Remyelination of Demyelinated CNS Axons by Transplanted Human Schwann Cells: The Deleterious Effect of Contaminating Fibroblasts

2001 ◽  
Vol 10 (3) ◽  
pp. 305-315 ◽  
Author(s):  
C. M. H. Brierley ◽  
A. J. Crang ◽  
Y. Iwashita ◽  
J. M. Gilson ◽  
N. J. Scolding ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Schwann Cell ◽  
Schwann Cells ◽  
Axonal Degeneration ◽  
Autologous Transplantation ◽  
Growth Factor Receptor ◽  
Adult Rats ◽  
Demyelinating Lesions ◽  
Cell Implantation

Areas of demyelination can be remyelinated by transplanting myelin-forming cells. Schwann cells are the naturally remyelinating cells of the peripheral nervous system and have a number of features that may make them attractive for cell implantation therapies in multiple sclerosis, in which spontaneous but limited Schwann cell remyelination has been well documented. Schwann cells can be expanded in vitro, potentially affording the opportunity of autologous transplantation; and they might also be spared the demyelinating process in multiple sclerosis. Although rat, cat, and monkey Schwann cells have been transplanted into rodent demyelinating lesions, the behavior of transplanted human Schwann cells has not been evaluated. In this study we examined the consequences of injecting human Schwann cells into areas of acute demyelination in the spinal cords of adult rats. We found that transplants containing significant fibroblast contamination resulted in deposition of large amounts of collagen and extensive axonal degeneration. However, Schwann cell preparations that had been purified by positive immunoselection using antibodies to human low-affinity nerve growth factor receptor containing less than 10% fibroblasts were associated with remyelination. This result indicates that fibroblast contamination of human Schwann cells represents a greater problem than would have been appreciated from previous studies.

scholarly journals Interleukin-4 Regulates the Expression of CD209 and Subsequent Uptake of Mycobacterium leprae by Schwann Cells in Human Leprosy

2010 ◽  
Vol 78 (11) ◽  
pp. 4634-4643 ◽  
Author(s):  
Rosane M. B. Teles ◽  
Stephan R. Krutzik ◽  
Maria T. Ochoa ◽  
Rosane B. Oliveira ◽  
Euzenir N. Sarno ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Primary Cultures ◽  
Mycobacterium Leprae ◽  
Microbial Pathogens ◽  
Interleukin 4 ◽  
Common Mechanism ◽  
Specific Cell

ABSTRACT The ability of microbial pathogens to target specific cell types is a key aspect of the pathogenesis of infectious disease. Mycobacterium leprae, by infecting Schwann cells, contributes to nerve injury in patients with leprosy. Here, we investigated mechanisms of host-pathogen interaction in the peripheral nerve lesions of leprosy. We found that the expression of the C-type lectin, CD209, known to be expressed on tissue macrophages and to mediate the uptake of M. leprae, was present on Schwann cells, colocalizing with the Schwann cell marker, CNPase (2′,3′-cyclic nucleotide 3′-phosphodiesterase), along with the M. leprae antigen PGL-1 in the peripheral nerve biopsy specimens. In vitro, human CD209-positive Schwann cells, both from primary cultures and a long-term line, have a higher binding of M. leprae compared to CD209-negative Schwann cells. Interleukin-4, known to be expressed in skin lesions from multibacillary patients, increased CD209 expression on human Schwann cells and subsequent Schwann cell binding to M. leprae, whereas Th1 cytokines did not induce CD209 expression on these cells. Therefore, the regulated expression of CD209 represents a common mechanism by which Schwann cells and macrophages bind and take up M. leprae, contributing to the pathogenesis of leprosy.

scholarly journals Hydroxytyrosol Promotes Proliferation of Human Schwann Cells: An In Vitro Study

2020 ◽  
Vol 17 (12) ◽  
pp. 4404
Author(s):  
Khidhir Kamil ◽  
Muhammad Dain Yazid ◽  
Ruszymah Bt Hj Idrus ◽  
Jaya Kumar
Keyword(s):  
Cell Cycle ◽  
Protein Expression ◽  
Schwann Cells ◽  
Growth Factor Receptor ◽  
In Vitro Study ◽  
Cell Cycle Analysis ◽  
Proliferation Index ◽  
Proliferation Markers ◽  
Diphenyltetrazolium Bromide

Recent advances in phytomedicine have explored some potential candidates for nerve regeneration, including hydroxytyrosol (HT). This study was undertaken to explore the potential effects of HT on human Schwann cells’ proliferation. Methods: The primary human Schwann cell (hSC) was characterized, and the proliferation rate of hSC supplemented with various concentrations of HT was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle analysis and protein expression of glial fibrillary acidic protein (GFAP) and p75 nerve growth factor receptor (p75 NGFR) were evaluated via the immunofluorescence technique. Results: In vitro culture of hSCs revealed spindle-like, bipolar morphology with the expression of specific markers of hSC. Hydroxytyrosol at 10 and 20 ng/mL significantly increased the proliferation of hSCs by 30.12 ± 5.9% and 47.8 ± 6.7% compared to control (p < 0.05). Cell cycle analysis showed that HT-treated hSCs have a higher proliferation index (16.2 ± 0.2%) than the control (12.4 ± 0.4%) (p < 0.01). In addition, HT significantly increased the protein expression of GFAP and p75NGFR (p < 0.05). Conclusion: HT stimulates the proliferation of hSCs in vitro, indicated by a significant increase in the hSC proliferation index and protein expression of hSCs’ proliferation markers, namely p75 NGFR and GFAP.

Elevated endothelial microparticle—monocyte complexes induced by multiple sclerosis plasma and the inhibitory effects of interferon-β1b on release of endothelial microparticles, formation and transendothelial migration of monocyte-endothelial microparticle complexes

2005 ◽  
Vol 11 (3) ◽  
pp. 310-315 ◽  
Author(s):  
Joaquin J Jimenez ◽  
Wenche Jy ◽  
Lucia M Mauro ◽  
Lawrence L Horstman ◽  
Eugene R Ahn ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Transendothelial Migration ◽  
Endothelial Microparticles ◽  
Functional Roles ◽  
Monocyte Migration ◽  
Therapeutic Mechanism ◽  
Demyelinating Lesions ◽  
Vitro Model ◽  
And Control

Monocyte migration through the disrupted cerebral endothelial cell (EC) junctions plays an essential role in formation of multiple sclerosis (MS) demyelinating lesions. During pathogenesis of MS, activated ECs release endothelial microparticles (EMP), which possibly facilitate transendothelial migration (TEMIG) of monocytes. To assess functional roles of EMP in MS, specifically, their (i) interaction with monocytes, (ii) effect on monocyte TEMIG in an in vitro model of the brain microvascular endothelial cells (BMVEC), (iii) phenotypic profiles of EMP elicited by MS plasma and (iv) the effects of IFN-b1b on release of EMP and on TEMIG of monocytes (mono) and monocytes:EMP complexes (mono:EMP) through the BMVEC. The effect of IFN-b1b on the release of EMP and the TEMIG of mono and mono:EMP was assessed by preincubating BMVEC cultures of IFN-b1b prior to addition of plasma. Three EMP phenotypes, CD54, CD62E and CD31 were assayed. Plasma specimens from 20 patients with relapsing—remitting MS (11 in exacerbation, MS-E, and 9 in remission, ME-R) and 10 healthy controls were studied. Incubation of BMVEC with MS-E plasma yielded elevated levels of EMPCD54, EMP62E and EMPCD31 relative to MS-R and control plasmas. MS-E but not MS-R or control plasma also augmented TEMIG of monocytes, respectively. Mono:EMP complexes further augmented TEMIG relative to mono alone, but only in the presence of MS-E plasma; there was no significant effect with MS-R or control plasmas. The presence of IFN-b1b inhibited TEMIG of mono and mono:EMP by 20% and 30%, respectively. MS-E but not MS-R plasma elicited release of activation-derived EMP and enhanced TEMIG of mono and mono:EMP. IFN-b1b inhibited TEMIG and release of EMP, suggesting a role of EMP and a novel therapeutic mechanism for IFN-β1b in MS.

Axonal signalling and the making of olfactory ensheathing cells: a hypothesis

2006 ◽  
Vol 2 (3) ◽  
pp. 217-224 ◽  
Author(s):  
KONSTANTIN WEWETZER ◽  
GUDRUN BRANDES
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Specific Interaction ◽  
Neurotrophin Receptor ◽  
Olfactory Ensheathing Cells ◽  
Experimental Conditions ◽  
Neural Repair ◽  
Ensheathing Cells

Olfactory ensheathing cells (OECs) are Schwann cell-like glial cells of the olfactory system that promote neural repair under experimental conditions. It is a matter of debate in how far OECs resemble Schwann cells and whether they possess specific properties. Although OECs have been characterized mainly with respect to their regenerative effects after transplantation, both their cellular identity and the regulating factors involved have remained vague. The aim of this article is to define OEC and Schwann-cell identity in molecular terms, and to discuss crucial factors that are involved in determination in vitro and in vivo. Distinct OEC features such as the down-regulation of the low affinity neurotrophin receptor p75NTR by neuronal contact are apparent in vivo under physiological conditions, whereas OECs acquire a Schwann cell-like phenotype and up-regulate p75NTR expression in vitro and following transplantation into the lesioned spinal cord. This might indicate that establishment of the OEC phenotype depends on specific axonal stimuli. In this review we hypothesize that OECs and Schwann cells possess malleable cellular phenotypes that acquire distinct features only upon specific interaction with their natural neuronal partner. This concept is consistent with previous findings in vitro and in vivo, and might be relevant for studies that use OECs and Schwann cells for nervous system repair.

scholarly journals Nf1-deficient mouse Schwann cells are angiogenic and invasive and can be induced to hyperproliferate: reversion of some phenotypes by an inhibitor of farnesyl protein transferase.

1997 ◽  
Vol 17 (2) ◽  
pp. 862-872 ◽  
Author(s):  
H A Kim ◽  
B Ling ◽  
N Ratner
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Neurofibromatosis Type ◽  
Tumor Formation ◽  
Cell Hyperplasia ◽  
Farnesyl Transferase ◽  
Farnesyl Protein Transferase ◽  
Differentiation Marker ◽  
Mutant Cells

We have developed a potential model of Schwann cell tumor formation in neurofibromatosis type 1 (NF1). We show that mouse Schwann cells heterozygous or null at Nf1 display angiogenic and invasive properties, mimicking the behavior of Schwann cells from human neurofibromas. Mutations at Nf1 are insufficient to promote Schwann cell hyperplasia. Here we show that Schwann cell hyperplasia can be induced by protein kinase A activation in mutant cells. Removal of serum from the culture medium also stimulates hyperplasia, but only in some mutant cells. After serum removal, clones of hyperproliferating Schwann cells lose contact with axons in vitro, develop growth factor-independent proliferation, and exhibit decreased expression of the cell differentiation marker P0 protein; hyperproliferating cells develop after a 1-week lag in Schwann cells heterozygous at Nf1. The experiments suggest that events subsequent to Nf1 mutations are required for development of Schwann cell hyperplasia. Finally, an anti-Ras farnesyl protein transferase inhibitor greatly diminished both clone formation and hyperproliferation of null mutant cells, but not invasion; farnesyl transferase inhibitors could be useful in treating benign manifestations of NF1.

scholarly journals RNA-binding protein altered expression and mislocalization in multiple sclerosis

2019 ◽  
Author(s):  
Katsuhisa Masaki ◽  
Yoshifumi Sonobe ◽  
Ghanashyam Ghadge ◽  
Peter Pytel ◽  
Paula Lépine ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Metabolic Stress ◽  
Nucleocytoplasmic Transport ◽  
Altered Expression ◽  
Polypyrimidine Tract Binding Protein ◽  
Demyelinating Lesions

AbstractObjectiveNuclear depletion and mislocalization of RNA-binding proteins (RBPs) trans-activation response DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS) are thought to contribute to the pathogenesis of a number of disorders, including amyotrophic lateral sclerosis (ALS). We recently found that TDP-43 as well as polypyrimidine tract binding protein (PTB) have decreased expression and mislocalization in oligodendrocytes in demyelinated lesions in an experimental mouse model of multiple sclerosis (MS) caused by Theiler’s murine encephalomyelitis virus infection.MethodsThe latter finding prompted us to investigate TDP-43, FUS, and PTB in the demyelinated lesions of MS and in in vitro cultured human brain-derived oligodendrocytes.ResultsWe found: i) mislocalized TDP-43 in oligodendrocytes in active lesions in some MS patients; ii) decreased PTB1 expression in oligodendrocytes in mixed active/inactive demyelinating lesions; iii) decreased nuclear expression of PTB2 in neurons in cortical demyelinating lesions; iv) nuclear depletion of TDP-43 in oligodendrocytes under metabolic stress induced by low glucose/low nutrient conditions compared to optimal culture conditions.ConclusionTDP-43 has been found to have a key role in oligodendrocyte function and viability, while PTB is important in neuronal differentiation, suggesting that altered expression and mislocalization of these RBPs in MS lesions may contribute to the pathogenesis of demyelination and neurodegeneration. Our findings also identify nucleocytoplasmic transport as a target for treatment.

scholarly journals Neuron Regeneration and Proliferation Effects of Danshen and Tanshinone IIA

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Jui-Lung Shen ◽  
Yueh-Sheng Chen ◽  
Jing-Ying Lin ◽  
Yun-Chen Tien ◽  
Wen-Huang Peng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Schwann Cell ◽  
Schwann Cells ◽  
Map Kinases ◽  
Mapk Signaling ◽  
Tanshinone Iia ◽  
Dependent Manner ◽  
Neuron Regeneration

This study evaluates the proliferative effects of danshen and its monomer extract, tanshinone IIA, on Schwann cell proliferation. A piece of silicone rubber was guided across a 15-mm gap in the sciatic nerve of a rat. This nerve gap was then filled with different concentrations of danshen (0–100 mg/mL). The results showed that danshen increased the expressions of uPA, cyclin D1, E and ERK, JNK, and P38 MAP kinases via the FGF-2 signaling pathway in a dose-dependent manner. RSC96, Schwann cells were also administered with danshen (0, 20, 40, 60, 80, and 100 μg/mL) and tanshinone IIA (0, 2, 4, 6, 8, and 10 μg/mL). In lower concentrations, danshen and tanshinone IIA exhibited an apparent effect on Schwann cells. Similar effects were also demonstrated in the FGF-2-uPA regulating cascade and cell cycle proliferative protein results. Schwann cell migration was elevated as well. We used MAPK-signaling chemical inhibitors and identified the proliferative effects of danshen and tanshinone IIA as MAPK-signaling dependent. The results from thein vitrosystems indicate that danshen and tanshinone IIA can be used to induce Schwann cell proliferation, andin vivoresults potentially suggest that danshen and tanshinone IIA might enhance neuron regeneration.

Schwann cell transplantation and myelin repair of the CNS

1997 ◽  
Vol 3 (2) ◽  
pp. 157-161 ◽  
Author(s):  
A. Baron-Van Evercooren ◽  
V. Avellana-Adalid ◽  
F. Lachapelle ◽  
R. Liblau
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Schwann Cell ◽  
Schwann Cells ◽  
Cell Transplantation ◽  
Autologous Transplantation ◽  
Experimental Models ◽  
Primate Model ◽  
The Central Nervous System ◽  
Human Primate

Studies with experimental models of dysmyelination and demyelination have shown that rodent Schwann cells including a Schwann cell line, transplanted in the central nervous system compete with host oligodendrocytes to remyelinate denuded central axons of the spinal cord. The myelin produced by transplanted SC around these central nervous system axons is structurally normal and restores, secure nerve conduction. In the presence of a favorable substrate, transplanted Schwann cells migrate over considerable distances (several mm) and are recruited by a demyelinated lesion which they will partially repair. Thus Schwann cells, which can also support axonal growth, may be instrumental in central nervous system repair. In addition, the possibility of obtaining large quantities of human and non-human primate Schwann cells, makes it possible to consider autologous Schwann cell transplantation as a potential therapy for demyelinating or traumatic diseases. The various differences which may exist between rodents and humans, however, require further investigation of this possibility in a non-human primate model of demyelination. These experiments should provide not only insights on the potential of autologous transplantation in primates but also a better understanding of the process of central remyelination.

scholarly journals Immunoreactive myelin basic proteins are not detected when shiverer mutant Schwann cells and fibroblasts are co-cultured with normal neurons.

1984 ◽  
Vol 98 (4) ◽  
pp. 1291-1295 ◽  
Author(s):  
H D Shine ◽  
R L Sidman
Keyword(s):  
Nervous System ◽  
Schwann Cell ◽  
Schwann Cells ◽  
Genetic Locus ◽  
Neuronal Cells ◽  
Recessive Mutation ◽  
Basic Proteins ◽  
Cellular Target

Shiverer (shi) is an autosomal recessive mutation in mice that results in hypomyelination in the central nervous system (CNS) but normal myelination in the peripheral nervous system (PNS). Myelin basic proteins (MBPs) are virtually absent in both PNS and CNS. It is not known whether the cellular target in the PNS is the myelin-forming Schwann cell or another cell type which secondarily affects the Schwann cell. To determine the cellular target of the shi gene, we have adapted tissue culture techniques that allow co-culture of pure populations of mouse sensory neurons of one genotype with Schwann cells and fibroblasts of another genotype under conditions that permit myelin formation. These cultures were stained immunocytochemically as whole mounts to determine whether MBPs were expressed under various in vitro conditions. In single-genotype cultures, presence or absence of MBPs was consistent with earlier in vivo results: +/+ cultures were MBP-positive and shi/shi cultures were MBP-negative. In mixed-genotype cultures, visualization of MBPs in myelin accorded with the genotype of the non-neuronal Schwann cells and fibroblasts and not with the neurons--those cultures that contained +/+ non-neuronal cells were MBP-positive and those with shi/shi non-neuronal cells were MBP-negative, independent of the neuronal genotype. These results rule out neurons or circulating substances as mediators of the influence of the shi genetic locus on MBP synthesis and deposition in peripheral myelin.

scholarly journals Coordinate control of axon defasciculation and myelination by laminin-2 and -8

2005 ◽  
Vol 168 (4) ◽  
pp. 655-666 ◽  
Author(s):  
Dongren Yang ◽  
Jesse Bierman ◽  
Yukie S. Tarumi ◽  
Yong-Ping Zhong ◽  
Reshma Rangwala ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Schwann Cell ◽  
Schwann Cells ◽  
Dominant Role ◽  
Pathogenic Mechanism ◽  
Structural Defects ◽  
Autocrine Factors ◽  
Coordinate Control

Schwann cells form basal laminae (BLs) containing laminin-2 (Ln-2; heterotrimer α2β1γ1) and Ln-8 (α4β1γ1). Loss of Ln-2 in humans and mice carrying α2-chain mutations prevents developing Schwann cells from fully defasciculating axons, resulting in partial amyelination. The principal pathogenic mechanism is thought to derive from structural defects in Schwann cell BLs, which Ln-2 scaffolds. However, we found loss of Ln-8 caused partial amyelination in mice without affecting BL structure or Ln-2 levels. Combined Ln-2/Ln-8 deficiency caused nearly complete amyelination, revealing Ln-2 and -8 together have a dominant role in defasciculation, and that Ln-8 promotes myelination without BLs. Transgenic Ln-10 (α5β1γ1) expression also promoted myelination without BL formation. Rather than BL structure, we found Ln-2 and -8 were specifically required for the increased perinatal Schwann cell proliferation that attends myelination. Purified Ln-2 and -8 directly enhanced in vitro Schwann cell proliferation in collaboration with autocrine factors, suggesting Lns control the onset of myelination by modulating responses to mitogens in vivo.

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