE) induced by the MBP-PLP fusion protein MP4, MOG peptide 35-55, or PLP peptide 178-191 in C57BL/6 mice, respectively, displays distinct features of CNS pathology. Major differences between the three models resided in (i) the region-/tract-specificity and disseminated nature of spinal cord degeneration, (ii) the extent and kinetics of demyelination, and (iii) the involvement of motoneurons in the disease. In contrast, axonal damage was present in all models and to a similar extent, proposing this feature as a possible morphological correlate for the comparable chronic clinical course of the disease induced by the three antigens. The data suggest that the antigen targeted in autoimmune encephalomyelitis is crucial to the induction of differential histopathological disease manifestations. The use of MP4-, MOG:35-55-, and PLP:178-191-induced EAE on the C57BL/6 background can be a valuable tool when it comes to reproducing and studying the structural-morphological diversity of multiple sclerosis.
Apmis 06/2011; 119(6):336-46. · 1.99 Impact Factor
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ABSTRACT: In the present study, we demonstrate that the histopathologic features of myelin oligodendrocyte glycoprotein (MOG) peptide 35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice closely mirror the hallmarks of MS pathology. On the one hand, we depict a time-dependent transition from acute inflammation to chronic neurodegeneration in spinal cord histopathology and provide distinct criteria (i.e. parenchymal edema, cellular infiltration and perivascular inflammatory infiltrates) by which acute and chronic stages of the disease can be distinguished. On the other hand, we assessed the extent of spinal cord plaque formation in relation to the total white matter area and we demonstrate a strong correlation with the clinical disease severity. Additionally, we report on the involvement of different spinal cord regions, focusing on the anterolateral, posterior and pyramidal tract. Our results help to further characterize histopathology of MOG peptide 35-55-induced EAE and reinforce the importance of this model for structural and functional studies of MS features.
Neuroscience Letters 03/2011; 494(3):227-31. · 2.11 Impact Factor
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ABSTRACT: The role of brain-derived neurotrophic factor (BDNF) in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is still unclear. Here we investigate the clinical course, CNS histopathology and peripheral antigen-specific immunity in MP4-induced EAE of BDNF (-/+) mice. We demonstrate that these mice displayed less severe disease compared to BDNF (+/+) mice, reflected by decreased inflammation and demyelination. In correspondence to diminished frequencies of T and B cells in CNS infiltrates, the peripheral MP4-specific T(H)1/T(H)17 response was attenuated in BDNF (-/+), but not in wild-type animals. In contrast, immunization with ovalbumin triggered similar frequencies of IFN-γ- and IL-17-secreting T cells in both groups. The cytokine secretion and proliferative activity upon mitogen stimulation did not reveal any global defect of T cell function in BDNF (-/+) mice. By influencing the antigen-specific immune response in autoimmune encephalomyelitis, BDNF may support and maintain the disease in ways that go beyond its alleged neuroprotective role.
Clinical Immunology 11/2010; 137(2):181-9. · 4.05 Impact Factor
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ABSTRACT: Due to the limited numbers of PBMCs that can be obtained from the blood of individual mice, the key question whether central disease parameters such as onset, progression and severity correlate with the magnitude and cytokine quality of the T cell response in experimental autoimmune encephalomyelitis (EAE) has remained unanswered. Here we introduce an ELISPOT-based PBMC test system in which as little as 150 μl of murine blood are sufficient, allowing to bleed mice repeatedly while continuing to observe the clinical course of EAE. Using this technique, we demonstrate that longitudinal measurements of antigen-specific IFN-γ and IL-17 production in the blood are a highly suitable approach to predict the disease outcome in remitting-relapsing PLP:139-151- and chronic MOG:35-55-induced EAE of SJL/J and C57BL/6 mice, respectively. Our data propound cytokine monitoring as promising tool in the quest for more efficient diagnostic and prognostic options in human multiple sclerosis and other autoimmune diseases.
Clinical Immunology 10/2010; 137(3):422-32. · 4.05 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) have long been regarded as primarily T helper cell type 1-mediated diseases. However, recent evidence suggests that T(H)17 cells, a mostly unexplored subset of T helper cells, may be even more pathogenic than T(H)1 cells. In the EAE model, this cell type is crucial for the recruitment of leukocytes into the CNS and for triggering parenchymal inflammation. In humans, T(H)17 cells are found in acutely active and on the borders of chronically active lesions. Overall, CD4(+) T cells only recognize antigens presented on MHC class II complexes, and these are seldom found in the CNS. MHC class I, in contrast, can be induced on neurons and myelin. This also makes CD8(+) T cells promising candidates as effector cell types. Indeed, CD8(+) T cells outnumber CD4(+) T cells in the lesions of MS patients, and can induce axonal pathology. New data on B cells have likewise stimulated unconventional paths of reasoning about the disease. B cells can contribute to the pathogenesis by secreting autoantibodies and presenting antigens to T cells. By the formation of ectopic B cell aggregates in the CNS, B cell differentiation and response can take place remote from the periphery, thus autonomously fueling pathology. In addition, cells of the innate immune system including macrophages, dendritic cells and mast cells are present in the inflamed CNS. On the one hand, these cells can recognize pathogen-associated molecular patterns via Toll-like receptors (TLRs), generating proinflammatory signals that trigger adaptive immune responses. On the other hand, these cells support the autoimmune process by the secretion of effector molecules such as nitric oxide (NO). Apart from a solely pathogenic autoimmune role, regulatory T cells, NK cells and NKT cells can suppress autoreactive cells. In this paper, we review data on how a complex network of immune mechanisms is involved in the pathogenesis of MS and EAE. We also critically reevaluate the traditional CD4/T(H)1 paradigm.
Annals of anatomy = Anatomischer Anzeiger: official organ of the Anatomische Gesellschaft 08/2010; 192(4):179-93. · 0.88 Impact Factor
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ABSTRACT: MBP-PLP fusion protein (MP4)-induced experimental autoimmune encephalomyelitis (EAE) is a model for multiple sclerosis (MS) that encompasses both a time-dependent attack on central nervous system (CNS) regions and a B cell component, mirroring important features of human multiple sclerosis. Comparing C57BL/6 with B6.129 mice immunized with MP4, we point out similarities regarding these hallmarks and thus propose that they are largely dependent on the nature of the MP4 antigen itself, while differences between the two strains suggest that additional fine-tuning is brought about by the genetic repertoire of the animal. Overall, our data imply that (i) the interplay between both the antigenic trigger and genetic variables can define the outcome of MP4-induced autoimmune encephalomyelitis in C57BL/6 and B6.129 mice and (ii) that MP4 is not only a strong neuroantigen when it comes to reproducing the dynamics in effector mechanisms as is typical of the disease but also a promising agent for studying interindividual heterogeneity derived from genetic diversity in EAE/MS.
Apmis 12/2009; 117(12):923-35. · 1.99 Impact Factor
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ABSTRACT: MBP-PLP fusion protein (MP4)-induced experimental autoimmune encephalomyelitis (EAE) is a model for multiple sclerosis (MS) that encompasses both a time-dependent attack on central nervous system (CNS) regions and a B cell component, mirroring important features of human multiple sclerosis. Comparing C57BL/6 with B6.129 mice immunized with MP4, we point out similarities regarding these hallmarks and thus propose that they are largely dependent on the nature of the MP4 antigen itself, while differences between the two strains suggest that additional fine-tuning is brought about by the genetic repertoire of the animal. Overall, our data imply that (i) the interplay between both the antigenic trigger and genetic variables can define the outcome of MP4-induced autoimmune encephalomyelitis in C57BL/6 and B6.129 mice and (ii) that MP4 is not only a strong neuroantigen when it comes to reproducing the dynamics in effector mechanisms as is typical of the disease but also a promising agent for studying interindividual heterogeneity derived from genetic diversity in EAE/MS.
Apmis 11/2009; 117(12):923 - 935. · 1.99 Impact Factor
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Anna Bischoff,
Maria Grosheva,
Andrey Irintchev,
Emmanouil Skouras,
Katerina Kaidoglou,
Joern Michael,
Srebrina K Angelova, Stefanie Kuerten,
Nektarios Sinis,
Sarah A Dunlop,
Doychin N Angelov
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ABSTRACT: We have shown that manual stimulation of rat whisker-pad muscles following facial-facial-anastomosis (FFA) restores normal whisking by lowering the proportion of polyinnervated motor endplates. Here we examined whether manual stimulation of the orbicularis oculi muscle (OOM) after FFA would also improve outcome. Blink responses to standardized air puffs were analyzed using video-based motion analysis. Two months after FFA, blink capacity was impaired, as indicated by a largely increased minimum distance between the eyelids after air-puff stimulation compared with intact rats (2.7 +/- 0.4 vs. 0.2 +/- 0.01 mm). Manual stimulation reduced this deficit by a factor of two (1.3 +/- 0.5 mm). The functional improvement after manual stimulation was associated with a 2-fold decrease in the proportion of polyinnervated OOM endplates (21 +/- 10% vs. 42 +/- 10% without manual stimulation, 0% in intact rats). We conclude that manual stimulation is a noninvasive and simple procedure with immediate potential for clinical rehabilitation of eyelid closure following facial nerve injury.
Muscle & Nerve 11/2008; 39(2):197-205. · 2.37 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is characterized by a dynamic inflammatory process in which CNS lesions of distinct cellular composition coexist. In particular the formation of B cell plaques has been ascribed an important role as predictor of disease progression. Here we show that the novel MBP-PLP fusion protein (MP4)-induced experimental autoimmune encephalomyelitis (EAE) of C57BL/6 mice fulfils these criteria inducing differential cellular infiltration of B cells, T cells, macrophages and granulocytes and permitting the quantification and staging of the disease. On the contrary, both key features - dynamic CNS inflammation and B cell infiltration - were absent in the classical MOG:35-55-induced EAE of C57BL/6 mice, which was characterized by a static CD4(+) T cell and macrophage-mediated CNS immunopathology throughout the disease. MP4-induced EAE may thus provide a unique opportunity for studying immune-pathomechanisms of the disease that have been previously neglected due to experimental shortcomings in murine EAE.
Clinical Immunology 09/2008; 129(2):256-67. · 4.05 Impact Factor
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ABSTRACT: Our understanding of how CD4(+) T cells can regulate CD8(+) T cell responses in HIV infection is still incomplete. Recent evidence obtained in mice suggests that CD4(+) T cell help is required for efficient CD8(+) T cell-mediated immunity in chronic infection: CD8(+) T cells primed in the absence of such help release the TNF-related apoptosis-inducing ligand TRAIL and undergo apoptosis. Using a novel ELISPOT assay, in the present study we show that CD8(+) T cells are also a source of the antigen-specific TRAIL response in HIV-infected patients with CD4(+) T cell counts below 200. In patients with CD4(+) T cell counts above 200 TRAIL was not detectable. Accordingly, antigens to which patients have likely been exposed when CD4(+) T cell levels were high (e.g., influenza, CMV, and EBV) did not induce TRAIL. Within the HIV-positive donor population with low CD4(+) T cell counts a dissociation of the interferon-gamma (IFN-gamma) and TRAIL response to different HIV peptide epitopes was detectable suggesting impaired immunity to antigens that triggered TRAIL in the absence of IFN-gamma. Our findings emphasize that "helpless" CD8(+) T cells, i.e., cells that have been primed in the absence of CD4(+) T cell help, may play a crucial role in HIV infection. A "helpless" phenotype may impair CD8(+) T cell control of HIV and other infections and possibly contribute to the depletion of CD4(+) T cells via apoptosis. Immunizations and infections in this "helpless" state might result in ineffective CD8(+) T cell responses.
AIDS research and human retroviruses 09/2008; 24(9):1175-83. · 2.18 Impact Factor
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Emilia Evgenieva,
Patrick Schweigert,
Orlando Guntinas-Lichius,
Stoyan Pavlov,
Maria Grosheva,
Srebrina Angelova,
Michael Streppel,
Andrey Irintchev,
Emmanouil Skouras, Stefanie Kuerten,
Nektarios Sinis,
Sarah Dunlop,
Victoria Radeva,
Doychin N Angelov
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ABSTRACT: Using the rat facial nerve axotomy model, the authors recently showed that manual stimulation of denervated whiskerpad muscles reduced the posttransectional polyinnervation at the neuromuscular junctions and promoted full recovery of vibrissal whisking.
Prompted by implications for rehabilitation therapy, the authors examined whether manual stimulation of denervated supra- and infrahyoid muscles would also improve recovery after unilateral lesion on the hypoglossal nerve.
Adult rats underwent transection of the right hypoglossal nerve. Half of the animals received no postoperative treatment, and the other half were subjected to daily manual stimulation of the suprahyoid/sublingual region for 2 months. Recovery was assessed by measuring the angle of tongue-tip deviation from the midline, degree of collateral axonal branching at the lesion site (counts after retrograde labeling with 2 fluorescent dyes), synaptic input to the hypoglossal motoneurons using synaptophysin immunocytochemistry, tongue-muscles motor representation in the cerebral cortex after c-Fos immunocytochemistry, and portion of polyinnervated neuromuscular junctions.
In animals receiving manual stimulation, the tongue-tip deviation was 37.0 +/- 49.37 degrees , whereas values in control nonstimulated rats were significantly higher (50.1 +/- 9.01 degrees ; P < .05; mean +/- SD). Improved recovery was not associated with reduced collateral axonal branching; there were also no differences in tongue-muscles representation in the motor cortex. However, manual stimulation restored the total synaptic input to levels in intact animals and reduced the proportion of polyinnervated neuromuscular junctions compared with nonstimulated animals.
The data show that manual stimulation of denervated muscles improves functional outcome following peripheral nerve injury. This suggests immediate potential for enhancing clinical rehabilitation strategies.
Neurorehabilitation and neural repair 07/2008; 22(6):754-68. · 4.49 Impact Factor
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Maria Grosheva,
Orlando Guntinas-Lichius,
Stephan Arnhold,
Emmanouil Skouras, Stefanie Kuerten,
Michael Streppel,
Srebrina K Angelova,
Konstantin Wewetzer,
Christine Radtke,
Sarah A Dunlop,
Doychin N Angelov
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ABSTRACT: Recently, we devised and validated a novel strategy in rats to improve the outcome of facial nerve reconstruction by daily manual stimulation of the target muscles. The treatment resulted in full recovery of facial movements (whisking), which was achieved by reducing the proportion of pathologically polyinnervated motor endplates. Here, we posed whether manual stimulation could also be beneficial after a surgical procedure potentially useful for treatment of large peripheral nerve defects, i.e., entubulation of the transected facial nerve in a conduit filled with suspension of isogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) in collagen. Compared to control treatment with collagen only, entubulation with BM-MSCs failed to decrease the extent of collateral axonal branching at the lesion site and did not improve functional recovery. Post-operative manual stimulation of vibrissal muscles also failed to promote a better recovery following entubulation with BM-MSCs. We suggest that BM-MSCs promote excessive trophic support for regenerating axons which, in turn, results in excessive collateral branching at the lesion site and extensive polyinnervation of the motor endplates. Furthermore, such deleterious effects cannot be overridden by manual stimulation. We conclude that entubulation with BM-MSCs is not beneficial for facial nerve repair.
Biological Chemistry 07/2008; 389(7):873-88. · 2.96 Impact Factor
