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Sample records for oligodendrocyte ablation affects

  1. Oligodendrocyte ablation affects the coordinated interaction between granule and Purkinje neurons during cerebellum development

    SciTech Connect

    Collin, Ludovic; Doretto, Sandrine; Malerba, Monica; Ruat, Martial; Borrelli, Emiliana . E-mail: borrelli@uci.edu

    2007-08-01

    Oligodendrocytes (OLs) are the glial cells of the central nervous system (CNS) classically known to be devoted to the formation of myelin sheaths around most axons of the vertebrate brain. We have addressed the role of these cells during cerebellar development, by ablating OLs in vivo. Previous analyses had indicated that OL ablation during the first six postnatal days results into a striking cerebellar phenotype, whose major features are a strong reduction of granule neurons and aberrant Purkinje cells development. These two cell types are highly interconnected during cerebellar development through the production of molecules that help their proliferation, differentiation and maintenance. In this article, we present data showing that OL ablation has major effects on the physiology of Purkinje (PC) and granule cells (GC). In particular, OL ablation results into a reduction of sonic hedgehog (Shh), Brain Derived Neurotrophic Factor (BDNF), and Reelin (Rln) expression. These results indicate that absence of OLs profoundly alters the normal cerebellar developmental program.

  2. Motor training compensates for cerebellar dysfunctions caused by oligodendrocyte ablation

    PubMed Central

    Collin, Ludovic; Usiello, Alessandro; Erbs, Eric; Mathis, Carole; Borrelli, Emiliana

    2004-01-01

    The role played by oligodendrocytes (OLs), the myelinating cells of the CNS, during brain development has not been fully explored. We have addressed this question by inducing a temporal and reversible ablation of OLs on postnatal CNS development. OL ablation in newborn mice leads to a profound alteration in the structure of the cerebellar cortex, which can be progressively rescued by newly generated cells, leading to a delayed myelination. Nevertheless, the temporal shift of the OL proliferation and myelinating program cannot completely compensate for developmental defects, resulting in impaired motor functions in the adult. Strikingly, we show that, despite these abnormalities, epigenetic factors, such as motor training, are able to fully rescue cerebellar-directed motor skills. PMID:14694200

  3. Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro.

    PubMed

    Fan, Lir-Wan; Bhatt, Abhay; Tien, Lu-Tai; Zheng, Baoying; Simpson, Kimberly L; Lin, Rick C S; Cai, Zhengwei; Kumar, Praveen; Pang, Yi

    2015-05-01

    patterns of contactin-associated protein (Caspr) clustering were observed at the sites of Node of Ranvier, suggesting that 5-HT exposure may affect other axon-derived factors for myelination. In summary, this is the first study to demonstrate that manipulation of serotonin levels affects OL development and myelination, which may contribute to altered neural connectivity noted in SSRIs-treated animals. The current in vitro study demonstrated that exposure to high level of serotonin (5-HT) led to aberrant oligodendrocyte (OL) development, cell injury, and myelination deficit. We propose that elevated extracellular serotonin levels in the fetal brain, such as upon the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, may adversely affect OL development and/or myelination, thus contributing to altered neural connectivity seen in Autism Spectrum Disorders. OPC = oligodendrocyte progenitor cell.

  4. Staufen Recruitment into Stress Granules Does Not Affect Early mRNA Transport in Oligodendrocytes

    PubMed Central

    Thomas, María G.; Tosar, Leandro J. Martinez; Loschi, Mariela; Pasquini, Juana M.; Correale, Jorge; Kindler, Stefan; Boccaccio, Graciela L.

    2005-01-01

    Staufen is a conserved double-stranded RNA-binding protein required for mRNA localization in Drosophila oocytes and embryos. The mammalian homologues Staufen 1 and Staufen 2 have been implicated in dendritic RNA targeting in neurons. Here we show that in rodent oligodendrocytes, these two proteins are present in two independent sets of RNA granules located at the distal myelinating processes. A third kind of RNA granules lacks Staufen and contains major myelin mRNAs. Myelin Staufen granules associate with microfilaments and microtubules, and their subcellular distribution is affected by polysome-disrupting drugs. Under oxidative stress, both Staufen 1 and Staufen 2 are recruited into stress granules (SGs), which are stress-induced organelles containing transiently silenced messengers. Staufen SGs contain the poly(A)-binding protein (PABP), the RNA-binding proteins HuR and TIAR, and small but not large ribosomal subunits. Staufen recruitment into perinuclear SGs is paralleled by a similar change in the overall localization of polyadenylated RNA. Under the same conditions, the distribution of recently transcribed and exported mRNAs is not affected. Our results indicate that Staufen 1 and Staufen 2 are novel and ubiquitous SG components and suggest that Staufen RNPs are involved in repositioning of most polysomal mRNAs, but not of recently synthesized transcripts, during the stress response. PMID:15525674

  5. CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS.

    PubMed

    Uchida, Tsukasa; Tamaki, Yoshitaka; Ayaki, Takashi; Shodai, Akemi; Kaji, Seiji; Morimura, Toshifumi; Banno, Yoshinori; Nishitsuji, Kazuchika; Sakashita, Naomi; Maki, Takakuni; Yamashita, Hirofumi; Ito, Hidefumi; Takahashi, Ryosuke; Urushitani, Makoto

    2016-01-11

    The molecular machinery responsible for cytosolic accumulation of misfolded TDP-43 in amyotrophic lateral sclerosis (ALS) remains elusive. Here we identified a cullin-2 (CUL2) RING complex as a novel ubiquitin ligase for fragmented forms of TDP-43. The von Hippel Lindau protein (VHL), a substrate binding component of the complex, preferentially recognized misfolded TDP-43 at Glu246 in RNA-recognition motif 2. Recombinant full-length TDP-43 was structurally fragile and readily cleaved, suggesting that misfolded TDP-43 is cleared by VHL/CUL2 in a step-wise manner via fragmentation. Surprisingly, excess VHL stabilized and led to inclusion formation of TDP-43, as well as mutant SOD1, at the juxtanuclear protein quality control center. Moreover, TDP-43 knockdown elevated VHL expression in cultured cells, implying an aberrant interaction between VHL and mislocalized TDP-43 in ALS. Finally, cytoplasmic inclusions especially in oligodendrocytes in ALS spinal cords were immunoreactive to both phosphorylated TDP-43 and VHL. Thus, our results suggest that an imbalance in VHL and CUL2 may underlie oligodendrocyte dysfunction in ALS, and highlight CUL2 E3 ligase emerges as a novel therapeutic potential for ALS.

  6. CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS

    PubMed Central

    Uchida, Tsukasa; Tamaki, Yoshitaka; Ayaki, Takashi; Shodai, Akemi; Kaji, Seiji; Morimura, Toshifumi; Banno, Yoshinori; Nishitsuji, Kazuchika; Sakashita, Naomi; Maki, Takakuni; Yamashita, Hirofumi; Ito, Hidefumi; Takahashi, Ryosuke; Urushitani, Makoto

    2016-01-01

    The molecular machinery responsible for cytosolic accumulation of misfolded TDP-43 in amyotrophic lateral sclerosis (ALS) remains elusive. Here we identified a cullin-2 (CUL2) RING complex as a novel ubiquitin ligase for fragmented forms of TDP-43. The von Hippel Lindau protein (VHL), a substrate binding component of the complex, preferentially recognized misfolded TDP-43 at Glu246 in RNA-recognition motif 2. Recombinant full-length TDP-43 was structurally fragile and readily cleaved, suggesting that misfolded TDP-43 is cleared by VHL/CUL2 in a step-wise manner via fragmentation. Surprisingly, excess VHL stabilized and led to inclusion formation of TDP-43, as well as mutant SOD1, at the juxtanuclear protein quality control center. Moreover, TDP-43 knockdown elevated VHL expression in cultured cells, implying an aberrant interaction between VHL and mislocalized TDP-43 in ALS. Finally, cytoplasmic inclusions especially in oligodendrocytes in ALS spinal cords were immunoreactive to both phosphorylated TDP-43 and VHL. Thus, our results suggest that an imbalance in VHL and CUL2 may underlie oligodendrocyte dysfunction in ALS, and highlight CUL2 E3 ligase emerges as a novel therapeutic potential for ALS. PMID:26751167

  7. Heat-affected zone of metals ablated with femtosecond laser pulses

    NASA Astrophysics Data System (ADS)

    Hirayama, Yoichi; Obara, Minoru

    2003-07-01

    The melted area is found on the surface ablated by nanosecond and picosecond laser pulses. However, the heat effect is little on the ablated surface in the case of femtosecond laser due to non-thermal ablation process. Heat-affected zone of metallic bulk crystal ablated with femtosecond Ti:sapphire laser pulses is experimentally studied. As a result of XRD (X-ray diffraction) measurements, the XRD peak signal of the area ablated with Ti:sapphire laser becomes smaller than that of the crystalline metal sample. While the crystallinity of the metal sample is crystalline before the laser ablation, the crystallinity in the ablated area is partially changed into the amorphous form. Because the residual pulse energy that is not used for the ablation process remains, leading to the formation of thin layer of melt phase. The melt layer is abruptly cooled down not to be re-crystallized, but to transform into the amorphous form. It is evident that the area ablated with femtosecond laser is changed into the amorphous metal. Additionally XRD measurements and AR+ etching are performed alternately to measure the thickness of the amorphous layer. In the case of iron, the thickness is measured to be 1 μm approximately, therefore heat-affected zone is quite small.

  8. Even extreme heat cannot affect the SP-ablator

    NASA Astrophysics Data System (ADS)

    Stoclfleth, Holger; Knabe, Helmut; Wahl, Juergen; Haug, Tilman

    A heat-protection system that was successfully tested in a plasma wind tunnel is described. The system is capable of withstanding extreme short-term heat loads when reentering the atmosphere. The surface-protected (SP) ablator exhibits significant increase in the efficiency of the cooling effect and dynamic pressure resistance due to a ceramic matrix composite layer that protects its surface.

  9. Molecular dynamics simulation of heat-affected zone of copper metal ablated with femtosecond laser

    NASA Astrophysics Data System (ADS)

    Hirayama, Yoichi; Obara, Minoru

    2005-03-01

    Femtosecond laser ablation of materials with high thermal conductivity is of paramount importance, because the chemical composition and properties of the area ablated with femtosecond laser are kept unchanged. The material processing by femtosecond laser can well control the heat-affected zone, compared to nanosecond laser ablation. We report on the heat-affected zone of crystalline copper (Cu) by use of femtosecond laser experimentally and theoretically. Laser ablation of Cu is investigated theoretically by two temperature model and molecular dynamics (MD) simulation. The MD simulation takes into account of electron temperature and thermal diffusion length calculated by two temperature model. The dependence of lattice temperature on time and depth is calculated by the MD simulation and two temperature model. The heat-affected zone estimated from the temperature is mainly studied and calculated to be 3 nm at 0.02 J/cm2 which is below the threshold fluence of 0.137 J/cm2. In addition, the thickness of heat-affected zone of copper crystal ablated with femtosecond Ti:sapphire laser is experimentally studied. As a result of X-ray diffraction (XRD) of the ablated surface, the surface crystallinity is partially changed into disordered structure from crystal form. The residual energy left in the metal, which is not used for ablation, will induce liquid phase, leading to the amorphous phase of the metal during resolidification. The thickness of heat-affected zone depends on laser fluence and is experimentally measured to be less than 1 μm at higher laser fluences than the ablation threshold.

  10. Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury

    PubMed Central

    Nanescu, Sonia E.

    2017-01-01

    Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in adenosine triphosphate (ATP) buffering, in oligodendrocyte function. We found that creatine increased mitochondrial ATP production directly in oligodendrocyte lineage cell cultures and exerted robust protection on oligodendrocytes by preventing cell death in both naive and lipopolysaccharide-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase (Gamt) did not affect oligodendrocyte precursor cell recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in central nervous system (CNS) lesions. Remarkably, creatine administration into Gamt-deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination. SIGNIFICANCE STATEMENT We report that creatine enhances oligodendrocyte mitochondrial function and protects against caspase-dependent oligodendrocyte apoptosis during CNS remyelination. This work has important implications for the development of therapeutic targets for diseases characterized by

  11. Analysis of laser ablation dynamics of CFRP in order to reduce heat affected zone

    NASA Astrophysics Data System (ADS)

    Sato, Yuji; Tsukamoto, Masahiro; Nariyama, Tatsuya; Nakai, Kazuki; Matsuoka, Fumihiro; Takahashi, Kenjiro; Masuno, Shinichiro; Ohkubo, Tomomasa; Nakano, Hitoshi

    2014-03-01

    A carbon fiber reinforced plastic [CFRP], which has high strength, light weight and weather resistance, is attractive material applied for automobile, aircraft and so on. The laser processing of CFRP is one of suitable way to machining tool. However, thermal affected zone was formed at the exposure part, since the heat conduction property of the matrix is different from that of carbon fiber. In this paper, we demonstrated that the CFRP plates were cut with UV nanosecond laser to reduce the heat affected zone. The ablation plume and ablation mass were investigated by laser microscope and ultra-high speed camera. Furthermore, the ablation model was constructed by energy balance, and it was confirmed that the ablation rate was 0.028 μg/ pulse in good agreement with the calculation value of 0.03 μg/ pulse.

  12. Interactions between oligodendrocyte precursors control the onset of CNS myelination

    PubMed Central

    Yang, Yan; Lewis, Rebecca; Miller, Robert H.

    2011-01-01

    The formation of CNS myelin is dependent on the differentiation of oligodendrocyte precursor cells (OPCs) and oligodendrocyte maturation. How the initiation of myelination is regulated is unclear but it is likely to depend on the development of competence by oligodendrocytes and receptivity by target axons. Here we identify an additional level of control of oligodendrocyte maturation mediated by interactions between the different cellular components of the oligodendrocyte lineage. During development oligodendrocyte precursors mature through a series of stages defined by labeling with monoclonal antibodies A2B5 and O4. Newly differentiated oligodendrocytes begin to express galactocerebroside recognized by O1 antibodies and subsequently mature to myelin basic protein (MBP) positive cells prior to formation of compact myelin. Using an in vitro brain slice culture system that supports robust myelination, the consequences of ablating cells at different stages of the oligodendrocyte lineage on myelination has been assayed. Elimination of all OPC lineage cells through A2B5+, O4+ and O1+ complement mediated cell lysis resulted in a delay in development of MBP cells and myelination. Selective elimination of early OPCs (A2B5+) also unexpectedly resulted in delayed MBP expression compared to controls suggesting early OPCs contribute to the timing of myelination onset. By contrast, elimination of differentiated (O1+) immature oligodendrocytes permanently inhibited the appearance of MBP+ cells suggesting that oligodendrocytes are critical to facilitate the maturation of OPCs. These data illuminate that the presence of intra-lineage feed-forward and feedback cues are important for timely myelination by oligodendrocytes. PMID:21144846

  13. Oligodendrocytes in a Nutshell

    PubMed Central

    Michalski, John-Paul; Kothary, Rashmi

    2015-01-01

    Oligodendrocytes are the myelinating cells of the central nervous system (CNS). While the phrase is oft repeated and holds true, the last few years have borne witness to radical change in our understanding of this unique cell type. Once considered static glue, oligodendrocytes are now seen as plastic and adaptive, capable of reacting to a changing CNS. This review is intended as a primer and guide, exploring how the past 5 years have fundamentally altered our appreciation of oligodendrocyte development and CNS myelination. PMID:26388730

  14. G protein-coupled receptor 37 is a negative regulator of oligodendrocyte differentiation and myelination

    PubMed Central

    Yang, Hyun-Jeong; Vainshtein, Anna; Maik-Rachline, Galia; Peles, Elior

    2016-01-01

    While the formation of myelin by oligodendrocytes is critical for the function of the central nervous system, the molecular mechanism controlling oligodendrocyte differentiation remains largely unknown. Here we identify G protein-coupled receptor 37 (GPR37) as an inhibitor of late-stage oligodendrocyte differentiation and myelination. GPR37 is enriched in oligodendrocytes and its expression increases during their differentiation into myelin forming cells. Genetic deletion of Gpr37 does not affect the number of oligodendrocyte precursor cells, but results in precocious oligodendrocyte differentiation and hypermyelination. The inhibition of oligodendrocyte differentiation by GPR37 is mediated by suppression of an exchange protein activated by cAMP (EPAC)-dependent activation of Raf-MAPK-ERK1/2 module and nuclear translocation of ERK1/2. Our data suggest that GPR37 regulates central nervous system myelination by controlling the transition from early-differentiated to mature oligodendrocytes. PMID:26961174

  15. Endometrial ablation

    MedlinePlus

    Hysteroscopy-endometrial ablation; Laser thermal ablation; Endometrial ablation-radiofrequency; Endometrial ablation-thermal balloon ablation; Rollerball ablation; Hydrothermal ablation; Novasure ablation

  16. Partial XBP1 knockdown does not affect viability of oligodendrocyte precursor cells exposed to new models of hypoxia and ischemia in vitro.

    PubMed

    Kraskiewicz, Honorata; FitzGerald, Una

    2011-05-01

    The endoplasmic reticulum (ER) stress signaling pathway has been implicated in tissue injury in several rodent models of brain ischemia. To understand better the effects of ischemia on white matter in particular, we developed several in vitro models of hypoxia and ischemia in oligodendrocyte precursors. For the first time, we present data showing that exposure of rat oligodendrocyte precursor cells (OPCs) to cobalt chloride (CoCl(2)), antimycin A (AA), or oxygen, glucose and nutrient deprivation (OGND) causes up-regulation of glucose-regulated protein 78/B-cell immunoglobulin-binding protein (Grp78/BiP), C/EBP homologous binding protein (CHOP), and spliced X-box-binding protein 1 (XBP1). To mimic the effects of ischemia, OPCs supplemented with 5% normal growth medium and 95% Hank's balanced salt solution were incubated in a hypoxia chamber set at 0.1% oxygen. Because the toxic effects of AA on OPCs more closely resembled those seen when OPCs were subjected to OGND, we found AA treatment preferable to CoCl(2) as an in vitro model. To investigate the role of XBP1 in survival following an ischemic insult, we generated a stable XBP1 knockdown OPC cell line and subjected it to simulated hypoxia or ischemia. Surprisingly, 65% XBP1 knockdown had no effect on viability following chemical treatment or OGND. These data strengthen the case for targeting the ER stress signalling pathway in an effort to develop new early treatments for ischemic stroke patients but at the same time demonstrate that partial knockdown of XBP1 is not sufficient to protect precursor oligodendrocytes from ischemic damage.

  17. How to make an oligodendrocyte

    PubMed Central

    Goldman, Steven A.; Kuypers, Nicholas J.

    2015-01-01

    Oligodendrocytes produce myelin, an insulating sheath required for the saltatory conduction of electrical impulses along axons. Oligodendrocyte loss results in demyelination, which leads to impaired neurological function in a broad array of diseases ranging from pediatric leukodystrophies and cerebral palsy, to multiple sclerosis and white matter stroke. Accordingly, replacing lost oligodendrocytes, whether by transplanting oligodendrocyte progenitor cells (OPCs) or by mobilizing endogenous progenitors, holds great promise as a therapeutic strategy for the diseases of central white matter. In this Primer, we describe the molecular events regulating oligodendrocyte development and how our understanding of this process has led to the establishment of methods for producing OPCs and oligodendrocytes from embryonic stem cells and induced pluripotent stem cells, as well as directly from somatic cells. In addition, we will discuss the safety of engrafted stem cell-derived OPCs, as well as approaches by which to modulate their differentiation and myelinogenesis in vivo following transplantation. PMID:26628089

  18. Interleukin-1 regulates proliferation and differentiation of oligodendrocyte progenitor cells.

    PubMed

    Vela, José M; Molina-Holgado, Eduardo; Arévalo-Martín, Angel; Almazán, Guillermina; Guaza, Carmen

    2002-07-01

    Interleukin-1 (IL-1) is a pleiotropic cytokine expressed during normal CNS development and in inflammatory demyelinating diseases, but remarkably little is known about its effect on oligodendroglial cells. In this study we explored the role of IL-1beta in oligodendrocyte progenitors and differentiated oligodendrocytes. The effects of IL-1beta were compared to those of IL-1 receptor antagonist, the specific inhibitor of IL-1 activity, since progenitors and differentiated oligodendrocytes produce IL-1beta and express IL-1 receptors. Unlike other proinflammatory cytokines (TNFalpha and IFNgamma), IL-1beta was not toxic for oligodendrocyte lineage cells. However, this cytokine inhibited proliferation of oligodendrocyte progenitors in the presence of growth factors (PDGF plus bFGF). This was evidenced by a significant decrease in both cells incorporating bromodeoxyuridine (45%) and total cell numbers (57%) after 6 days of treatment. Interestingly, IL-1beta blocked proliferation at the late progenitor/prooligodendrocyte (O4+) stage but did not affect proliferation of early progenitors (A2B5+). Inhibition of proliferation paralleled with promotion of differentiation, as revealed by the increased percentage of R-mab+ cells (6.7-fold). Moreover, when oligodendrocyte progenitors were allowed to differentiate in the absence of growth factors, treatment with IL-1beta promoted maturation to the MBP+ stage (4.2-fold) and survival of differentiating oligodendrocytes (2.1-fold). Regarding intracellular signaling, IL-1beta activated the p38 mitogen-activated protein kinase (MAPK) but not the p42/p44 MAPK and, when combined with growth factors, intensified p38 activation but inhibited the growth-factor-induced p42/p44 activation. IL-1beta also induced a time-dependent inhibition of PFGF-Ralpha gene expression. These results support a role for IL-1beta in promoting mitotic arrest and differentiation of oligodendrocyte progenitors as well as maturation and survival of differentiating

  19. Hyperforin promotes mitochondrial function and development of oligodendrocytes.

    PubMed

    Wang, Yanlin; Zhang, Yanbo; He, Jue; Zhang, Handi; Xiao, Lan; Nazarali, Adil; Zhang, Zhijun; Zhang, Dai; Tan, Qingrong; Kong, Jiming; Li, Xin-Min

    2011-11-01

    St. John's wort has been found to be an effective and safe herbal treatment for depression in several clinical trials. However, the underlying mechanism of its therapeutic effects is unclear. Recent studies show that the loss and malfunction of oligodendrocytes are closely related to the neuropathological changes in depression, which can be reversed by antidepressant treatment. In this study, we evaluated the effects of hyperforin, a major active component of St. John's wort, on the proliferation, development and mitochondrial function of oligodendrocytes. The study results revealed that hyperforin promotes maturation of oligodendrocytes and increases mitochondrial function without affecting proliferation of an oligodendrocyte progenitor cell line and neural stem/progenitor cells. Hyperforin also prevented mitochondrial toxin-induced cytotoxicity in an oligodendrocyte progenitor cell line. These findings suggest that hyperforin may stimulate the development and function of oligodendrocytes, which could be a mechanism of its effect in depression. Future in vitro and in vivo studies are required to further characterize the mechanisms of hyperforin.

  20. Oligodendrocyte Development in the Absence of Their Target Axons In Vivo

    PubMed Central

    Lyons, David

    2016-01-01

    Oligodendrocytes form myelin around axons of the central nervous system, enabling saltatory conduction. Recent work has established that axons can regulate certain aspects of oligodendrocyte development and myelination, yet remarkably oligodendrocytes in culture retain the ability to differentiate in the absence of axons and elaborate myelin sheaths around synthetic axon-like substrates. It remains unclear the extent to which the life-course of oligodendrocytes requires the presence of, or signals derived from axons in vivo. In particular, it is unclear whether the specific axons fated for myelination regulate the oligodendrocyte population in a living organism, and if so, which precise steps of oligodendrocyte-cell lineage progression are regulated by target axons. Here, we use live-imaging of zebrafish larvae carrying transgenic reporters that label oligodendrocyte-lineage cells to investigate which aspects of oligodendrocyte development, from specification to differentiation, are affected when we manipulate the target axonal environment. To drastically reduce the number of axons targeted for myelination, we use a previously identified kinesin-binding protein (kbp) mutant, in which the first myelinated axons in the spinal cord, reticulospinal axons, do not fully grow in length, creating a region in the posterior spinal cord where most initial targets for myelination are absent. We find that a 73% reduction of reticulospinal axon surface in the posterior spinal cord of kbp mutants results in a 27% reduction in the number of oligodendrocytes. By time-lapse analysis of transgenic OPC reporters, we find that the reduction in oligodendrocyte number is explained by a reduction in OPC proliferation and survival. Interestingly, OPC specification and migration are unaltered in the near absence of normal axonal targets. Finally, we find that timely differentiation of OPCs into oligodendrocytes does not depend at all on the presence of target axons. Together, our data

  1. Vehicle type affects filling of fractional laser-ablated channels imaged by optical coherence tomography.

    PubMed

    Olesen, Uffe Høgh; Mogensen, Mette; Haedersdal, Merete

    2017-04-01

    Ablative fractional laser (AFXL) is an emerging method that enhances topical drug delivery. Penetrating the skin in microscopic, vertical channels, termed microscopic treatment zones (MTZs), the fractional technique circumvents the skin barrier and allows increased uptake of topically applied drugs. This study aims to elucidate the impact of vehicle type on the filling of MTZs from application of liquid, gel, and cream vehicles. Ex vivo pig skin was exposed to 10,600 nm fractional CO2 laser at 5% density, 120 μm beam diameter, and fluences of 40 and 80 mJ/microbeam (mJ/mb). Six repetitions were performed for each of six interventions (2 fluences and 3 vehicle types, n = 36). MTZ dimensions and filling by vehicle type were evaluated by optical coherence tomography, using blue tissue dye as a contrast-enhancing agent. Outcome measure was degree of MTZ filling assessed as percentages of empty, partially filled, and completely filled MTZs (108-127 MTZs/intervention analyzed) and evaluated statistically using Kruskal-Wallis and Dunn's tests. MTZs reached mid-dermal levels of 225 μm (40 mJ/mb) and 375 μm (80 mJ/mb) penetration depths (p < 0.0001). Filling of MTZs depended on type of applied vehicle. At 80 mJ/mb, liquid (67% completely filled, p < 0.01) and gel (60%, p < 0.05) formulations filled MTZs significantly better than cream formulation (31%). At 40 mJ/mb, liquid and gel formulations filled 90% (p < 0.05) and 77% (p > 0.05) of MTZs completely versus 55% for cream formulation. Thus, filling was overall greater for more superficial MTZs. In conclusion, vehicle type affects filling of MTZs, which may be of importance for AFXL-assisted drug delivery.

  2. Impaired oligodendrocyte maturation in preterm infants: Potential therapeutic targets.

    PubMed

    van Tilborg, Erik; Heijnen, Cobi J; Benders, Manon J; van Bel, Frank; Fleiss, Bobbi; Gressens, Pierre; Nijboer, Cora H

    2016-01-01

    Preterm birth is an evolving challenge in neonatal health care. Despite declining mortality rates among extremely premature neonates, morbidity rates remain very high. Currently, perinatal diffuse white matter injury (WMI) is the most commonly observed type of brain injury in preterm infants and has become an important research area. Diffuse WMI is associated with impaired cognitive, sensory and psychological functioning and is increasingly being recognized as a risk factor for autism-spectrum disorders, ADHD, and other psychological disturbances. No treatment options are currently available for diffuse WMI and the underlying pathophysiological mechanisms are far from being completely understood. Preterm birth is associated with maternal inflammation, perinatal infections and disrupted oxygen supply which can affect the cerebral microenvironment by causing activation of microglia, astrogliosis, excitotoxicity, and oxidative stress. This intricate interplay of events negatively influences oligodendrocyte development, causing arrested oligodendrocyte maturation or oligodendrocyte cell death, which ultimately results in myelination failure in the developing white matter. This review discusses the current state in perinatal WMI research, ranging from a clinical perspective to basic molecular pathophysiology. The complex regulation of oligodendrocyte development in healthy and pathological conditions is described, with a specific focus on signaling cascades that may play a role in WMI. Furthermore, emerging concepts in the field of WMI and issues regarding currently available animal models are put forward. Novel insights into the molecular mechanisms underlying impeded oligodendrocyte maturation in diffuse WMI may aid the development of novel treatment options which are desperately needed to improve the quality-of-life of preterm neonates.

  3. Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice

    SciTech Connect

    Mirrione, M.M.; Mirrione, M.M.; Konomosa, D.K.; Ioradanis, G.; Dewey, S.L.; Agzzid, A.; Heppnerd, F.L.; Tsirka, St.E.

    2010-04-01

    Activated microglia have been associated with neurodegeneration in patients and in animal models of Temporal Lobe Epilepsy (TLE), however their precise functions as neurotoxic or neuroprotective is a topic of significant investigation. To explore this, we examined the effects of pilocarpine-induced seizures in transgenic mice where microglia/macrophages were conditionally ablated. We found that unilateral ablation of microglia from the dorsal hippocampus did not alter acute seizure sensitivity. However, when this procedure was coupled with lipopolysaccharide (LPS) preconditioning (1 mg/kg given 24 h prior to acute seizure), we observed a significant pro-convulsant phenomenon. This effect was associated with lower metabolic activation in the ipsilateral hippocampus during acute seizures, and could be attributed to activity in the mossy fiber pathway. These findings reveal that preconditioning with LPS 24 h prior to seizure induction may have a protective effect which is abolished by unilateral hippocampal microglia/macrophage ablation.

  4. Vestibular ablation and a semicircular canal prosthesis affect postural stability during head turns.

    PubMed

    Thompson, Lara A; Haburcakova, Csilla; Lewis, Richard F

    2016-11-01

    In our study, we examined postural stability during head turns for two rhesus monkeys: one animal study contrasted normal and mild bilateral vestibular ablation and a second animal study contrasted severe bilateral vestibular ablation with and without prosthetic stimulation. The monkeys freely stood, unrestrained on a balance platform and made voluntary head turns between visual targets. To quantify each animals' posture, motions of the head and trunk, as well as torque about the body's center of mass, were measured. In the mildly ablated animal, we observed less foretrunk sway in comparison with the normal state. When the canal prosthesis provided electric stimulation to the severely ablated animal, it showed a decrease in trunk sway during head turns. Because the rhesus monkey with severe bilateral vestibular loss exhibited a decrease in trunk sway when receiving vestibular prosthetic stimulation, we propose that the prosthetic electrical stimulation partially restored head velocity information. Our results provide an indication that a semicircular canal prosthesis may be an effective way to improve postural stability in patients with severe peripheral vestibular dysfunction.

  5. Vestibular ablation and a semicircular canal prosthesis affect postural stability during head turns

    PubMed Central

    Thompson, Lara A.; Haburcakova, Csilla; Lewis, Richard F.

    2016-01-01

    In our study, we examined postural stability during head turns for two rhesus monkeys: one, single animal study contrasted normal and mild bilateral vestibular ablation and a second animal study contrasted severe bilateral vestibular ablation with and without prosthetic stimulation. The monkeys freely stood, unrestrained on a balance platform and made voluntary head turns between visual targets. To quantify each animals’ posture, motions of the head and trunk, as well as torque about the body’s center-of-mass, were measured. In the mildly ablated animal, we observed less foretrunk sway in comparison to the normal state. When the canal prosthesis provided electric stimulation to the severely ablated animal, it showed a decrease in trunk sway during head turns. Because the rhesus monkey with severe bilateral vestibular loss exhibited a decrease in trunk sway when receiving vestibular prosthetic stimulation, we propose that the prosthetic electrical stimulation partially restored head velocity information. Our results provide an indication that a semicircular canal prosthesis may be an effective way to improve postural stability in patients with severe peripheral vestibular dysfunction. PMID:27405997

  6. The transcription factor Yin Yang1 is essential for oligodendrocyte progenitor differentiation

    PubMed Central

    He, Y.; Dupree, J.; Wang, J.; Sandoval, J.; Li, J.; Liu, H.; Shi, Y.; Nave, K. A.; Casaccia-Bonnefil, P.

    2007-01-01

    Summary The progression of progenitors to oligodendrocytes requires proliferative arrest and the activation of a transcriptional program of differentiation. While regulation of cell cycle exit has been extensively characterized, the molecular mechanisms responsible for the initiation of differentiation remain ill-defined. Here, we identify the transcription factor Yin Yang1 (YY1) as a critical regulator of oligodendrocyte progenitor differentiation. Conditional ablation of yy1 in the oligodendrocyte lineage in vivo, induces a phenotype characterized by defective myelination, ataxia and tremor. At the cellular level, lack of YY1 arrests differentiation of oligodendrocyte progenitors after they exit from the cell cycle. At the molecular level, YY1 acts as a lineage-specific repressor of transcriptional inhibitors of myelin gene expression (Tcf4 and Id4), by recruiting histone deacetylase-1 to their promoters during oligodendrocyte differentiation. Thus, we identify YY1 as an essential component of the transcriptional network regulating the transition of oligodendrocyte progenitors from cell cycle exit to differentiation. PMID:17640524

  7. Oligodendroglial TNFR2 Mediates Membrane TNF-Dependent Repair in Experimental Autoimmune Encephalomyelitis by Promoting Oligodendrocyte Differentiation and Remyelination

    PubMed Central

    Madsen, Pernille M.; Motti, Dario; Karmally, Shaffiat; Szymkowski, David E.; Lambertsen, Kate Lykke; Bethea, John R.

    2016-01-01

    Tumor necrosis factor (TNF) is associated with the pathophysiology of various neurological disorders, including multiple sclerosis. It exists as a transmembrane form tmTNF, signaling via TNF receptor 2 (TNFR2) and TNFR1, and a soluble form, solTNF, signaling via TNFR1. Multiple sclerosis is associated with the detrimental effects of solTNF acting through TNFR1, while tmTNF promotes repair and remyelination. Here we demonstrate that oligodendroglial TNFR2 is a key mediator of tmTNF-dependent protection in experimental autoimmune encephalomyelitis (EAE). CNP-cre:TNFR2fl/fl mice with TNFR2 ablation in oligodendrocytes show exacerbation of the disease with increased axon and myelin pathology, reduced remyelination, and increased loss of oligodendrocyte precursor cells and mature oligodendrocytes. The clinical course of EAE is not improved by the solTNF inhibitor XPro1595 in CNP-cre:TNFR2fl/fl mice, indicating that for tmTNF to promote recovery TNFR2 in oligodendrocytes is required. We show that TNFR2 drives differentiation of oligodendrocyte precursor cells, but not proliferation or survival. TNFR2 ablation leads to dysregulated expression of microRNAs, among which are regulators of oligodendrocyte differentiation and inflammation, including miR-7a. Our data provide the first direct in vivo evidence that TNFR2 in oligodendrocytes is important for oligodendrocyte differentiation, thereby sustaining tmTNF-dependent repair in neuroimmune disease. Our studies identify TNFR2 in the CNS as a molecular target for the development of remyelinating agents, addressing the most pressing need in multiple sclerosis therapy nowadays. SIGNIFICANCE STATEMENT Our study, using novel TNF receptor 2 (TNFR2) conditional KO mice with selective TNFR2 ablation in oligodendrocytes, provides the first direct evidence that TNFR2 is an important signal for oligodendrocyte differentiation. Following activation by transmembrane TNF, TNFR2 initiates pathways that drive oligodendrocytes into a

  8. Adjuvant liposomal doxorubicin markedly affects radiofrequency (RF) ablation-induced effects on periablational microvasculature

    PubMed Central

    Moussa, Marwan; Goldberg, S. Nahum; Tasawwar, Beenish; Sawant, Rupa R.; Levchenko, Tatyana; Kumar, Gaurav; Torchilin, Vladimir P.; Ahmed, Muneeb

    2013-01-01

    Purpose To evaluate the effects of radiofrequency (RF) ablation without and with adjuvant IV liposomal doxorubicin (Doxil®) on microvessel morphology and patency and intratumoral drug delivery and retention. Materials and Methods A total of 133 tumors/animals were used. First, single subcutaneous tumors (R3230 in Fischer rats, and 786-0 in nude mice) were randomized to receive RF alone or no treatment, and sacrificed 0-72hr post-treatment. Next, combined RF/liposomal doxorubicin (1mg given 15min post-RF) was studied in R3230 tumors at 0-72hr post-treatment. Histopathologic assessment including immunohistochemical staining for ced caspase-3), heat shock protein 70 and CD34 were performed to assess morphologic vessel appearance, vessel diameter, and microvascular density. Subsequently, animals were randomized to receive RF alone, RF/liposomal doxorubicin, or control tumors, followed by intravenous fluorescent-labeled liposomes (a surrogate marker) given 0-24hr post-RF to permit qualitative assessment. Results RF ablation alone results in enlarged and dysmorphic vessels from 0-4hr, peaking at 12-24hr post-RF, occurring preferentially closer to the electrode. The addition of doxorubicin resulted in earlier vessel contraction (mean vessel area 47539±9544μm² vs. 1854±458μm² for RF alone at 15min, p<0.05). Combined RF/liposomal doxorubicin produced similar fluorescence 1hr post-treatment (40.88±33.53 AU/μm² vs. 22.1±13.19 AU/μm², p=0.14), but significantly less fluorescence at 4hr (24.3±3.65 AU/μm² vs. 2.8 ±3.14 AU/μm², p<0.002) compared to RF alone denoting earlier reduction in microvascular patency. Conclusion RF ablation induces morphologic changes to vessels within the ablation zone lasting up to 12-24hr post-treatment. The addition liposomal doxorubicin causes early vessel contraction and a reduction in periablational microvascular patency. Such changes will likely need to be considered when determining optimal drug administration and imaging

  9. Protandim Protects Oligodendrocytes against an Oxidative Insult.

    PubMed

    Lim, Jamie L; van der Pol, Susanne M A; Baron, Wia; McCord, Joe M; de Vries, Helga E; van Horssen, Jack

    2016-09-07

    Oligodendrocyte damage and loss are key features of multiple sclerosis (MS) pathology. Oligodendrocytes appear to be particularly vulnerable to reactive oxygen species (ROS) and cytokines, such as tumor necrosis factor-α (TNF), which induce cell death and prevent the differentiation of oligodendrocyte progenitor cells (OPCs). Here, we investigated the efficacy of sulforaphane (SFN), monomethyl fumarate (MMF) and Protandim to induce Nrf2-regulated antioxidant enzyme expression, and protect oligodendrocytes against ROS-induced cell death and ROS-and TNF-mediated inhibition of OPC differentiation. OLN-93 cells and primary rat oligodendrocytes were treated with SFN, MMF or Protandim resulting in significant induction of Nrf2-driven (antioxidant) proteins heme oygenase-1, nicotinamide adenine dinucleotide phosphate (NADPH): quinone oxidoreductase-1 and p62/SQSTM1, as analysed by Western blotting. After incubation with the compounds, oligodendrocytes were exposed to hydrogen peroxide. Protandim most potently promoted oligodendrocyte cell survival as measured by live/death viability assay. Moreover, OPCs were treated with Protandim or vehicle control prior to exposing them to TNF or hydrogen peroxide for five days, which inhibited OPC differentiation. Protandim significantly promoted OPC differentiation under influence of ROS, but not TNF. Protandim, a combination of five herbal ingredients, potently induces antioxidants in oligodendrocytes and is able to protect oligodendrocytes against oxidative stress by preventing ROS-induced cell death and promoting OPC differentiation.

  10. Protandim Protects Oligodendrocytes against an Oxidative Insult

    PubMed Central

    Lim, Jamie L.; van der Pol, Susanne M. A.; Baron, Wia; McCord, Joe M.; de Vries, Helga E.; van Horssen, Jack

    2016-01-01

    Oligodendrocyte damage and loss are key features of multiple sclerosis (MS) pathology. Oligodendrocytes appear to be particularly vulnerable to reactive oxygen species (ROS) and cytokines, such as tumor necrosis factor-α (TNF), which induce cell death and prevent the differentiation of oligodendrocyte progenitor cells (OPCs). Here, we investigated the efficacy of sulforaphane (SFN), monomethyl fumarate (MMF) and Protandim to induce Nrf2-regulated antioxidant enzyme expression, and protect oligodendrocytes against ROS-induced cell death and ROS-and TNF-mediated inhibition of OPC differentiation. OLN-93 cells and primary rat oligodendrocytes were treated with SFN, MMF or Protandim resulting in significant induction of Nrf2-driven (antioxidant) proteins heme oygenase-1, nicotinamide adenine dinucleotide phosphate (NADPH): quinone oxidoreductase-1 and p62/SQSTM1, as analysed by Western blotting. After incubation with the compounds, oligodendrocytes were exposed to hydrogen peroxide. Protandim most potently promoted oligodendrocyte cell survival as measured by live/death viability assay. Moreover, OPCs were treated with Protandim or vehicle control prior to exposing them to TNF or hydrogen peroxide for five days, which inhibited OPC differentiation. Protandim significantly promoted OPC differentiation under influence of ROS, but not TNF. Protandim, a combination of five herbal ingredients, potently induces antioxidants in oligodendrocytes and is able to protect oligodendrocytes against oxidative stress by preventing ROS-induced cell death and promoting OPC differentiation. PMID:27618111

  11. ANALYSIS OF FACTORS AFFECTING OUTCOME OF ULTRASOUND-GUIDED RADIOFREQUENCY HEAT ABLATION FOR TREATMENT OF PRIMARY HYPERPARATHYROIDISM IN DOGS.

    PubMed

    Bucy, Daniel; Pollard, Rachel; Nelson, Richard

    2017-01-01

    Radiofrequency (RF) parathyroid ablation is a noninvasive treatment for hyperparathyroidism in dogs. There are no published data assessing factors associated with RF parathyroid ablation success or failure in order to guide patient selection and improve outcome. The purpose of this retrospective analytical study was to determine whether imaging findings, biochemical data, or concurrent diseases were associated with RF heat ablation treatment failure. For inclusion in the study, dogs must have had a clinical diagnosis of primary hyperparathyroidism, undergone cervical ultrasound and RF ablation of abnormal parathyroid tissue, and must have had at least 3 months of follow-up information available following the date of ultrasound-guided parathyroid ablation. Dogs were grouped based on those with recurrent or persistent hypercalcemia and those without recurrent or persistent hypercalcemia following therapy. Parathyroid nodule size, thyroid lobe size, nodule location, and presence of concurrent disease were recorded. Recurrence of hypercalcemia occurred in 9/32 dogs that had ablation of abnormal parathyroid tissue (28%) and one patient had persistent hypercalcemia (3%) following parathyroid ablation. Nodule width (P = 0.036), height (P = 0.028), and largest cross-sectional area (P = 0.023) were larger in dogs that had recurrent or persistent hypercalcemia following ablation. Hypothyroidism was more common in dogs with recurrent disease (P = 0.044). Radiofrequency ablation was successful in 22/32 (69%) dogs. Larger parathyroid nodule size and/or concurrent hypothyroidism were associated with treatment failure in dogs that underwent ultrasound-guided RF parathyroid nodule ablation.

  12. Selective ablation of pillar and deiters' cells severely affects cochlear postnatal development and hearing in mice.

    PubMed

    Mellado Lagarde, Marcia M; Cox, Brandon C; Fang, Jie; Taylor, Ruth; Forge, Andrew; Zuo, Jian

    2013-01-23

    Mammalian auditory hair cells (HCs) are inserted into a well structured environment of supporting cells (SCs) and acellular matrices. It has been proposed that when HCs are irreversibly damaged by noise or ototoxic drugs, surrounding SCs seal the epithelial surface and likely extend the survival of auditory neurons. Because SCs are more resistant to damage than HCs, the effects of primary SC loss on HC survival and hearing have received little attention. We used the Cre/loxP system in mice to specifically ablate pillar cells (PCs) and Deiters' cells (DCs). In Prox1CreER(T2)+/-;Rosa26(DTA/+) (Prox1DTA) mice, Cre-estrogen receptor (CreER) expression is driven by the endogenous Prox1 promoter and, in presence of tamoxifen, removes a stop codon in the Rosa26(DTA/+) allele and induces diphtheria toxin fragment A (DTA) expression. DTA produces cell-autonomous apoptosis. Prox1DTA mice injected with tamoxifen at postnatal days 0 (P0) and P1 show significant DC and outer PC loss at P2-P4, that reaches ∼70% by 1 month. Outer HC loss follows at P14 and is almost complete at 1 month, while inner HCs remain intact. Neural innervation to the outer HCs is disrupted in Prox1DTA mice and auditory brainstem response thresholds in adults are 40-50 dB higher than in controls. The hearing deficit correlates with loss of cochlear amplification. Remarkably, in Prox1DTA mice, the auditory epithelium preserves the ability to seal the reticular lamina and spiral ganglion neuron counts are normal, a key requirement for cochlear implant success. In addition, our results show that cochlear SC pools should be appropriately replenished during HC regeneration strategies.

  13. Myocilin is involved in NgR1/Lingo-1-mediated oligodendrocyte differentiation and myelination of the optic nerve.

    PubMed

    Kwon, Heung Sun; Nakaya, Naoki; Abu-Asab, Mones; Kim, Hong Sug; Tomarev, Stanislav I

    2014-04-16

    Myocilin is a secreted glycoprotein that belongs to a family of olfactomedin domain-containing proteins. Although myocilin is detected in several ocular and nonocular tissues, the only reported human pathology related to mutations in the MYOCILIN gene is primary open-angle glaucoma. Functions of myocilin are poorly understood. Here we demonstrate that myocilin is a mediator of oligodendrocyte differentiation and is involved in the myelination of the optic nerve in mice. Myocilin is expressed and secreted by optic nerve astrocytes. Differentiation of optic nerve oligodendrocytes is delayed in Myocilin-null mice. Optic nerves of Myocilin-null mice contain reduced levels of several myelin-associated proteins including myelin basic protein, myelin proteolipid protein, and 2'3'-cyclic nucleotide 3'-phosphodiesterase compared with those of wild-type littermates. This leads to reduced myelin sheath thickness of optic nerve axons in Myocilin-null mice compared with wild-type littermates, and this difference is more pronounced at early postnatal stages compared with adult mice. Myocilin also affects differentiation of oligodendrocyte precursors in vitro. Its addition to primary cultures of differentiating oligodendrocyte precursors increases levels of tested markers of oligodendrocyte differentiation and stimulates elongation of oligodendrocyte processes. Myocilin stimulation of oligodendrocyte differentiation occurs through the NgR1/Lingo-1 receptor complex. Myocilin physically interacts with Lingo-1 and may be considered as a Lingo-1 ligand. Myocilin-induced elongation of oligodendrocyte processes may be mediated by activation of FYN and suppression of RhoA GTPase.

  14. The Activators of Cyclin-Dependent Kinase 5 p35 and p39 Are Essential for Oligodendrocyte Maturation, Process Formation, and Myelination.

    PubMed

    Luo, Fucheng; Zhang, Jessie; Burke, Kathryn; Miller, Robert H; Yang, Yan

    2016-03-09

    The regulation of oligodendrocyte development and myelin formation in the CNS is poorly defined. Multiple signals influence the rate and extent of CNS myelination, including the noncanonical cyclin-dependent kinase 5 (Cdk5) whose functions are regulated by its activators p35 and p39. Here we show that selective loss of either p35 or p39 perturbed specific aspects of oligodendrocyte development, whereas loss of both p35 and p39 completely inhibited the development of mature oligodendrocytes and myelination. In the absence of p35, oligodendrocyte differentiation was delayed, process outgrowth was truncated in vitro, and the patterning and extent of myelination were perturbed in the CNS of p35(-/-) mice. In the absence of p39, oligodendrocyte maturation was transiently affected both in vitro and in vivo. However, loss of both p35 and p39 in oligodendrocyte lineage cells completely inhibited oligodendrocyte progenitor cell differentiation and myelination both in vitro and after transplantation into shiverer slice cultures. Loss of p35 and p39 had a more profound effect on oligodendrocyte development than simply the loss of Cdk5 and could not be rescued by Cdk5 overexpression. These data suggest p35 and p39 have specific and overlapping roles in oligodendrocyte development, some of which may be independent of Cdk5 activation.

  15. Role of adenosine in oligodendrocyte precursor maturation

    PubMed Central

    Coppi, Elisabetta; Cellai, Lucrezia; Maraula, Giovanna; Dettori, Ilaria; Melani, Alessia; Pugliese, Anna Maria; Pedata, Felicita

    2015-01-01

    Differentiation and maturation of oligodendroglial cells are postnatal processes that involve specific morphological changes correlated with the expression of stage-specific surface antigens and functional voltage-gated ion channels. A small fraction of oligodendrocyte progenitor cells (OPCs) generated during development are maintained in an immature and slowly proliferative or quiescent state in the adult central nervous system (CNS) representing an endogenous reservoir of immature cells. Adenosine receptors are expressed by OPCs and a key role of adenosine in oligodendrocyte maturation has been recently recognized. As evaluated on OPC cultures, adenosine, by stimulating A1 receptors, promotes oligodendrocyte maturation and inhibits their proliferation; on the contrary, by stimulating A2A receptors, it inhibits oligodendrocyte maturation. A1 and A2A receptor-mediated effects are related to opposite modifications of outward delayed rectifying membrane K+ currents (IK) that are involved in the regulation of oligodendrocyte differentiation. Brain A1 and A2A receptors might represent new molecular targets for drugs useful in demyelinating pathologies, such as multiple sclerosis (MS), stroke and brain trauma. PMID:25964740

  16. LINGO-1 negatively regulates myelination by oligodendrocytes.

    PubMed

    Mi, Sha; Miller, Robert H; Lee, Xinhua; Scott, Martin L; Shulag-Morskaya, Svetlane; Shao, Zhaohui; Chang, Jufang; Thill, Greg; Levesque, Melissa; Zhang, Mingdi; Hession, Cathy; Sah, Dinah; Trapp, Bruce; He, Zhigang; Jung, Vincent; McCoy, John M; Pepinsky, R Blake

    2005-06-01

    The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier. The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination.

  17. The Activators of Cyclin-Dependent Kinase 5 p35 and p39 Are Essential for Oligodendrocyte Maturation, Process Formation, and Myelination

    PubMed Central

    Luo, Fucheng; Zhang, Jessie; Burke, Kathryn

    2016-01-01

    The regulation of oligodendrocyte development and myelin formation in the CNS is poorly defined. Multiple signals influence the rate and extent of CNS myelination, including the noncanonical cyclin-dependent kinase 5 (Cdk5) whose functions are regulated by its activators p35 and p39. Here we show that selective loss of either p35 or p39 perturbed specific aspects of oligodendrocyte development, whereas loss of both p35 and p39 completely inhibited the development of mature oligodendrocytes and myelination. In the absence of p35, oligodendrocyte differentiation was delayed, process outgrowth was truncated in vitro, and the patterning and extent of myelination were perturbed in the CNS of p35−/− mice. In the absence of p39, oligodendrocyte maturation was transiently affected both in vitro and in vivo. However, loss of both p35 and p39 in oligodendrocyte lineage cells completely inhibited oligodendrocyte progenitor cell differentiation and myelination both in vitro and after transplantation into shiverer slice cultures. Loss of p35 and p39 had a more profound effect on oligodendrocyte development than simply the loss of Cdk5 and could not be rescued by Cdk5 overexpression. These data suggest p35 and p39 have specific and overlapping roles in oligodendrocyte development, some of which may be independent of Cdk5 activation. SIGNIFICANCE STATEMENT The development of oligodendrocytes and myelination is essential for normal CNS function and cyclin-dependent kinase 5 (Cdk5) activity is critical for oligodendrocyte maturation, but how Cdk5 activity is controlled is unclear. Here we show that the coactivators of Cdk5, p35 and p39, regulate distinct stages of oligodendrocyte development and myelination. Loss of p35 perturbs oligodendrocyte progenitor cell differentiation, whereas loss of p39 delays oligodendrocyte maturation. Loss of both completely inhibits oligodendrogenesis and myelination. Disruption of oligodendrocyte development was more pronounced in p35−/−;p39

  18. Modulation of oligodendrocyte differentiation and maturation by combined biochemical and mechanical cues

    PubMed Central

    Lourenço, Tânia; Paes de Faria, Joana; Bippes, Christian A.; Maia, João; Lopes-da-Silva, José A.; Relvas, João B.; Grãos, Mário

    2016-01-01

    Extracellular matrix (ECM) proteins play a key role during oligodendrogenesis. While fibronectin (FN) is involved in the maintenance and proliferation of oligodendrocyte progenitor cells (OPCs), merosin (MN) promotes differentiation into oligodendrocytes (OLs). Mechanical properties of the ECM also seem to affect OL differentiation, hence this study aimed to clarify the impact of combined biophysical and biochemical elements during oligodendrocyte differentiation and maturation using synthetic elastic polymeric ECM-like substrates. CG-4 cells presented OPC- or OL-like morphology in response to brain-compliant substrates functionalised with FN or MN, respectively. The expression of the differentiation and maturation markers myelin basic protein — MBP — and proteolipid protein — PLP — (respectively) by primary rat oligodendrocytes was enhanced in presence of MN, but only on brain-compliant conditions, considering the distribution (MBP) or amount (PLP) of the protein. It was also observed that maturation of OLs was attained earlier (by assessing PLP expression) by cells differentiated on MN-functionalised brain-compliant substrates than on standard culture conditions. Moreover, the combination of MN and substrate compliance enhanced the maturation and morphological complexity of OLs. Considering the distinct degrees of stiffness tested ranging within those of the central nervous system, our results indicate that 6.5 kPa is the most suitable rigidity for oligodendrocyte differentiation. PMID:26879561

  19. Oligodendrocyte Regeneration after Neonatal Hypoxia Requires FoxO1-Mediated p27Kip1 Expression

    PubMed Central

    Jablonska, Beata; Scafidi, Joseph; Aguirre, Adan; Vaccarino, Flora; Nguyen, Vien; Borok, Erzsebet; Horvath, Tamas L.; Rowitch, David H.; Gallo, Vittorio

    2012-01-01

    Diffuse white matter injury (DWMI) caused by hypoxia is associated with permanent neurodevelopmental disabilities in preterm infants. The cellular and molecular mechanisms producing DWMI are poorly defined. Using a mouse model of neonatal hypoxia, we demonstrate a biphasic effect on oligodendrocyte development, resulting in hypomyelination. Oligodendrocyte death and oligodendrocyte progenitor cell (OPC) proliferation during the week after hypoxia were followed by delayed oligodendrocyte differentiation and abnormal myelination, as demonstrated by electron microscopy. Cdk2 activation was essential for the regenerative OPC response after hypoxia and was accompanied by reduced FoxO1-dependent p27 Kip1 expression. p27 Kip1 was also reduced in OPCs in human infant white matter lesions after hypoxia. The negative effects of hypoxia on oligodendrogenesis and myelination were more pronounced in p27 Kip1-null mice; conversely, overexpression of FoxO1 or p27 Kip1 in OPCs after hypoxia promoted oligodendrogenesis. Our studies demonstrate for the first time that neonatal hypoxia affects the Foxo1/p27 Kip1 pathway during white matter development. We also show that molecular manipulation of this pathway enhances oligodendrocyte regeneration during a critical developmental time window after DWMI. Thus, FoxO1 and p27 Kip1 may serve as promising target molecules for promoting timely oligodendrogenesis in neonatal DWMI. PMID:23077062

  20. Regulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes

    PubMed Central

    Jiang, Minqing; Liu, Lei; He, Xuelian; Wang, Haibo; Lin, Wensheng; Wang, Huimin; Yoon, Sung O.; Wood, Teresa L.; Lu, Q. Richard

    2016-01-01

    Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, including myelin deficits in the CNS; however, underlying mechanisms are not fully understood. TSC1/2 negatively regulate the function of mTOR, which is required for oligodendrocyte differentiation. Here we report that, unexpectedly, constitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death in mice, despite an initial increase of oligodendrocyte precursors during early development. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses by activating a PERK–eIF2α signalling axis and Fas–JNK apoptotic pathways. Enhancement of the phospho-eIF2α adaptation pathway by inhibition of Gadd34-PP1 phosphatase with guanabenz protects oligodendrocytes and partially rescues myelination defects in Tsc1 mutants. Thus, TSC1-mTOR signalling acts as an important checkpoint for maintaining oligodendrocyte homoeostasis, pointing to a previously uncharacterized ER stress mechanism that contributes to hypomyelination in tuberous sclerosis. PMID:27416896

  1. OLIGODENDROCYTE DEGENERATION AND RECOVERY AFTER FOCAL CEREBRAL ISCHEMIA

    PubMed Central

    McIver, Sally R.; Muccigrosso, Megan; Gonzales, Ernesto R.; Lee, Jin-Moo; Roberts, Marie S.; Sands, Mark S.; Goldberg, Mark P.

    2013-01-01

    The vulnerability of oligodendrocytes to ischemic injury may contribute to functional loss in diseases of central white matter. Immunocytochemical methods to identify oligodendrocyte injury in experimental models rely on epitope availability, and fail to discriminate structural changes in oligodendrocyte morphology. We previously described the use of a lentiviral vector (LV) carrying eGFP under the myelin basic protein (MBP) promoter for selective visualization of oligodendrocyte cell bodies and processes. In this study, we used LV-MBP-eGFP to label oligodendrocytes in rat cerebral white matter prior to transient focal cerebral ischemia, and examined oligodendrocyte injury 24 hours, 48 hours and one week post-reperfusion by quantifying cell survival and assaying the integrity of myelin processes. There was progressive loss of GFP+ oligodendrocytes in ischemic white matter at 24 and 48 hrs. Surviving GFP+ cells had non-pyknotic nuclear morphology and were TUNEL-negative, but there was marked fragmentation of myelin processes as early as 24 hours after stroke. One week after stroke, we observed a restoration of GFP+ oligodendrocytes in ischemic white matter, reflected both by cell counts and by structural integrity of myelin processes. Proliferating cells were not the main source of GFP+ oligodendrocytes, as revealed by BrdU incorporation. These observations identify novel transient structural changes in oligodendrocyte cell bodies and myelinating processes, which may have consequences for white matter function after stroke. PMID:20621643

  2. MicroRNA-Mediated Control of Oligodendrocyte Differentiation

    PubMed Central

    Zhao, Xianghui; He, Xuelian; Han, Xiaolei; Yu, Yang; Ye, Feng; Chen, Ying; Hoang, ThaoNguyen; Xu, Xiaomei; Li, Huashun; Xin, Mei; Wang, Fang; Appel, Bruce; Lu, Q. Richard

    2010-01-01

    Summary MicroRNAs (miRNAs) regulate various biological processes, but evidence for miRNAs that control the differentiation program of specific neural cell types has been elusive. To determine the role of miRNAs in the formation of myelinating oligodendrocytes, we selectively deleted a miRNA-processing enzyme Dicer1 in oligodendrocyte lineage cells. Mice lacking Dicer1 display severe myelinating deficits despite an expansion of oligodendrocyte progenitor pool. To search for miRNAs responsible for the induction of oligodendrocyte maturation, we identified miR-219 and miR-338 as oligodendrocyte-specific miRNAs in spinal cord. Overexpression of these miRNAs is sufficient to promote oligodendrocyte differentiation. Additionally, blockage of these miRNA activities in oligodendrocyte precursor culture and knockdown of miR-219 in zebrafish inhibit oligodendrocyte maturation. miR-219 and miR-338 function in part by directly repressing negative regulators of oligodendrocyte differentiation, including transcription factors Sox6 and Hes5. These findings illustrate that miRNAs are important regulators of oligodendrocyte differentiation, providing new targets for myelin repair. PMID:20223198

  3. MicroRNA-mediated control of oligodendrocyte differentiation.

    PubMed

    Zhao, Xianghui; He, Xuelian; Han, Xiaolei; Yu, Yang; Ye, Feng; Chen, Ying; Hoang, ThaoNguyen; Xu, Xiaomei; Mi, Qing-Sheng; Xin, Mei; Wang, Fan; Appel, Bruce; Lu, Q Richard

    2010-03-11

    MicroRNAs (miRNAs) regulate various biological processes, but evidence for miRNAs that control the differentiation program of specific neural cell types has been elusive. To determine the role of miRNAs in the formation of myelinating oligodendrocytes, we selectively deleted a miRNA-processing enzyme, Dicer1, in oligodendrocyte lineage cells. Mice lacking Dicer1 display severe myelinating deficits despite an expansion of the oligodendrocyte progenitor pool. To search for miRNAs responsible for the induction of oligodendrocyte maturation, we identified miR-219 and miR-338 as oligodendrocyte-specific miRNAs in spinal cord. Overexpression of these miRNAs is sufficient to promote oligodendrocyte differentiation. Additionally, blockage of these miRNA activities in oligodendrocyte precursor culture and knockdown of miR-219 in zebrafish inhibit oligodendrocyte maturation. miR-219 and miR-338 function in part by directly repressing negative regulators of oligodendrocyte differentiation, including transcription factors Sox6 and Hes5. These findings illustrate that miRNAs are important regulators of oligodendrocyte differentiation, providing new targets for myelin repair.

  4. Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes

    PubMed Central

    von Jonquieres, Georg; Fröhlich, Dominik; Klugmann, Claudia B.; Wen, Xin; Harasta, Anne E.; Ramkumar, Roshini; Spencer, Ziggy H. T.; Housley, Gary D.; Klugmann, Matthias

    2016-01-01

    Leukodystrophies are hereditary central white matter disorders caused by oligodendrocyte dysfunction. Recent clinical trials for some of these devastating neurological conditions have employed an ex vivo gene therapy approach that showed improved endpoints because cross-correction of affected myelin-forming cells occurred following secretion of therapeutic proteins by transduced autologous grafts. However, direct gene transfer to oligodendrocytes is required for the majority of leukodystrophies with underlying mutations in genes encoding non-secreted oligodendroglial proteins. Recombinant adeno-associated viral (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in rodents have shown that the use of cellular promoters is sufficient to target AAV-mediated transgene expression to glia. The potential of this strategy has not been exploited. The major caveat of the AAV system is its limited packaging capacity of ~5 kb, providing the rationale for identifying small yet selective recombinant promoters. Here, we characterize the human myelin associated glycoprotein (MAG) promoter for reliable targeting of AAV-mediated transgene expression to oligodendrocytes in vivo. A homology screen revealed highly conserved genomic regions among mammalian species upstream of the transcription start site. Recombinant AAV expression cassettes carrying the cDNA encoding enhanced green fluorescent protein (GFP) driven by truncated versions of the recombinant MAG promoter (2.2, 1.5 and 0.3 kb in size) were packaged as cy5 vectors and delivered into the dorsal striatum of mice. At 3 weeks post-injection, oligodendrocytes, neurons and astrocytes expressing the reporter were quantified by immunohistochemical staining. Our results revealed that both 2.2 and 1.5 kb MAG promoters targeted more than 95% of transgene expression to oligodendrocytes. Even the short 0.3 kb fragment conveyed high oligodendroglial specific transgene

  5. Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes.

    PubMed

    von Jonquieres, Georg; Fröhlich, Dominik; Klugmann, Claudia B; Wen, Xin; Harasta, Anne E; Ramkumar, Roshini; Spencer, Ziggy H T; Housley, Gary D; Klugmann, Matthias

    2016-01-01

    Leukodystrophies are hereditary central white matter disorders caused by oligodendrocyte dysfunction. Recent clinical trials for some of these devastating neurological conditions have employed an ex vivo gene therapy approach that showed improved endpoints because cross-correction of affected myelin-forming cells occurred following secretion of therapeutic proteins by transduced autologous grafts. However, direct gene transfer to oligodendrocytes is required for the majority of leukodystrophies with underlying mutations in genes encoding non-secreted oligodendroglial proteins. Recombinant adeno-associated viral (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in rodents have shown that the use of cellular promoters is sufficient to target AAV-mediated transgene expression to glia. The potential of this strategy has not been exploited. The major caveat of the AAV system is its limited packaging capacity of ~5 kb, providing the rationale for identifying small yet selective recombinant promoters. Here, we characterize the human myelin associated glycoprotein (MAG) promoter for reliable targeting of AAV-mediated transgene expression to oligodendrocytes in vivo. A homology screen revealed highly conserved genomic regions among mammalian species upstream of the transcription start site. Recombinant AAV expression cassettes carrying the cDNA encoding enhanced green fluorescent protein (GFP) driven by truncated versions of the recombinant MAG promoter (2.2, 1.5 and 0.3 kb in size) were packaged as cy5 vectors and delivered into the dorsal striatum of mice. At 3 weeks post-injection, oligodendrocytes, neurons and astrocytes expressing the reporter were quantified by immunohistochemical staining. Our results revealed that both 2.2 and 1.5 kb MAG promoters targeted more than 95% of transgene expression to oligodendrocytes. Even the short 0.3 kb fragment conveyed high oligodendroglial specific transgene

  6. Synergistic ablation does not affect atrophy or altered myosin heavy chain expression in the non-weight bearing soleus muscle

    NASA Technical Reports Server (NTRS)

    Linderman, J. K.; Talmadge, R. J.; Gosselink, K. L.; Tri, P. N.; Roy, R. R.; Grindeland, R. E.

    1996-01-01

    The purpose of this study was to investigate whether the soleus muscle undergoes atrophy and alterations in myosin heavy chain (MHC) composition during non-weight bearing in the absence of synergists. Thirty-two female rats were randomly assigned to four groups: control (C), synergistic ablation (ABL) of the gastrocnemius and plantaris muscles to overload the soleus muscle, hindlimb suspension (HLS), or a combination of synergistic ablation and hindlimb suspension (HLS-ABL). After 28 days of hindlimb suspension, soleus atrophy was more pronounced in HLS (58%) than in HLS-ABL (43%) rats. Compared to C rats, non-weight bearing decreased mixed and myofibrillar protein contents and Type I MHC 49%, 45%, and 7%, respectively, in HLS animals. In addition, de novo expression of fast Type IIx and Type IIb MHC (5% and 2%, respectively) was observed in HLS animals. Similarly, when compared to C rats, mixed and myofibrillar protein contents and Type I MHC decreased 43%, 46%, and 4%, respectively, in HLS-ABL animals. Also, de novo expression of Type IIx (4%) and IIb (1%) MHC was observed. Collectively, these data indicate that the loss of muscle protein and Type I MHC, and the de novo expression of Type IIx and Type IIb MHC in the rat soleus occur independently of the presence of synergists during non-weight bearing. Furthermore, these results confirm the contention that soleus mass and MHC expression are highly sensitive to alterations in mechanical load.

  7. Targeting human oligodendrocyte progenitors for myelin repair.

    PubMed

    Dietz, Karen C; Polanco, Jessie J; Pol, Suyog U; Sim, Fraser J

    2016-09-01

    Oligodendrocyte development has been studied for several decades, and has served as a model system for both neurodevelopmental and stem/progenitor cell biology. Until recently, the vast majority of studies have been conducted in lower species, especially those focused on rodent development and remyelination. In humans, the process of myelination requires the generation of vastly more myelinating glia, occurring over a period of years rather than weeks. Furthermore, as evidenced by the presence of chronic demyelination in a variety of human neurologic diseases, it appears likely that the mechanisms that regulate development and become dysfunctional in disease may be, in key ways, divergent across species. Improvements in isolation techniques, applied to primary human neural and oligodendrocyte progenitors from both fetal and adult brain, as well as advancements in the derivation of defined progenitors from human pluripotent stem cells, have begun to reveal the extent of both species-conserved signaling pathways and potential key differences at cellular and molecular levels. In this article, we will review the commonalities and differences in myelin development between rodents and man, describing the approaches used to study human oligodendrocyte differentiation and myelination, as well as heterogeneity within targetable progenitor pools, and discuss the advances made in determining which conserved pathways may be both modeled in rodents and translate into viable therapeutic strategies to promote myelin repair.

  8. Oligodendrocyte Lineage Cells in Chronic Demyelination of Multiple Sclerosis Optic Nerve.

    PubMed

    Jennings, Alison Ruth; Carroll, William M

    2015-09-01

    Reports that chronically demyelinated multiple sclerosis brain and spinal cord lesions contained immature oligodendrocyte lineage cells have generated major interest aimed at the potential for promotion of endogenous repair. Despite the prominence of the optic nerve as a lesion site and its importance in clinical disease assessment, no detailed studies of multiple sclerosis-affected optic nerve exist. This study aims to provide insight into the cellular pathology of chronic demyelination in multiple sclerosis through direct morphological and immunohistochemical analysis of optic nerve in conjunction with observations from an experimental cat optic nerve model of successful remyelination. Myelin staining was followed by immunohistochemistry to differentially label neuroglia. Digitally immortalized sections were then analyzed to generate quantification data and antigenic phenotypes including maturational stages within the oligodendrocyte lineage. It was found that some chronically demyelinated multiple sclerosis optic nerve lesions contained oligodendroglial cells and that heterogeneity existed in the presence of myelin sheaths, oligodendrocyte maturational stages and extent of axonal investment. The findings advance our understanding of oligodendrocyte activity in chronically demyelinated human optic nerve and may have implications for studies aimed at enhancement of endogenous repair in multiple sclerosis.

  9. Doublecortin in Oligodendrocyte Precursor Cells in the Adult Mouse Brain

    PubMed Central

    Boulanger, Jenna J.; Messier, Claude

    2017-01-01

    Key Points Oligodendrocyte precursor cells express doublecortin, a microtubule-associated protein.Oligodendrocyte precursor cells express doublecortin, but at a lower level of expression than in neuronal precursor.Doublecortin is not associated with a potential immature neuronal phenotype in Oligodendrocyte precursor cells. Oligodendrocyte precursor cells (OPC) are glial cells that differentiate into myelinating oligodendrocytes during embryogenesis and early stages of post-natal life. OPCs continue to divide throughout adulthood and some eventually differentiate into oligodendrocytes in response to demyelinating lesions. There is growing evidence that OPCs are also involved in activity-driven de novo myelination of previously unmyelinated axons and myelin remodeling in adulthood. Considering these roles in the adult brain, OPCs are likely mobile cells that can migrate on some distances before they differentiate into myelinating oligodendrocytes. A number of studies have noted that OPCs express doublecortin (DCX), a microtubule-associated protein expressed in neural precursor cells and in migrating immature neurons. Here we describe the distribution of DCX in OPCs. We found that almost all OPCs express DCX, but the level of expression appears to be much lower than what is found in neural precursor. We found that DCX is downregulated when OPCs start expressing mature oligodendrocyte markers and is absent in myelinating oligodendrocytes. DCX does not appear to signal an immature neuronal phenotype in OPCs in the adult mouse brain. Rather, it could be involved either in cell migration, or as a marker of an immature oligodendroglial cell phenotype.

  10. Investigation of astrocyte - oligodendrocyte interactions in human cultures.

    PubMed

    John, Gareth R

    2012-01-01

    Multiple sclerosis (MS) is characterized by CNS demyelination and oligodendrocyte depletion, axonal loss, and reactive astrogliosis. Myelin loss causes conduction block, while remyelination is associated with recovery of conduction and return of function. Reactive astrocytes are a prominent feature of MS plaques, and have been implicated as producing factors regulating oligodendrocyte progenitor differentiation and myelin formation. Understanding their impact on these events may lead to new approaches for oligodendrocyte protection and/or remyelination in MS. Here, we outline protocols for the establishment and analysis of primary monocultures and cocultures of human astrocytes and oligodendrocytes. These approaches are designed to facilitate analysis of mechanisms underlying astrocytic regulation of progenitor survival and myelin repair.

  11. GAT-1 mediated GABA uptake in rat oligodendrocytes.

    PubMed

    Fattorini, Giorgia; Melone, Marcello; Sánchez-Gómez, María Victoria; Arellano, Rogelio O; Bassi, Silvia; Matute, Carlos; Conti, Fiorenzo

    2017-03-01

    Stimulated by the results of a recent paper on the effects of tiagabine, a selective inhibitor of the main GABA transporter GAT-1, on oligodendrogenesis, we verified the possibility that GAT-1 may be expressed in oligodendrocytes using immunocytochemical methods and functional assays. Light microscopic analysis of the subcortical white matter of all animals revealed the presence of numerous GAT-1+ cells of different size (from 3 to 29 µm) and morphology. An electron microscope analysis revealed that, besides fibrous astrocytes and interstitial neurons, GAT-1 immunoreactivity was present in immature and mature oligodendrocytes. Co-localization studies between GAT-1 and markers specific for oligodendrocytes (NG2 and RIP) showed that about 12% of GAT-1 positive cells in the white matter were immature oligodendrocytes, while about 15% were mature oligodendrocytes. In vitro functional assays showed that oligodendrocytes exhibit tiagabine-sensitive Na(+) -dependent GABA uptake. Although relationships between GABA and oligodendrocytes have been known for many years, this is the first demonstration that GAT-1 is expressed in oligodendrocytes. The present results on the one hand definitely closes the era of "neuronal" and "glial" GABA transporters, on the other they suggest that oligodendrocytes may contribute to pathophysiology of the several diseases in which GAT-1 have been implicated to date. GLIA 2017;65:514-522.

  12. Laser ablation ICP-MS screening of corals for diagenetically affected areas applied to Tahiti corals from the last deglaciation

    NASA Astrophysics Data System (ADS)

    Hathorne, Ed C.; Felis, Thomas; James, Rachael H.; Thomas, Alex

    2011-03-01

    Fossil corals are unique archives of past seasonal climate variability, providing vital information about seasonal climate phenomena such as ENSO and monsoons. However, submarine diagenetic processes can potentially obscure the original climate signals and lead to false interpretations. Here we demonstrate the potential of laser ablation ICP-MS to rapidly detect secondary aragonite precipitates in fossil Porites colonies recovered by Integrated Ocean Drilling Program (IODP) Expedition 310 from submerged deglacial reefs off Tahiti. High resolution (100 μm) measurements of coralline B/Ca, Mg/Ca, S/Ca, and U/Ca ratios are used to distinguish areas of pristine skeleton from those afflicted with secondary aragonite. Measurements of coralline Sr/Ca, U/Ca and oxygen isotope ratios, from areas identified as pristine, reveal that the seasonal range of sea surface temperature in the tropical south Pacific during the last deglaciation (14.7 and 11 ka) was similar to that of today.

  13. Genetic Ablation of Soluble TNF Does Not Affect Lesion Size and Functional Recovery after Moderate Spinal Cord Injury in Mice

    PubMed Central

    Ellman, Ditte Gry; Degn, Matilda; Lund, Minna Christiansen; Clausen, Bettina Hjelm; Novrup, Hans Gram; Flæng, Simon Bertram; Jørgensen, Louise Helskov; Suntharalingam, Lujitha; Svenningsen, Åsa Fex; Brambilla, Roberta

    2016-01-01

    Traumatic spinal cord injury (SCI) is followed by an instant increase in expression of the microglial-derived proinflammatory cytokine tumor necrosis factor (TNF) within the lesioned cord. TNF exists both as membrane-anchored TNF (mTNF) and as cleaved soluble TNF (solTNF). We previously demonstrated that epidural administration of a dominant-negative inhibitor of solTNF, XPro1595, to the contused spinal cord resulted in changes in Iba1 protein expression in microglia/macrophages, decreased lesion volume, and improved locomotor function. Here, we extend our studies using mice expressing mTNF, but no solTNF (mTNFΔ/Δ), to study the effect of genetic ablation of solTNF on SCI. We demonstrate that TNF levels were significantly decreased within the lesioned spinal cord 3 days after SCI in mTNFΔ/Δ mice compared to littermates. This decrease did, however, not translate into significant changes in other pro- and anti-inflammatory cytokines (IL-10, IL-1β, IL-6, IL-5, IL-2, CXCL1, CCL2, or CCL5), despite a tendency towards increased IL-10 and decreased IL-1β, TNFR1, and TNFR2 levels in mTNFΔ/Δ mice. In addition, microglial and leukocyte infiltration, activation state (Iba1, CD11b, CD11c, CD45, and MHCII), lesion size, and functional outcome after moderate SCI were comparable between genotypes. Collectively, our data demonstrate that genetic ablation of solTNF does not significantly modulate postlesion outcome after SCI. PMID:28070141

  14. Catheter ablation.

    PubMed

    Fromer, M; Shenasa, M

    1991-02-01

    Catheter ablation is gaining increasing interest for the therapy of symptomatic, sustained arrhythmias of various origins. The scope of this review is to give an overview of the biophysical aspects and major characteristics of some of the most widely used energy sources in catheter ablation, e.g., the discharge of conventional defibrillators, modified defibrillators, laser light, and radiofrequency current application. Results from animal studies are considered to explain the basic mechanisms of catheter ablation. The recent achievements with the use of radiofrequency current to modify or ablate cardiac conduction properties are outlined in more detail.

  15. Platelet-derived growth factor delays oligodendrocyte differentiation and axonal myelination in vivo in the anterior medullary velum of the developing rat.

    PubMed

    Butt, A M; Hornby, M F; Kirvell, S; Berry, M

    1997-06-15

    The AA dimeric form of platelet-derived growth factor (PDGF-AA) is implicated in the differentiation of cells of the oligodendrocyte lineage, which express PDGF receptors of the alpha subunit type (PDGF-alphaR). In the present study, we show that a single injection of PDGF-AA into the cerebrospinal fluid of neonatal rats delays oligodendrocyte differentiation and interrupts the progress of myelination in the anterior medullary velum (AMV), a white matter tract roofing the IVth ventricle of the brain. PDGF-AA or saline was injected intrathecally in postnatal day (P) 7 rats, and the AMV was subsequently removed and immunolabelled with the oligodendrocyte-specific antibody Rip, at P9, P12, and P21, corresponding to postinjection days (PID) 2, 5, and 14. At P9 (PID2), myelination was retarded in PDGF-AA-treated rats as opposed to saline-treated controls but progressed rapidly after P12 (PID5). Quantification supported the qualitative observations that PDGF-AA mediated an acute decrease in the number of Rip+ oligodendrocytes at P9-12, which largely recovered by P21, suggesting that PDGF-AA may have delayed recruitment of myelinating oligodendrocytes. However, the definitive number of Rip+ oligodendrocytes in the AMV was not increased, suggesting that its action as a promoter of early oligodendrocyte survival may not ultimately affect the definitive number of myelinating oliogdendrocytes in vivo. We discuss the possibilities that excess PDGF-AA may have acted on early oligodendrocytes (precursors or preoligodendrocytes) to either (1) delay their differentiation by maintaining them in the cell cycle or (2) accelerate their differentiation, which may result in premature cell death in the absence of synchronised survival signals. This study supports a role for PDGF-AA in the timing of oligodendrocyte differentiation in vivo, as has been shown in vitro.

  16. Selective ploidy ablation, a high-throughput plasmid transfer protocol, identifies new genes affecting topoisomerase I–induced DNA damage

    PubMed Central

    Reid, Robert J.D.; González-Barrera, Sergio; Sunjevaric, Ivana; Alvaro, David; Ciccone, Samantha; Wagner, Marisa; Rothstein, Rodney

    2011-01-01

    We have streamlined the process of transferring plasmids into any yeast strain library by developing a novel mating-based, high-throughput method called selective ploidy ablation (SPA). SPA uses a universal plasmid donor strain that contains conditional centromeres on every chromosome. The plasmid-bearing donor is mated to a recipient, followed by removal of all donor-strain chromosomes, producing a haploid strain containing the transferred plasmid. As proof of principle, we used SPA to transfer plasmids containing wild-type and mutant alleles of DNA topoisomerase I (TOP1) into the haploid yeast gene-disruption library. Overexpression of Top1 identified only one sensitive mutation, rpa34, while overexpression of top1-T722A allele, a camptothecin mimetic, identified 190 sensitive gene-disruption strains along with rpa34. In addition to known camptothecin-sensitive strains, this set contained mutations in genes involved in the Rpd3 histone deacetylase complex, the kinetochore, and vesicle trafficking. We further show that mutations in several ESCRT vesicle trafficking components increase Top1 levels, which is dependent on SUMO modification. These findings demonstrate the utility of the SPA technique to introduce plasmids into the haploid gene-disruption library to discover new interacting pathways. PMID:21173034

  17. Oligodendrocyte Precursor Cells Synthesize Neuromodulatory Factors

    PubMed Central

    Sakry, Dominik; Yigit, Hatice; Dimou, Leda; Trotter, Jacqueline

    2015-01-01

    NG2 protein-expressing oligodendrocyte progenitor cells (OPC) are a persisting and major glial cell population in the adult mammalian brain. Direct synaptic innervation of OPC by neurons throughout the brain together with their ability to sense neuronal network activity raises the question of additional physiological roles of OPC, supplementary to generating myelinating oligodendrocytes. In this study we investigated whether OPC express neuromodulatory factors, typically synthesized by other CNS cell types. Our results show that OPC express two well-characterized neuromodulatory proteins: Prostaglandin D2 synthase (PTGDS) and neuronal Pentraxin 2 (Nptx2/Narp). Expression levels of the enzyme PTGDS are influenced in cultured OPC by the NG2 intracellular region which can be released by cleavage and localizes to glial nuclei upon transfection. Furthermore PTGDS mRNA levels are reduced in OPC from NG2-KO mouse brain compared to WT cells after isolation by cell sorting and direct analysis. These results show that OPC can contribute to the expression of these proteins within the CNS and suggest PTGDS expression as a downstream target of NG2 signaling. PMID:25966014

  18. Thermal ablation.

    PubMed

    Webb, Heather; Lubner, Meghan G; Hinshaw, J Louis

    2011-04-01

    Image-guided tumor ablation refers to a group of treatment modalities that have emerged during the past 2 decades as important tools in the treatment of a wide range of tumors throughout the body. Although most widely recognized in the treatment of hepatic and renal malignancies, the role of thermal ablation has expanded to include lesions of the lung, breast, prostate, bone, as well as other organs and its clinical applications continue to increase. In the following article, we discuss the major thermal ablation modalities, their respective strengths and weaknesses, potential complications and how to avoid them, as well as possible future applications.

  19. Catheter Ablation

    MedlinePlus

    ... you during the procedure. Machines will measure your heart’s activity. All types of ablation require cardiac catheterization to place flexible tubes, or catheters, inside your heart to make the scars. Your doctor will clean ...

  20. TRPM3 is expressed in sphingosine-responsive myelinating oligodendrocytes.

    PubMed

    Hoffmann, Anja; Grimm, Christian; Kraft, Robert; Goldbaum, Olaf; Wrede, Arne; Nolte, Christiane; Hanisch, Uwe-Karsten; Richter-Landsberg, Christiane; Brück, Wolfgang; Kettenmann, Helmut; Harteneck, Christian

    2010-08-01

    Oligodendrocytes are the myelin-forming cells of the CNS and guarantee proper nerve conduction. Sphingosine, one major component of myelin, has recently been identified to activate TRPM3, a member of the melastatin-related subfamily of transient receptor potential (TRP) channels. TRPM3 has been demonstrated to be expressed in brain with unknown cellular distribution. Here, we show for the first time that TRPM3 is expressed in oligodendrocytes in vitro and in vivo. TRPM3 is present during oligodendrocyte differentiation. Immunohistochemistry of adult rat brain slices revealed staining of white matter areas, which co-localized with oligodendrocyte markers. Analysis of the developmental distribution revealed that, prior to myelination, TRPM3 channels are localized on neurons. On oligodendrocytes they are found after the onset of myelination. RT-PCR studies showed that the transcription of TRPM3 splice variants is also developmentally regulated in vitro. Ca(2+) imaging approaches revealed the presence of a sphingosine-induced Ca(2+) entry mechanism in oligodendrocytes - with a pharmacological profile similar to the profile published for heterologously expressed TRPM3. These findings indicate that TRPM3 participates as a Ca(2+)-permeable and sphingosine-activated channel in oligodendrocyte differentiation and CNS myelination.

  1. Oligodendrocyte precursor cells generate pituicytes in vivo during neurohypophysis development.

    PubMed

    Virard, Isabelle; Coquillat, Delphine; Bancila, Mircea; Kaing, Sovann; Durbec, Pascale

    2006-02-01

    In the vertebrate brain, much remains to be understood concerning the origin of glial cell diversity and the potential lineage relationships between the various types of glia. Besides astrocytes and myelin-forming oligodendrocytes, other macroglial cell populations are found in discrete areas of the central nervous system (CNS). They share functional features with astrocytes and oligodendrocytes but also display specific characteristics. Such specialized cells, called pituicytes, are located in the neurohypophysis (NH). Our work focuses on the lineage of the pituicytes during rodent development. First, we show that cells identified with a combination of oligodendrocyte precursor cell (OPC) markers are present in the developing rat NH. In culture, neonatal NH progenitors also share major functional characteristics with OPCs, being both migratory and bipotential, i.e. able to give rise to type 2 astrocytes and oligodendrocytes. We then observe that, either in vitro or after transplantation into myelin-deficient Shiverer brain, pieces of NH generate myelinating oligodendrocytes, confirming the oligodendrogenic potentiality of NH cells. However, no mature oligodendrocyte can be found in the NH. This led us to hypothesize that the OPCs present in the developing NH might be generating other glial cells, especially the pituicytes. Consistent with this hypothesis, the OPCs appear during NH development before pituicytes differentiate. Finally, we establish a lineage relationship between olig1+ cells, most likely OPCs, and the pituicytes by fate-mapping experiments using genetically engineered mice. This constitutes the first demonstration that OPCs generate glial cells other than oligodendrocytes in vivo.

  2. Chromatin Landscape Defined by Repressive Histone Methylation during Oligodendrocyte Differentiation

    PubMed Central

    Liu, Jia; Magri, Laura; Zhang, Fan; Marsh, Nidaa O.; Albrecht, Stefanie; Huynh, Jimmy L.; Kaur, Jasbir; Kuhlmann, Tanja; Zhang, Weijia; Slesinger, Paul A.

    2015-01-01

    In many cell types, differentiation requires an interplay between extrinsic signals and transcriptional changes mediated by repressive and activating histone modifications. Oligodendrocyte progenitors (OPCs) are electrically responsive cells receiving synaptic input. The differentiation of these cells into myelinating oligodendrocytes is characterized by temporal waves of gene repression followed by activation of myelin genes and progressive decline of electrical responsiveness. In this study, we used chromatin isolated from rat OPCs and immature oligodendrocytes, to characterize the genome-wide distribution of the repressive histone marks, H3K9me3 and H3K27me3, during differentiation. Although both marks were present at the OPC stage, only H3K9me3 marks (but not H3K27me3) were found to be increased during differentiation, at genes related to neuronal lineage and regulation of membrane excitability. Consistent with these findings, the levels and activity of H3K9 methyltransferases (H3K9 HMT), but not H3K27 HMT, increased more prominently upon exposure to oligodendrocyte differentiating stimuli and were detected in stage-specific repressive protein complexes containing the transcription factors SOX10 or YY1. Silencing H3K9 HMT, but not H3K27 HMT, impaired oligodendrocyte differentiation and functionally altered the response of oligodendrocytes to electrical stimulation. Together, these results identify repressive H3K9 methylation as critical for gene repression during oligodendrocyte differentiation. PMID:25568127

  3. Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination.

    PubMed

    Du, Changsheng; Duan, Yanhui; Wei, Wei; Cai, Yingying; Chai, Hui; Lv, Jie; Du, Xiling; Zhu, Jian; Xie, Xin

    2016-04-04

    Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches.

  4. Activated Immune Response in an Inherited Leukodystrophy Disease Caused by the Loss of Oligodendrocyte Gap Junctions

    PubMed Central

    Wasseff, Sameh K.; Scherer, Steven S.

    2015-01-01

    Oligodendrocyte:oligodendrocyte (O:O) gap junction (GJ) coupling is a widespread and essential feature of the CNS, and is mediated by connexin47 (Cx47) and Cx32. Loss of function mutations affecting Cx47 results in a severe leukodystrophy, Pelizeus-Merzbacher-like disease (also known as Hypomyelinating Leukodystrophy 2), which can be reproduced in mice lacking both Cx47 and Cx32. Here we report the gene expression profile of the cerebellum – an affected brain region – in mice lacking both Cx47 and Cx32. Of the 43,174 mRNA probes examined, we find decreased expression of 23 probes (corresponding to 23 genes) and increased expression of 545 probes (corresponding to 348 genes). Many of the genes with reduced expression map to oligodendrocytes, and two of them (Fa2h and Ugt8a) are involved in the synthesis of myelin lipids. Many of the genes with increased expression map to microglia and lymphocytes, and to leukotriene/prostaglandin synthesis and chemokine/cytokine pathways. In accord, immunostaining showed activated microglia and astrocytes, as well as T- and B-cells in the cerebella of mutant mice. Thus, in addition to the loss of GJ coupling, there is a prominent immune response in mice lacking both Cx47 and Cx32. PMID:26051537

  5. Laminin regulates postnatal oligodendrocyte production by promoting oligodendrocyte progenitor survival in the subventricular zone.

    PubMed

    Relucio, Jenne; Menezes, Michael J; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi; Colognato, Holly

    2012-10-01

    The laminin family of extracellular matrix proteins are expressed broadly during embryonic brain development, but are enriched at ventricular and pial surfaces where laminins mediate radial glial attachment during corticogenesis. In the adult brain, however, laminin distribution is restricted, yet is found within the vascular basal lamina and associated fractones of the ventricular zone (VZ)-subventricular zone (SVZ) stem cell niche, where laminins regulate adult neural progenitor cell proliferation. It remains unknown, however, if laminins regulate the wave of oligodendrogenesis that occurs in the neonatal/early postnatal VZ-SVZ. Here we report that Lama2, the gene that encodes the laminin α2-subunit, regulates postnatal oligodendrogenesis. At birth, Lama2-/- mice had significantly higher levels of dying oligodendrocyte progenitor cells (OPCs) in the OPC germinal zone of the dorsal SVZ. This translated into fewer OPCs, both in the dorsal SVZ well as in an adjacent developing white matter tract, the corpus callosum. In addition, intermediate progenitor cells that give rise to OPCs in the Lama2-/- VZ-SVZ were mislocalized and proliferated nearer to the ventricle surface. Later, delays in oligodendrocyte maturation (with accompanying OPC accumulation), were observed in the Lama2-/- corpus callosum, leading to dysmyelination by postnatal day 21. Together these data suggest that prosurvival laminin interactions in the developing postnatal VZ-SVZ germinal zone regulate the ability, or timing, of oligodendrocyte production to occur appropriately.

  6. Epigenetic mechanisms facilitating oligodendrocyte development, maturation, and aging.

    PubMed

    Copray, Sjef; Huynh, Jimmy Long; Sher, Falak; Casaccia-Bonnefil, Patrizia; Boddeke, Erik

    2009-11-15

    The process of oligodendrocyte differentiation is regulated by a dynamic interaction between a genetic and an epigenetic program. Recent studies, addressing nucleosomal histone modifications have considerably increased our knowledge regarding epigenetic regulation of gene expression during oligodendrocyte development and aging. These results have generated new hypotheses regarding the mechanisms underlying the decreased efficiency of endogenous remyelination in response to demyelinating injuries with increasing age. In this review, we present an overview of the epigenetic mechanisms regulating gene expression at specific stages of oligodendrocyte differentiation and maturation as well as the changes that occur with aging.

  7. Oligodendrocyte precursor cells differentially expressing Nogo-A but not MAG are more permissive to neurite outgrowth than mature oligodendrocytes.

    PubMed

    Ma, Zhengwen; Cao, Qilin; Zhang, Liqun; Hu, Jianguo; Howard, Russell M; Lu, Peihua; Whittemore, Scott R; Xu, Xiao-Ming

    2009-05-01

    Grafting oligodendrocyte precursor cells (OPCs) has been used as a strategy to repair demyelination of the central nervous system (CNS). Whether OPCs can promote CNS axonal regeneration remains to be tested. If so, they should be permissive to axonal growth and may express less inhibitory molecules on their surface. Here we examined the expression of two oligodendrocyte-associated myelin inhibitors Nogo-A and myelin-associated glycoprotein (MAG) during oligodendrogliogenesis and tested their abilities to promote neurite outgrowth in vitro. Whereas the intracellular domain of Nogo-A was consistently expressed throughout oligodendrocyte differentiation, MAG was expressed only at later stages. Furthermore, the membrane-associated extracellular domain of Nogo-A was not expressed in OPCs but expressed in mature oligodendrocytes. In a dorsal root ganglion (DRG) and OPC/oligodendrocyte co-culture model, significantly greater DRG neurite outgrowth onto OPC monolayer than mature oligodendrocyte was found (1042+/-123 vs. 717+/-342 micrometer; p=0.011). Moreover, DRG neurites elongated as fasciculated fiber tracts and contacted directly on OPCs (133+/-37 cells/fascicle). In contrast, few, if any, direct contacts were found between DRG neurites and mature oligodendrocytes (5+/-3 cells/fascicle, p<0.001). In fact, acellular spaces were found between neurites and surrounding mature oligodendrocytes in contrast to the lack of such spaces in OPC/DRG coculture (51.1+/-16.5 vs. 2.4+/-3.9 micrometer; p<0.001). Thus, OPCs expressing neither extracellular domain of Nogo-A nor MAG are significantly more permissive than mature oligodendrocytes expressing both. Grafting OPCs may thus represent a feasible strategy to foster CNS axonal regeneration.

  8. Co-ultramicronized Palmitoylethanolamide/Luteolin Promotes the Maturation of Oligodendrocyte Precursor Cells.

    PubMed

    Barbierato, Massimo; Facci, Laura; Marinelli, Carla; Zusso, Morena; Argentini, Carla; Skaper, Stephen D; Giusti, Pietro

    2015-11-18

    Oligodendrocytes have limited ability to repair the damage to themselves or to other nerve cells, as seen in demyelinating diseases like multiple sclerosis. An important strategy may be to replace the lost oligodendrocytes and/or promote the maturation of undifferentiated oligodendrocyte precursor cells (OPCs). Recent studies show that a composite of co-ultramicronized N-palmitoylethanolamine (PEA) and luteolin (co-ultramicronized PEA/luteolin, 10:1 by mass) is efficacious in improving outcome in experimental models of spinal cord and traumatic brain injuries. Here, we examined the ability of co-ultramicronized PEA/luteolin to promote progression of OPCs into a more differentiated phenotype. OPCs derived from newborn rat cortex were placed in culture and treated the following day with 10 μM co-ultramicronized PEA/luteolin. Cells were collected 1, 4 and 8 days later and analyzed for expression of myelin basic protein (MBP). qPCR and Western blot analyses revealed a time-dependent increase in expression of both mRNA for MBP and MBP content, along with an increased expression of genes involved in lipid biogenesis. Ultramicronized PEA or luteolin, either singly or in simple combination, were ineffective. Further, co-ultramicronized PEA/luteolin promoted morphological development of OPCs and total protein content without affecting proliferation. Co-ultramicronized PEA/luteolin may represent a novel pharmacological strategy to promote OPC maturation.

  9. Co-ultramicronized Palmitoylethanolamide/Luteolin Promotes the Maturation of Oligodendrocyte Precursor Cells

    PubMed Central

    Barbierato, Massimo; Facci, Laura; Marinelli, Carla; Zusso, Morena; Argentini, Carla; Skaper, Stephen D.; Giusti, Pietro

    2015-01-01

    Oligodendrocytes have limited ability to repair the damage to themselves or to other nerve cells, as seen in demyelinating diseases like multiple sclerosis. An important strategy may be to replace the lost oligodendrocytes and/or promote the maturation of undifferentiated oligodendrocyte precursor cells (OPCs). Recent studies show that a composite of co-ultramicronized N-palmitoylethanolamine (PEA) and luteolin (co-ultramicronized PEA/luteolin, 10:1 by mass) is efficacious in improving outcome in experimental models of spinal cord and traumatic brain injuries. Here, we examined the ability of co-ultramicronized PEA/luteolin to promote progression of OPCs into a more differentiated phenotype. OPCs derived from newborn rat cortex were placed in culture and treated the following day with 10 μM co-ultramicronized PEA/luteolin. Cells were collected 1, 4 and 8 days later and analyzed for expression of myelin basic protein (MBP). qPCR and Western blot analyses revealed a time-dependent increase in expression of both mRNA for MBP and MBP content, along with an increased expression of genes involved in lipid biogenesis. Ultramicronized PEA or luteolin, either singly or in simple combination, were ineffective. Further, co-ultramicronized PEA/luteolin promoted morphological development of OPCs and total protein content without affecting proliferation. Co-ultramicronized PEA/luteolin may represent a novel pharmacological strategy to promote OPC maturation. PMID:26578323

  10. Oligodendrocyte lineage and subventricular zone response to traumatic axonal injury in the corpus callosum.

    PubMed

    Sullivan, Genevieve M; Mierzwa, Amanda J; Kijpaisalratana, Naruchorn; Tang, Haiying; Wang, Yong; Song, Sheng-Kwei; Selwyn, Reed; Armstrong, Regina C

    2013-12-01

    Traumatic brain injury frequently causes traumatic axonal injury (TAI) in white matter tracts. Experimental TAI in the corpus callosum of adult mice was used to examine the effects on oligodendrocyte lineage cells and myelin in conjunction with neuroimaging. The injury targeted the corpus callosum over the subventricular zone, a source of neural stem/progenitor cells. Traumatic axonal injury was produced in the rostral body of the corpus callosum by impact onto the skull at the bregma. During the first week after injury, magnetic resonance diffusion tensor imaging showed that axial diffusivity decreased in the corpus callosum and that corresponding regions exhibited significant axon damage accompanied by hypertrophic microglia and reactive astrocytes. Oligodendrocyte progenitor proliferation increased in the subventricular zone and corpus callosum. Oligodendrocytes in the corpus callosum shifted toward upregulation of myelin gene transcription. Plp/CreER(T):R26IAP reporter mice showed normal reporter labeling of myelin sheaths 0 to 2 days after injury but labeling was increased between 2 and 7 days after injury. Electron microscopy revealed axon degeneration, demyelination, and redundant myelin figures. These findings expand the cell types and responses to white matter injuries that inform diffusion tensor imaging evaluation and identify pivotal white matter changes after TAI that may affect axon vulnerability vs. recovery after brain injury.

  11. Oligodendrocyte Progenitor Cells Directly Utilize Lactate for Promoting Cell Cycling and Differentiation

    PubMed Central

    Ichihara, Yoshinori; Doi, Toru; Ryu, Youngjae; Nagao, Motoshi; Sawada, Yasuhiro

    2016-01-01

    Oligodendrocyte progenitor cells (OPCs) undergo marked morphological changes to become mature oligodendrocytes, but the metabolic resources for this process have not been fully elucidated. Although lactate, a metabolic derivative of glycogen, has been reported to be consumed in oligodendrocytes as a metabolite, and to ameliorate hypomyelination induced by low glucose conditions, it is not clear about the direct contribution of lactate to cell cycling and differentiation of OPCs, and the source of lactate for remyelination. Therefore, we evaluated the effect of 1,4‐dideoxy‐1,4‐imino‐d‐arabinitol (DAB), an inhibitor of the glycogen catabolic enzyme glycogen phosphorylase, in a mouse cuprizone model. Cuprizone induced demyelination in the corpus callosum and remyelination occurred after cuprizone treatment ceased. This remyelination was inhibited by the administration of DAB. To further examine whether lactate affects proliferation or differentiation of OPCs, we cultured mouse primary OPC‐rich cells and analyzed the effect of lactate. Lactate rescued the slowed cell cycling induced by 0.4 mM glucose, as assessed by the BrdU‐positive cell ratio. Lactate also promoted OPC differentiation detected by monitoring the mature oligodendrocyte marker myelin basic protein, in the presence of both 36.6 mM and 0.4 mM glucose. Furthermore, these lactate‐mediated effects were suppressed by the reported monocarboxylate transporter inhibitor, α‐cyano‐4‐hydroxy‐cinnamate. These results suggest that lactate directly promotes the cell cycling rate and differentiation of OPCs, and that glycogen, one of the sources of lactate, contributes to remyelination in vivo. J. Cell. Physiol. 232: 986–995, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. PMID:27861886

  12. Oligodendrocyte Progenitor Cells Directly Utilize Lactate for Promoting Cell Cycling and Differentiation.

    PubMed

    Ichihara, Yoshinori; Doi, Toru; Ryu, Youngjae; Nagao, Motoshi; Sawada, Yasuhiro; Ogata, Toru

    2017-05-01

    Oligodendrocyte progenitor cells (OPCs) undergo marked morphological changes to become mature oligodendrocytes, but the metabolic resources for this process have not been fully elucidated. Although lactate, a metabolic derivative of glycogen, has been reported to be consumed in oligodendrocytes as a metabolite, and to ameliorate hypomyelination induced by low glucose conditions, it is not clear about the direct contribution of lactate to cell cycling and differentiation of OPCs, and the source of lactate for remyelination. Therefore, we evaluated the effect of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), an inhibitor of the glycogen catabolic enzyme glycogen phosphorylase, in a mouse cuprizone model. Cuprizone induced demyelination in the corpus callosum and remyelination occurred after cuprizone treatment ceased. This remyelination was inhibited by the administration of DAB. To further examine whether lactate affects proliferation or differentiation of OPCs, we cultured mouse primary OPC-rich cells and analyzed the effect of lactate. Lactate rescued the slowed cell cycling induced by 0.4 mM glucose, as assessed by the BrdU-positive cell ratio. Lactate also promoted OPC differentiation detected by monitoring the mature oligodendrocyte marker myelin basic protein, in the presence of both 36.6 mM and 0.4 mM glucose. Furthermore, these lactate-mediated effects were suppressed by the reported monocarboxylate transporter inhibitor, α-cyano-4-hydroxy-cinnamate. These results suggest that lactate directly promotes the cell cycling rate and differentiation of OPCs, and that glycogen, one of the sources of lactate, contributes to remyelination in vivo. J. Cell. Physiol. 232: 986-995, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

  13. Anti-Muscarinic Adjunct Therapy Accelerates Functional Human Oligodendrocyte Repair

    PubMed Central

    Abiraman, Kavitha; Pol, Suyog U.; O'Bara, Melanie A.; Chen, Guang-Di; Khaku, Zainab M.; Wang, Jing; Thorn, David; Vedia, Bansi H.; Ekwegbalu, Ezinne C.; Li, Jun-Xu; Salvi, Richard J.

    2015-01-01

    Therapeutic repair of myelin disorders may be limited by the relatively slow rate of human oligodendrocyte differentiation. To identify appropriate pharmacological targets with which to accelerate differentiation of human oligodendrocyte progenitors (hOPCs) directly, we used CD140a/O4-based FACS of human forebrain and microarray to hOPC-specific receptors. Among these, we identified CHRM3, a M3R muscarinic acetylcholine receptor, as being restricted to oligodendrocyte-biased CD140a+O4+ cells. Muscarinic agonist treatment of hOPCs resulted in a specific and dose-dependent blockade of oligodendrocyte commitment. Conversely, when hOPCs were cocultured with human neurons, M3R antagonist treatment stimulated oligodendrocytic differentiation. Systemic treatment with solifenacin, an FDA-approved muscarinic receptor antagonist, increased oligodendrocyte differentiation of transplanted hOPCs in hypomyelinated shiverer/rag2 brain. Importantly, solifenacin treatment of engrafted animals reduced auditory brainstem response interpeak latency, indicative of increased conduction velocity and thereby enhanced functional repair. Therefore, solifenacin and other selective muscarinic antagonists represent new adjunct approaches to accelerate repair by engrafted human progenitors. PMID:25716865

  14. Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes

    PubMed Central

    Steiner, Johann; Martins-de-Souza, Daniel; Schiltz, Kolja; Sarnyai, Zoltan; Westphal, Sabine; Isermann, Berend; Dobrowolny, Henrik; Turck, Christoph W.; Bogerts, Bernhard; Bernstein, Hans-Gert; Horvath, Tamas L.; Schild, Lorenz; Keilhoff, Gerburg

    2014-01-01

    Clozapine displays stronger systemic metabolic side effects than haloperidol and it has been hypothesized that therapeutic antipsychotic and adverse metabolic effects of these drugs are related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production. Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT) and monocarboxylate (MCT) transporters was determined after 6 and 24 h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed. Both drugs altered oligodendrocyte glucose metabolism, but in opposite directions. Clozapine improved the glucose uptake, production and release of lactate, without altering GLUT and MCT. In contrast, haloperidol led to higher extracellular levels of glucose and lower levels of lactate, suggesting reduced glycolysis. Antipsychotics did not alter significantly the number of functionally intact mitochondria, but clozapine enhanced the efficacy of oxidative phosphorylation and expression of galactocerebroside. Our findings support the superior impact of clozapine on white matter integrity in schizophrenia as previously observed, suggesting that this drug improves the energy supply and myelin lipid synthesis in oligodendrocytes. Characterizing the underlying signal transduction pathways may pave the way for novel oligodendrocyte-directed schizophrenia therapies. PMID:25477781

  15. Subtype-specific oligodendrocyte dynamics in organotypic culture.

    PubMed

    Haber, Michael; Vautrin, Sandrine; Fry, Elizabeth J; Murai, Keith K

    2009-07-01

    The morphogenesis of oligodendrocytes is essential for central nervous system myelin formation and the rapid propagation of axon potentials through saltatory conduction. However, the discrete cellular events involved in the three-dimensional maturation of oligodendrocytes remain to be fully described. To address this, we followed the developmental stages of oligodendrocytes in mouse organotypic hippocampal slice cultures for 7-60 days using viral-mediated gene delivery of membrane-targeted fluorescent proteins. Using static and time-lapse confocal imaging, we find that postmigratory NG2-expressing cells exhibit slow anatomical reorganization over the course of hours. This is in direct contrast to oligodendrocytes that take on a promyelinating and transitional phenotype, which display a more complex morphology and undergo dramatic actin-dependent structural remodeling over just minutes. More mature myelinating oligodendrocytes, which have pruned most of their processes, still retain some local remodeling behavior at developing internodes, but in general, revert to a relatively stable state. Our findings provide a detailed characterization of cellular events that help shape oligodendrocyte morphology and likely participate in neuron-glial cell interactions and the process of myelination.

  16. Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes

    PubMed Central

    Matute, Carlos; Sánchez-Gómez, M. Victoria; Martínez-Millán, Luis; Miledi, Ricardo

    1997-01-01

    In cultured oligodendrocytes isolated from perinatal rat optic nerves, we have analyzed the expression of ionotropic glutamate receptor subunits as well as the effect of the activation of these receptors on oligodendrocyte viability. Reverse transcription–PCR, in combination with immunocytochemistry, demonstrated that most oligodendrocytes differentiated in vitro express the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR3 and GluR4 and the kainate receptor subunits GluR6, GluR7, KA1 and KA2. Acute and chronic exposure to kainate caused extensive oligodendrocyte death in culture. This effect was partially prevented by the AMPA receptor antagonist GYKI 52466 and was completely abolished by the non-N-methyl-d-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), suggesting that both AMPA and kainate receptors mediate the observed kainate toxicity. Furthermore, chronic application of kainate to optic nerves in vivo resulted in massive oligodendrocyte death which, as in vitro, could be prevented by coinfusion of the toxin with CNQX. These findings suggest that excessive activation of the ionotropic glutamate receptors expressed by oligodendrocytes may act as a negative regulator of the size of this cell population. PMID:9238063

  17. Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes.

    PubMed

    Steiner, Johann; Martins-de-Souza, Daniel; Schiltz, Kolja; Sarnyai, Zoltan; Westphal, Sabine; Isermann, Berend; Dobrowolny, Henrik; Turck, Christoph W; Bogerts, Bernhard; Bernstein, Hans-Gert; Horvath, Tamas L; Schild, Lorenz; Keilhoff, Gerburg

    2014-01-01

    Clozapine displays stronger systemic metabolic side effects than haloperidol and it has been hypothesized that therapeutic antipsychotic and adverse metabolic effects of these drugs are related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production. Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT) and monocarboxylate (MCT) transporters was determined after 6 and 24 h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed. Both drugs altered oligodendrocyte glucose metabolism, but in opposite directions. Clozapine improved the glucose uptake, production and release of lactate, without altering GLUT and MCT. In contrast, haloperidol led to higher extracellular levels of glucose and lower levels of lactate, suggesting reduced glycolysis. Antipsychotics did not alter significantly the number of functionally intact mitochondria, but clozapine enhanced the efficacy of oxidative phosphorylation and expression of galactocerebroside. Our findings support the superior impact of clozapine on white matter integrity in schizophrenia as previously observed, suggesting that this drug improves the energy supply and myelin lipid synthesis in oligodendrocytes. Characterizing the underlying signal transduction pathways may pave the way for novel oligodendrocyte-directed schizophrenia therapies.

  18. Microwave Ablation Compared with Radiofrequency Ablation for Breast Tissue in an Ex Vivo Bovine Udder Model

    SciTech Connect

    Tanaka, Toshihiro; Westphal, Saskia; Isfort, Peter; Braunschweig, Till; Penzkofer, Tobias Bruners, Philipp; Kichikawa, Kimihiko; Schmitz-Rode, Thomas Mahnken, Andreas H.

    2012-08-15

    Purpose: To compare the effectiveness of microwave (MW) ablation with radiofrequency (RF) ablation for treating breast tissue in a nonperfused ex vivo model of healthy bovine udder tissue. Materials and Methods: MW ablations were performed at power outputs of 25W, 35W, and 45W using a 915-MHz frequency generator and a 2-cm active tip antenna. RF ablations were performed with a bipolar RF system with 2- and 3-cm active tip electrodes. Tissue temperatures were continuously monitored during ablation. Results: The mean short-axis diameters of the coagulation zones were 1.34 {+-} 0.14, 1.45 {+-} 0.13, and 1.74 {+-} 0.11 cm for MW ablation at outputs of 25W, 35W, and 45W. For RF ablation, the corresponding values were 1.16 {+-} 0.09 and 1.26 {+-} 0.14 cm with electrodes having 2- and 3-cm active tips, respectively. The mean coagulation volumes were 2.27 {+-} 0.65, 2.85 {+-} 0.72, and 4.45 {+-} 0.47 cm{sup 3} for MW ablation at outputs of 25W, 35W, and 45W and 1.18 {+-} 0.30 and 2.29 {+-} 0.55 cm{sup 3} got RF ablation with 2- and 3-cm electrodes, respectively. MW ablations at 35W and 45W achieved significantly longer short-axis diameters than RF ablations (P < 0.05). The highest tissue temperature was achieved with MW ablation at 45W (P < 0.05). On histological examination, the extent of the ablation zone in MW ablations was less affected by tissue heterogeneity than that in RF ablations. Conclusion: MW ablation appears to be advantageous with respect to the volume of ablation and the shape of the margin of necrosis compared with RF ablation in an ex vivo bovine udder.

  19. Karyopherin Alpha Proteins Regulate Oligodendrocyte Differentiation

    PubMed Central

    Mariani, John N.; Zhang, Chi; Sawai, Setsu; John, Gareth R.

    2017-01-01

    Proper regulation of the coordinated transcriptional program that drives oligodendrocyte (OL) differentiation is essential for central nervous system myelin formation and repair. Nuclear import, mediated in part by a group of karyopherin alpha (Kpna) proteins, regulates transcription factor access to the genome. Understanding how canonical nuclear import functions to control genomic access in OL differentiation may aid in the creation of novel therapeutics to stimulate myelination and remyelination. Here, we show that members of the Kpna family regulate OL differentiation, and may play distinct roles downstream of different pro-myelinating stimuli. Multiple family members are expressed in OLs, and their pharmacologic inactivation dose-dependently decreases the rate of differentiation. Additionally, upon differentiation, the three major Kpna subtypes (P/α2, Q/α3, S/α1) display differential responses to the pro-myelinating cues T3 and CNTF. Most notably, the Q/α3 karyopherin Kpna4 is strongly upregulated by CNTF treatment both compared with T3 treatment and other Kpna responses. Kpna4 inactivation results in inhibition of CNTF-induced OL differentiation, in the absence of changes in proliferation or viability. Collectively, these findings suggest that canonical nuclear import is an integral component of OL differentiation, and that specific Kpnas may serve vital and distinct functions downstream of different pro-myelinating cues. PMID:28107514

  20. Modulation of Oligodendrocyte Differentiation by Mechanotransduction

    PubMed Central

    Lourenço, Tânia; Grãos, Mário

    2016-01-01

    Oligodendrocytes (OLs) are responsible for the myelination of axons in the central nervous system (CNS). The differentiation of OLs encompasses several stages, through which cells undergo dramatic biochemical and morphological changes. OL differentiation is modulated by soluble factors (SFs)—such as growth factors and hormones—, known to be essential for each maturation stage. Besides SFs, insoluble factors such as extracellular matrix (ECM) proteins and other microenvironmental elements also play a pivotal role during OL differentiation. Recently, a growing number of studies were published concerning the effect of biophysical properties of the extracellular milieu on OL differentiation and myelination, showing the importance of ECM stiffness and topography, strain forces and spatial constraints. For instance, it was shown in vitro that OL differentiation and maturation is enhanced by substrates within the reported range of stiffness of the brain and that this effect is potentiated by the presence of merosin, whereas the myelination process is influenced by the diameter of axonal-like fibers. In this mini review article, we will discuss the effect of mechanical cues during OL differentiation and the possible molecular mechanisms involved in such regulation. PMID:27965541

  1. Karyopherin Alpha Proteins Regulate Oligodendrocyte Differentiation.

    PubMed

    Laitman, Benjamin M; Mariani, John N; Zhang, Chi; Sawai, Setsu; John, Gareth R

    2017-01-01

    Proper regulation of the coordinated transcriptional program that drives oligodendrocyte (OL) differentiation is essential for central nervous system myelin formation and repair. Nuclear import, mediated in part by a group of karyopherin alpha (Kpna) proteins, regulates transcription factor access to the genome. Understanding how canonical nuclear import functions to control genomic access in OL differentiation may aid in the creation of novel therapeutics to stimulate myelination and remyelination. Here, we show that members of the Kpna family regulate OL differentiation, and may play distinct roles downstream of different pro-myelinating stimuli. Multiple family members are expressed in OLs, and their pharmacologic inactivation dose-dependently decreases the rate of differentiation. Additionally, upon differentiation, the three major Kpna subtypes (P/α2, Q/α3, S/α1) display differential responses to the pro-myelinating cues T3 and CNTF. Most notably, the Q/α3 karyopherin Kpna4 is strongly upregulated by CNTF treatment both compared with T3 treatment and other Kpna responses. Kpna4 inactivation results in inhibition of CNTF-induced OL differentiation, in the absence of changes in proliferation or viability. Collectively, these findings suggest that canonical nuclear import is an integral component of OL differentiation, and that specific Kpnas may serve vital and distinct functions downstream of different pro-myelinating cues.

  2. IKAP Deficiency in an FD Mouse Model and in Oligodendrocyte Precursor Cells Results in Downregulation of Genes Involved in Oligodendrocyte Differentiation and Myelin Formation

    PubMed Central

    Cheishvili, David; Dietrich, Paula; Maayan, Channa; Even, Aviel; Weil, Miguel; Dragatsis, Ioannis; Razin, Aharon

    2014-01-01

    The splice site mutation in the IKBKAP gene coding for IKAP protein leads to the tissue-specific skipping of exon 20, with concomitant reduction in IKAP protein production. This causes the neurodevelopmental, autosomal-recessive genetic disorder - Familial Dysautonomia (FD). The molecular hallmark of FD is the severe reduction of IKAP protein in the nervous system that is believed to be the main reason for the devastating symptoms of this disease. Our recent studies showed that in the brain of two FD patients, genes linked to oligodendrocyte differentiation and/or myelin formation are significantly downregulated, implicating IKAP in the process of myelination. However, due to the scarcity of FD patient tissues, these results awaited further validation in other models. Recently, two FD mouse models that faithfully recapitulate FD were generated, with two types of mutations resulting in severely low levels of IKAP expression. Here we demonstrate that IKAP deficiency in these FD mouse models affects a similar set of genes as in FD patients' brains. In addition, we identified two new IKAP target genes involved in oligodendrocyte cells differentiation and myelination, further underscoring the essential role of IKAP in this process. We also provide proof that IKAP expression is needed cell-autonomously for the regulation of expression of genes involved in myelin formation since knockdown of IKAP in the Oli-neu oligodendrocyte precursor cell line results in similar deficiencies. Further analyses of these two experimental models will compensate for the lack of human postmortem tissues and will advance our understanding of the role of IKAP in myelination and the disease pathology. PMID:24760006

  3. Colitogenic role of tumour necrosis factor (TNF) receptors in trinitrobenzene sulphonic acid colitis: TNF-R1 ablation does not affect systemic inflammatory response.

    PubMed

    Yang, Y; Wang, H; Dou, Y; Wang, Y; Han, G; Wang, Renxi; Wang, L; Guo, R; Xiao, H; Li, X; Shen, B; Shi, Y; Chen, G; Li, Y

    2011-09-01

    Tumour necrosis factor (TNF)-α plays a critical role in the pathogenesis of T helper type 1-mediated colitis such as Crohn's disease. However, the roles of its two receptors in mediating pathology remain largely unknown. In this study, trinitrobenzene sulphonic acid (TNBS) was used to induce colitis in TNF-receptor single or double knock-out (DKO) BALB/c mice and in wild-type counterparts. TNF-R1(-/-) mice had significantly less weight loss, reduced mortality, colon shortening and oedema, colon histological damage and lower levels of colon myeloperoxidase compared with wild-type (WT) BALB/c mice. A similar manifestation was also observed in TNF-R2(-/-) and TNF-R1(-/-) TNF-R2(-/-) (TNF-R DKO) mice. Strikingly, systemic inflammatory response (including splenomegaly and monocyte expansion) was found in WT and TNF-R1(-/-) mice after TNBS, instead of TNF-R2(-/-) and TNF-R DKO mice. Attenuated pathology of colitis in TNF-R1(-/-) or TNF-R2(-/-) mice correlated with lower amounts of interleukin (IL)-6, IL-1β, monocyte chemotactic protein (MCP)-1, IL-12p70 and interferon (IFN)-γ production in the colons. Importantly, ablation of TNF-R1 or TNF-R2 reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL)-positive apoptotic epithelial cells in the affected colons compared with WT TNBS-instilled controls, which might be due to the heightened ratio of Bcl-2/Bax and reduced activity of nuclear factor (NF)-κB. These findings suggest that either TNF-R1 or TNF-R2 plays a pathogenic role in the pathology of colitis and TNF signalling via TNF-R1 or TNF-R2 alone is not sufficient for inducing mucosal damage.

  4. Differentiation of oligodendrocytes cultured from developing rat brain is enhanced by exogenous GM3 ganglioside.

    PubMed

    Yim, S H; Farrer, R G; Hammer, J A; Yavin, E; Quarles, R H

    1994-06-15

    incorporation into myelin basic protein (MBP) was not affected. Although the overall effect of added GM3 was to decrease the phosphorylation of most proteins in the oligodendrocytes, including MBP, GM3 enhanced the phosphorylation of MAG. These findings indicate that GM3 ganglioside has an important role in the differentiation of cells of the O-2A lineage toward myelin production, since differentiation is associated with increased metabolic labeling of endogenous GM3 in control cultures and is enhanced by the addition of exogenous GM3.

  5. Rapid production of new oligodendrocytes is required in the earliest stages of motor skill learning

    PubMed Central

    McKenzie, Ian A.; Sinclair-Wilson, Alexander; Wright, Jordan L.; Fudge, Alexander D.; Emery, Ben; Li, Huiliang; Richardson, William D

    2016-01-01

    Summary We identified a novel marker of newly-forming oligodendrocytes – the ecto-enzyme Enpp6 – and used this to track oligodendrocyte differentiation in adult mice as they learned a motor skill (running on a wheel with unevenly spaced rungs). Production of Enpp6 - expressing immature oligodendrocytes was accelerated within just 2.5 hours exposure to the complex wheel in subcortical white matter and within 4 hours in motor cortex. Conditional deletion of Myelin regulatory factor (Myrf) in oligodendrocyte precursors blocked formation of new Enpp6+ oligodendrocytes and impaired learning within the same ~2-3 hour time frame. This very early requirement for oligodendrocytes suggests a direct and active role in learning, closely linked to synaptic strengthening. Running performance of normal mice continued to improve over the following week accompanied by secondary waves of oligodendrocyte precursor proliferation and differentiation. We conclude that new oligodendrocytes contribute to both early and late stages of motor skill learning. PMID:27455109

  6. Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system

    PubMed Central

    Codeluppi, Simone; van Bruggen, David; Mendanha Falcão, Ana; Xiao, Lin; Li, Huiliang; Häring, Martin; Hochgerner, Hannah; Romanov, Roman A.; Gyllborg, Daniel; Muñoz Manchado, Ana; La Manno, Gioele; Lönnerberg, Peter; Floriddia, Elisa M.; Rezayee, Fatemah; Ernfors, Patrik; Arenas, Ernest; Hjerling-Leffler, Jens; Harkany, Tibor; Richardson, William D.; Linnarsson, Sten; Castelo-Branco, Gonçalo

    2016-01-01

    Oligodendrocytes have been considered as a functionally homogenous population in the central nervous system (CNS). We performed single-cell RNA-Seq on 5072 cells of the oligodendrocyte lineage from ten regions of the mouse juvenile/adult CNS. Twelve populations were identified, representing a continuum from Pdgfra+ oligodendrocyte precursors (OPCs) to distinct mature oligodendrocytes. Initial stages of differentiation were similar across the juvenile CNS, whereas subsets of mature oligodendrocytes were enriched in specific regions in the adult brain. Newly-formed oligodendrocytes were found to be resident in the adult CNS and responsive to complex motor learning. A second Pdgfra+ population, distinct from OPCs, was found along vessels. Our study reveals the dynamics of oligodendrocyte differentiation and maturation, uncoupling them at a transcriptional level and highlighting oligodendrocyte heterogeneity in the CNS. PMID:27284195

  7. Olig1 Acetylation and Nuclear Export Mediate Oligodendrocyte Development

    PubMed Central

    Dai, Jinxiang; Bercury, Kathryn K.; Jin, Weilin

    2015-01-01

    The oligodendrocyte transcription factor Olig1 is critical for both oligodendrocyte development and remyelination in mice. Nuclear to cytoplasmic translocation of Olig1 protein occurs during brain development and in multiple sclerosis, but the detailed molecular mechanism of this translocation remains elusive. Here, we report that Olig1 acetylation and deacetylation drive its active translocation between the nucleus and the cytoplasm in both mouse and rat oligodendrocytes. We identified three functional nuclear export sequences (NES) localized in the basic helix-loop-helix domain and one specific acetylation site at Lys 150 (human Olig1) in NES1. Olig1 acetylation and deacetylation are regulated by the acetyltransferase CREB-binding protein and the histone deacetylases HDAC1, HDAC3, and HDAC10. Acetylation of Olig1 decreased its chromatin association, increased its interaction with inhibitor of DNA binding 2 and facilitated its retention in the cytoplasm of mature oligodendrocytes. These studies establish that acetylation of Olig1 regulates its chromatin dissociation and subsequent translocation to the cytoplasm and is required for its function in oligodendrocyte maturation. SIGNIFICANCE STATEMENT The nuclear to cytoplasmic translocation of Olig1 protein has been observed during mouse and human brain development and in multiple sclerosis in several studies, but the detailed molecular mechanism of this translocation remains elusive. Here, we provide insight into the mechanism by which acetylation of Olig1 regulates its unique nuclear-cytoplasmic shuttling during oligodendrocyte development and how the acetylation status of Olig1 modulates its distinct function in the nucleus versus the cytoplasm. The current study provides a unique example of a lineage-specific transcription factor that is actively translocated from the nucleus to the cytoplasm as the cell differentiates. Importantly, we demonstrate that this process is tightly controlled by acetylation at a single

  8. Methylprednisolone protects oligodendrocytes but not neurons following spinal cord injury

    PubMed Central

    Lee, Jin-Moo; Yan, Ping; Xiao, Qingli; Chen, Shawei; Lee, Kuang-Yung; Hsu, Chung Y.; Xu, Jan

    2009-01-01

    Methylprednisolone (MP) is used to treat a variety of neurological disorders involving white matter injury, including multiple sclerosis, acute disseminated encephalomyelitis, and spinal cord injury (SCI). While its mechanism of action has been attributed to anti-inflammatory or anti-oxidant properties, we examined the possibility that MP may have direct neuroprotective activities. Neurons and oligodendrocytes treated with AMPA (alpha-amino-3-hydroxy-5- methylisoxazole-4-propionate) or staurosporine died within 24 hrs after treatment. MP attenuated oligodendrocyte death in a dose-dependent manner; however, neurons were not rescued by the same doses of MP. This protective effect was reversed by the glucocorticoid receptor (GR) antagonist, RU486, and siRNA directed against GR, suggesting a receptor-dependent mechanism. MP reversed AMPA-induced decreases in the expression of antiapoptotic Bcl-xL, caspase-3 activation, and DNA laddering, suggesting anti-apoptotic activity in oligodendrocytes. To examine if MP demonstrated this selective protection in vivo, neuronal and oligodendrocyte survival was assessed in rats subjected to SCI; groups of rats were treated with or without MP in the presence or absence of RU486. Eight days after SCI, MP significantly increased oligodendrocytes (CC-1 immunoreactive cells) following SCI, but neuronal (NeuN immunoreactive cells) number remained unchanged; RU486 reversed this protective effect. MP also inhibited SCI-induced decreases in Bcl-xL and caspase-3 activation. Consistent with these findings, the volume of demyelination, assessed by Luxol Fast Blue staining, was attenuated by MP and reversed by RU486. These results suggest that MP selectively inhibits oligodendrocyte but not neuronal cell death via a receptor-mediated action, and may be a mechanism for its limited protective effect following SCI. PMID:18354017

  9. Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation

    PubMed Central

    Jäkel, Sarah; Dimou, Leda

    2017-01-01

    Glial cells, consisting of microglia, astrocytes, and oligodendrocyte lineage cells as their major components, constitute a large fraction of the mammalian brain. Originally considered as purely non-functional glue for neurons, decades of research have highlighted the importance as well as further functions of glial cells. Although many aspects of these cells are well characterized nowadays, the functions of the different glial populations in the brain under both physiological and pathological conditions remain, at least to a certain extent, unresolved. To tackle these important questions, a broad range of depletion approaches have been developed in which microglia, astrocytes, or oligodendrocyte lineage cells (i.e., NG2-glia and oligodendrocytes) are specifically ablated from the adult brain network with a subsequent analysis of the consequences. As the different glial populations are very heterogeneous, it is imperative to specifically ablate single cell populations instead of inducing cell death in all glial cells in general. Thanks to modern genetic manipulation methods, the approaches can now directly be targeted to the cell type of interest making the ablation more specific compared to general cell ablation approaches that have been used earlier on. In this review, we will give a detailed summary on different glial ablation studies, focusing on the adult mouse central nervous system and the functional readouts. We will also provide an outlook on how these approaches could be further exploited in the future. PMID:28243193

  10. Differentiation of oligodendrocyte progenitor cells from dissociated monolayer and feeder-free cultured pluripotent stem cells

    PubMed Central

    Miyamoto, Yuki; Bando, Yoshio; Ono, Takashi; Kobayashi, Sakurako; Doi, Ayano; Araki, Toshihiro; Kato, Yosuke; Shirakawa, Takayuki; Suzuki, Yutaka; Yamauchi, Junji; Yoshida, Shigetaka; Sato, Naoya

    2017-01-01

    Oligodendrocytes myelinate axons and form myelin sheaths in the central nervous system. The development of therapies for demyelinating diseases, including multiple sclerosis and leukodystrophies, is a challenge because the pathogenic mechanisms of disease remain poorly understood. Primate pluripotent stem cell-derived oligodendrocytes are expected to help elucidate the molecular pathogenesis of these diseases. Oligodendrocytes have been successfully differentiated from human pluripotent stem cells. However, it is challenging to prepare large amounts of oligodendrocytes over a short amount of time because of manipulation difficulties under conventional primate pluripotent stem cell culture methods. We developed a proprietary dissociated monolayer and feeder-free culture system to handle pluripotent stem cell cultures. Because the dissociated monolayer and feeder-free culture system improves the quality and growth of primate pluripotent stem cells, these cells could potentially be differentiated into any desired functional cells and consistently cultured in large-scale conditions. In the current study, oligodendrocyte progenitor cells and mature oligodendrocytes were generated within three months from monkey embryonic stem cells. The embryonic stem cell-derived oligodendrocytes exhibited in vitro myelinogenic potency with rat dorsal root ganglion neurons. Additionally, the transplanted oligodendrocyte progenitor cells differentiated into myelin basic protein-positive mature oligodendrocytes in the mouse corpus callosum. This preparative method was used for human induced pluripotent stem cells, which were also successfully differentiated into oligodendrocyte progenitor cells and mature oligodendrocytes that were capable of myelinating rat dorsal root ganglion neurons. Moreover, it was possible to freeze, thaw, and successfully re-culture the differentiating cells. These results showed that embryonic stem cells and human induced pluripotent stem cells maintained in a

  11. Differentiation of oligodendrocyte progenitor cells from dissociated monolayer and feeder-free cultured pluripotent stem cells.

    PubMed

    Yamashita, Tomoko; Miyamoto, Yuki; Bando, Yoshio; Ono, Takashi; Kobayashi, Sakurako; Doi, Ayano; Araki, Toshihiro; Kato, Yosuke; Shirakawa, Takayuki; Suzuki, Yutaka; Yamauchi, Junji; Yoshida, Shigetaka; Sato, Naoya

    2017-01-01

    Oligodendrocytes myelinate axons and form myelin sheaths in the central nervous system. The development of therapies for demyelinating diseases, including multiple sclerosis and leukodystrophies, is a challenge because the pathogenic mechanisms of disease remain poorly understood. Primate pluripotent stem cell-derived oligodendrocytes are expected to help elucidate the molecular pathogenesis of these diseases. Oligodendrocytes have been successfully differentiated from human pluripotent stem cells. However, it is challenging to prepare large amounts of oligodendrocytes over a short amount of time because of manipulation difficulties under conventional primate pluripotent stem cell culture methods. We developed a proprietary dissociated monolayer and feeder-free culture system to handle pluripotent stem cell cultures. Because the dissociated monolayer and feeder-free culture system improves the quality and growth of primate pluripotent stem cells, these cells could potentially be differentiated into any desired functional cells and consistently cultured in large-scale conditions. In the current study, oligodendrocyte progenitor cells and mature oligodendrocytes were generated within three months from monkey embryonic stem cells. The embryonic stem cell-derived oligodendrocytes exhibited in vitro myelinogenic potency with rat dorsal root ganglion neurons. Additionally, the transplanted oligodendrocyte progenitor cells differentiated into myelin basic protein-positive mature oligodendrocytes in the mouse corpus callosum. This preparative method was used for human induced pluripotent stem cells, which were also successfully differentiated into oligodendrocyte progenitor cells and mature oligodendrocytes that were capable of myelinating rat dorsal root ganglion neurons. Moreover, it was possible to freeze, thaw, and successfully re-culture the differentiating cells. These results showed that embryonic stem cells and human induced pluripotent stem cells maintained in a

  12. Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in vanishing white matter disease.

    PubMed

    Bugiani, Marianna; Postma, Nienke; Polder, Emiel; Dieleman, Nikki; Scheffer, Peter G; Sim, Fraser J; van der Knaap, Marjo S; Boor, Ilja

    2013-01-01

    Vanishing white matter disease is a genetic leukoencephalopathy caused by mutations in eukaryotic translation initiation factor 2B. Patients experience a slowly progressive neurological deterioration with episodes of rapid clinical worsening triggered by stress. The disease may occur at any age and leads to early death. Characteristic neuropathological findings include cystic degeneration of the white matter with feeble, if any, reactive gliosis, dysmorphic astrocytes and paucity of myelin despite an increase in oligodendrocytic density. These features have been linked to a maturation defect of astrocytes and oligodendrocytes. However, the nature of the link between glial immaturity and the observed neuropathological features is unclear. We hypothesized that the defects in maturation and function of astrocytes and oligodendrocytes are related. Brain tissue of seven patients with genetically proven vanishing white matter disease was investigated using immunohistochemistry, western blotting, quantitative polymerase chain reaction and size exclusion chromatography. The results were compared with those obtained from normal brain tissue of age-matched controls, from chronic demyelinated multiple sclerosis lesions and from other genetic and acquired white matter disorders. We found that the white matter of patients with vanishing white matter disease is enriched in CD44-expressing astrocyte precursor cells and accumulates the glycosaminoglycan hyaluronan. Hyaluronan is a major component of the extracellular matrix, and CD44 is a hyaluronan receptor. We found that a high molecular weight form of hyaluronan is overabundant, especially in the most severely affected areas. Comparison between the more severely affected frontal white matter and the relatively spared cerebellum confirms that high molecular weight hyaluronan accumulation is more pronounced in the frontal white matter than in the cerebellum. High molecular weight hyaluronan is known to inhibit astrocyte and

  13. FGF plays a subtle role in oligodendrocyte maintenance in vivo.

    PubMed

    Harari, D; Finkelstein, D; Bernard, O

    1997-08-15

    Numerous in vitro studies indicate that fibroblast growth factors (FGFs) play a role in both the development and maintenance of oligodendrocytes. Addition of FGF to mature oligodendrocytes in culture was reported to downregulate the expression of genes encoding proteins of the myelin sheath and to induce a loss of myelin compaction. In this study, a model was developed to functionally block FGF signaling in oligodendrocytes in vivo, by generating transgenic mice expressing a dominant-negative FGF receptor (FGFR1), under the control of the myelin basic protein (MBP) promoter. To demonstrate the effectiveness of this model, truncated FGFR1 was first overexpressed in an FGF-responsive cell line in vitro. It was confirmed that FGF-signalling was blocked in these cells. Subsequently, five independent transgenic lines ("MBP-FRD") were generated. Three lines expressing the highest level of the transgene were further studied. Initial investigation by Western blot and light microscopic analyses revealed no apparent alterations in myelination of the MBP-FRD mouse brains. However, ultrastructural analysis of myelinated optic nerve fibres from two independent MBP-FRD lines revealed a significant increase in myelin thickness as a function of fibre diameter for both transgenic lines (13% and 16% increase). This increase in myelin thickness was not accompanied by alterations in myelin compaction. These results support the idea that FGF signaling in oligodendrocytes plays a role in the modulation of axon myelination in vivo.

  14. Systematic Review of Pharmacological Properties of the Oligodendrocyte Lineage

    PubMed Central

    Marinelli, Carla; Bertalot, Thomas; Zusso, Morena; Skaper, Stephen D.; Giusti, Pietro

    2016-01-01

    Oligodendrogenesis and oligodendrocyte precursor maturation are essential processes during the course of central nervous system development, and lead to the myelination of axons. Cells of the oligodendrocyte lineage are generated in the germinal zone from migratory bipolar oligodendrocyte precursor cells (OPCs), and acquire cell surface markers as they mature and respond specifically to factors which regulate proliferation, migration, differentiation, and survival. Loss of myelin underlies a wide range of neurological disorders, some of an autoimmune nature—multiple sclerosis probably being the most prominent. Current therapies are based on the use of immunomodulatory agents which are likely to promote myelin repair (remyelination) indirectly by subverting the inflammatory response, aspects of which impair the differentiation of OPCs. Cells of the oligodendrocyte lineage express and are capable of responding to a diverse array of ligand-receptor pairs, including neurotransmitters and nuclear receptors such as γ-aminobutyric acid, glutamate, adenosine triphosphate, serotonin, acetylcholine, nitric oxide, opioids, prostaglandins, prolactin, and cannabinoids. The intent of this review is to provide the reader with a synopsis of our present state of knowledge concerning the pharmacological properties of the oligodendrocyte lineage, with particular attention to these receptor-ligand (i.e., neurotransmitters and nuclear receptor) interactions that can influence oligodendrocyte migration, proliferation, differentiation, and myelination, and an appraisal of their therapeutic potential. For example, many promising mediators work through Ca2+ signaling, and the balance between Ca2+ influx and efflux can determine the temporal and spatial properties of oligodendrocytes (OLs). Moreover, Ca2+ signaling in OPCs can influence not only differentiation and myelination, but also process extension and migration, as well as cell death in mature mouse OLs. There is also evidence

  15. Contact-mediated inhibition between oligodendrocyte progenitor cells and motor exit point glia establishes the spinal cord transition zone.

    PubMed

    Smith, Cody J; Morris, Angela D; Welsh, Taylor G; Kucenas, Sarah

    2014-09-01

    Rapid conduction of action potentials along motor axons requires that oligodendrocytes and Schwann cells myelinate distinct central and peripheral nervous system (CNS and PNS) domains along the same axon. Despite the importance of this arrangement for nervous system function, the mechanisms that establish and maintain this precise glial segregation at the motor exit point (MEP) transition zone are unknown. Using in vivo time-lapse imaging in zebrafish, we observed that prior to myelination, oligodendrocyte progenitor cells (OPCs) extend processes into the periphery via the MEP and immediately upon contact with spinal motor root glia retract back into the spinal cord. Characterization of the peripheral cell responsible for repelling OPC processes revealed that it was a novel, CNS-derived population of glia we propose calling MEP glia. Ablation of MEP glia resulted in the absence of myelinating glia along spinal motor root axons and an immediate breach of the MEP by OPCs. Taken together, our results identify a novel population of CNS-derived peripheral glia located at the MEP that selectively restrict the migration of OPCs into the periphery via contact-mediated inhibition.

  16. Pellet ablation and ablation model development

    SciTech Connect

    Houlberg, W.A.

    1989-01-01

    A broad survey of pellet ablation is given, based primarily on information presented at this meeting. The implications of various experimental observations for ablation theory are derived from qualitative arguments of the physics involved. The major elements of a more complete ablation theory are then outlined in terms of these observations. This is followed by a few suggestions on improving the connections between theory and experimental results through examination of ablation data. Although this is a rather aggressive undertaking for such a brief (and undoubtedly incomplete) assessment, some of the discussion may help us advance the understanding of pellet ablation. 17 refs.

  17. Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder.

    PubMed

    Barley, Kevin; Dracheva, Stella; Byne, William

    2009-07-01

    Deficits in the expression of oligodendrocyte and myelin genes have been described in numerous cortical regions in schizophrenia and affective disorders; however, relatively little attention has been paid to subcortical structures. Here we employed quantitative real time PCR to examine the mRNA expression of 17 genes that are expressed by oligodendrocyte precursors (OLPs) and their derivatives, including astrocytes. Four subcortical regions were examined (the anteroventral (AV) and mediodorsal thalamic nuclei (MDN), internal capsule (IC) and putamen (Put)) in postmortem material from subjects (age 25-68 at time of death) with no known psychiatric history (NCs) as well as in subjects with schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BPD). In all regions examined, genes expressed after the terminal differentiation of oligodendrocytes tended to have lower levels of mRNA expression in subjects with SZ compared to NCs. These differences were statistically significant across regions for four genes (CNP, GALC, MAG and MOG) and approached significance for TF. No genes were under expressed in MDD. Only TF was under expressed in BPD and only in the IC. In contrast, two astrocyte-associated genes (GFAP and ALDH1L1) had higher mean expression levels across regions in all psychiatric groups relative to NCs. These differences reached statistical significance for SZ and MDD relative to NCs. There were no age by diagnosis interactions. The majority of age regressions had negative slopes for the expression of oligodendrocyte-associated genes. GFAP but not ALDH1L1 expression was significantly and positively correlated with age in the MDN, AV and Put. Across subject groups the expression of both astrocyte genes was highly correlated with cumulative neuroleptic exposure in all regions except the Put. Significant positive correlations were also observed in some regions between cumulative neuroleptic exposure and the expression of genes associated with

  18. Oligodendrocyte and Interneuron Density in Hippocampal Subfields in Schizophrenia and Association of Oligodendrocyte Number with Cognitive Deficits

    PubMed Central

    Falkai, Peter; Steiner, Johann; Malchow, Berend; Shariati, Jawid; Knaus, Andreas; Bernstein, Hans-Gert; Schneider-Axmann, Thomas; Kraus, Theo; Hasan, Alkomiet; Bogerts, Bernhard; Schmitt, Andrea

    2016-01-01

    In schizophrenia, previous stereological post-mortem investigations of anterior, posterior, and total hippocampal subfields showed no alterations in total neuron number but did show decreased oligodendrocyte numbers in CA4, an area that corresponds to the polymorph layer of the dentate gyrus (DG). However, these investigations identified oligodendrocytes only on the basis of morphological criteria in Nissl staining and did not assess alterations of interneurons with immunohistochemical markers. Moreover, the association of findings in the posterior hippocampus with cognitive deficits remains unknown. On the basis of the available clinical records, we compared patients with definite and possible cognitive dysfunction; nine patients had evidence in their records of either definite (n = 4) or possible (n = 5) cognitive dysfunction. Additionally, we assessed the density of two oligodendrocyte subpopulations immunostained by the oligodendrocyte transcription factors Olig1 and Olig2 and of interneurons immunolabeled by parvalbumin. We investigated posterior hippocampal subregions in the post-mortem brains of the same schizophrenia patients (SZ; n = 10) and healthy controls (n = 10) we examined in our previously published stereological studies. Our stereological studies found that patients with definite cognitive deficits had decreased total/Nissl-stained oligodendrocyte numbers in the left (p = 0.014) and right (p = 0.050) CA4, left CA2/3 (p = 0.050), left CA1 (p = 0.027), and left (p = 0.050) and right (p = 0.014) subiculum of the anterior part of the hippocampus compared to patients with possible cognitive deficits. In the present study, we found no significant influence of definite cognitive deficits in the posterior part of the hippocampus, whereas in the entire hippocampus SZ with definite cognitive deficits showed decreased oligodendrocyte numbers in the left (p = 0.050) and right (p = 0.050) DG and left CA2/3 (p = 0.050). We did not find significant differences in

  19. BDNF +/− Mice Exhibit Deficits in Oligodendrocyte Lineage Cells of the Basal Forebrain

    PubMed Central

    VonDran, Melissa W.; Clinton-Luke, Patricia; Honeywell, Jean Z.; Dreyfus, Cheryl F.

    2009-01-01

    Previous work indicated that BDNF, through the trkB receptor, increases DNA synthesis in oligodendrocyte progenitor cells (OPCs) and differentiation of post-mitotic oligodendrocytes (OLGs) of the basal forebrain (BF). In the present studies, BDNF knockout animals were used to investigate BDNF’s effects on OLG lineage cells (OLCs) in vivo. OLCs of the BF were found to express the trkB receptor, suggesting they are responsive to BDNF. Immunohistochemistry using NG2 and CC1 antibodies was utilized to examine numbers of NG2+ OPCs and CC1+ post-mitotic BF OLGs. In the embryo (E17), BDNF −/− animals display reduced NG2+ cells. This reduction was also observed in BDNF +/− mice at E17 and at postnatal day 1 (P1), P14 and adult, suggesting that BDNF plays a role in OPC development. BDNF +/− mice do not exhibit deficits in numbers of CC1+ OLGs. However, myelin basic protein (MBP), myelin associated glycoprotein (MAG), and proteolipid protein (PLP) are reduced in BDNF +/− mice, suggesting that BDNF plays a role in differentiation. These data indicate that progenitor cells and myelin proteins may be affected in vivo by a decrease in BDNF. PMID:20091777

  20. Cytoskeletal Linker Protein Dystonin Is Not Critical to Terminal Oligodendrocyte Differentiation or CNS Myelination

    PubMed Central

    Bonin, Sawyer R.; Gibeault, Sabrina; De Repentigny, Yves; Kothary, Rashmi

    2016-01-01

    Oligodendrocyte differentiation and central nervous system myelination require massive reorganization of the oligodendrocyte cytoskeleton. Loss of specific actin- and tubulin-organizing factors can lead to impaired morphological and/or molecular differentiation of oligodendrocytes, resulting in a subsequent loss of myelination. Dystonin is a cytoskeletal linker protein with both actin- and tubulin-binding domains. Loss of function of this protein results in a sensory neuropathy called Hereditary Sensory Autonomic Neuropathy VI in humans and dystonia musculorum in mice. This disease presents with severe ataxia, dystonic muscle and is ultimately fatal early in life. While loss of the neuronal isoforms of dystonin primarily leads to sensory neuron degeneration, it has also been shown that peripheral myelination is compromised due to intrinsic Schwann cell differentiation abnormalities. The role of this cytoskeletal linker in oligodendrocytes, however, remains unclear. We sought to determine the effects of the loss of neuronal dystonin on oligodendrocyte differentiation and central myelination. To address this, primary oligodendrocytes were isolated from a severe model of dystonia musculorum, Dstdt-27J, and assessed for morphological and molecular differentiation capacity. No defects could be discerned in the differentiation of Dstdt-27J oligodendrocytes relative to oligodendrocytes from wild-type littermates. Survival was also compared between Dstdt-27J and wild-type oligodendrocytes, revealing no significant difference. Using a recently developed migration assay, we further analysed the ability of primary oligodendrocyte progenitor cell motility, and found that Dstdt-27J oligodendrocyte progenitor cells were able to migrate normally. Finally, in vivo analysis of oligodendrocyte myelination was done in phenotype-stage optic nerve, cerebral cortex and spinal cord. The density of myelinated axons and g-ratios of Dstdt-27J optic nerves was normal, as was myelin basic

  1. Oligodendrocyte precursors migrate along vasculature in the developing nervous system.

    PubMed

    Tsai, Hui-Hsin; Niu, Jianqin; Munji, Roeben; Davalos, Dimitrios; Chang, Junlei; Zhang, Haijing; Tien, An-Chi; Kuo, Calvin J; Chan, Jonah R; Daneman, Richard; Fancy, Stephen P J

    2016-01-22

    Oligodendrocytes myelinate axons in the central nervous system and develop from oligodendrocyte precursor cells (OPCs) that must first migrate extensively during brain and spinal cord development. We show that OPCs require the vasculature as a physical substrate for migration. We observed that OPCs of the embryonic mouse brain and spinal cord, as well as the human cortex, emerge from progenitor domains and associate with the abluminal endothelial surface of nearby blood vessels. Migrating OPCs crawl along and jump between vessels. OPC migration in vivo was disrupted in mice with defective vascular architecture but was normal in mice lacking pericytes. Thus, physical interactions with the vascular endothelium are required for OPC migration. We identify Wnt-Cxcr4 (chemokine receptor 4) signaling in regulation of OPC-endothelial interactions and propose that this signaling coordinates OPC migration with differentiation.

  2. Biochemical subtypes of oligodendrocyte in the anterior medullary velum of the rat as revealed by the monoclonal antibody Rip.

    PubMed

    Butt, A M; Ibrahim, M; Ruge, F M; Berry, M

    1995-07-01

    Oligodendrocytes were studied in the anterior medullary velum (AMV) of the rat using the monoclonal antibody Rip, an oligodendrocyte marker of unknown function. Confocal microscopic imaging of double immunofluorescent labelling with antibodies to Rip and carbonic anhydrase II (CAII) revealed two biochemically and morphologically distinct populations of oligodendrocyte which were either Rip+CAII+ or Rip+CAII-. Double immunofluorescent labelling with Rip and myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP) provided direct evidence that Rip-labelled cells were phenotypically oligodendrocytes and confirmed that Rip did not recognise astrocytes. Oligodendrocytes which were Rip+CAII+ supported numerous myelin sheaths for small diameter axons, whilst Rip+CAII- oligodendrocytes supported fewer myelin sheaths for large diameter axons. Morphologically, Rip+CAII+ oligodendrocytes corresponded to types I or II of classical nomenclature, whilst Rip+CAII- oligodendrocytes corresponded to types III and IV. The results demonstrated a biochemical difference between oligodendrocytes which myelinated small and large diameter fibres.

  3. Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors

    PubMed Central

    Gautier, Hélène O. B.; Evans, Kimberley A.; Volbracht, Katrin; James, Rachel; Sitnikov, Sergey; Lundgaard, Iben; James, Fiona; Lao-Peregrin, Cristina; Reynolds, Richard; Franklin, Robin J. M.; Káradóttir, Ragnhildur T

    2015-01-01

    Myelin regeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms and causes of its frequent failure remain incompletely understood. Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active and generate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early after lesion induction, sense neuronal activity by expressing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. In the absence of neuronal activity there is a ∼6-fold increase in OPC number within the lesions and a reduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity and release of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recover lost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that this mechanism may provide novel targets to therapeutically enhance remyelination. PMID:26439639

  4. Transcription factor induction of human oligodendrocyte progenitor fate and differentiation

    PubMed Central

    Wang, Jing; Pol, Suyog U.; Haberman, Alexa K.; Wang, Chunming; O’Bara, Melanie A.; Sim, Fraser J.

    2014-01-01

    Human oligodendrocyte progenitor cell (OPC) specification and differentiation occurs slowly and limits the potential for cell-based treatment of demyelinating disease. In this study, using FACS-based isolation and microarray analysis, we identified a set of transcription factors expressed by human primary CD140a+O4+ OPCs relative to CD133+CD140a− neural stem/progenitor cells (NPCs). Among these, lentiviral overexpression of transcription factors ASCL1, SOX10, and NKX2.2 in NPCs was sufficient to induce Sox10 enhancer activity, OPC mRNA, and protein expression consistent with OPC fate; however, unlike ASCL1 and NKX2.2, only the transcriptome of SOX10-infected NPCs was induced to a human OPC gene expression signature. Furthermore, only SOX10 promoted oligodendrocyte commitment, and did so at quantitatively equivalent levels to native OPCs. In xenografts of shiverer/rag2 animals, SOX10 increased the rate of mature oligodendrocyte differentiation and axon ensheathment. Thus, SOX10 appears to be the principle and rate-limiting regulator of myelinogenic fate from human NPCs. PMID:24982138

  5. Oligodendrocyte Injury and Pathogenesis of HIV-1-Associated Neurocognitive Disorders

    PubMed Central

    Liu, Han; Xu, Enquan; Liu, Jianuo; Xiong, Huangui

    2016-01-01

    Oligodendrocytes wrap neuronal axons to form myelin, an insulating sheath which is essential for nervous impulse conduction along axons. Axonal myelination is highly regulated by neuronal and astrocytic signals and the maintenance of myelin sheaths is a very complex process. Oligodendrocyte damage can cause axonal demyelination and neuronal injury, leading to neurological disorders. Demyelination in the cerebrum may produce cognitive impairment in a variety of neurological disorders, including human immunodeficiency virus type one (HIV-1)-associated neurocognitive disorders (HAND). Although the combined antiretroviral therapy has markedly reduced the incidence of HIV-1-associated dementia, a severe form of HAND, milder forms of HAND remain prevalent even when the peripheral viral load is well controlled. HAND manifests as a subcortical dementia with damage in the brain white matter (e.g., corpus callosum), which consists of myelinated axonal fibers. How HIV-1 brain infection causes myelin injury and resultant white matter damage is an interesting area of current HIV research. In this review, we tentatively address recent progress on oligodendrocyte dysregulation and HAND pathogenesis. PMID:27455335

  6. Radiofrequency Ablation of Liver Tumors

    MedlinePlus

    ... Site Index A-Z Radiofrequency Ablation (RFA) of Liver Tumors Radiofrequency ablation (RFA) is a treatment that ... of Liver Tumors? What is Radiofrequency Ablation of Liver Tumors? Radiofrequency ablation, sometimes referred to as RFA, ...

  7. Ablative skin resurfacing.

    PubMed

    Chwalek, Jennifer; Goldberg, David J

    2011-01-01

    Ablative skin resurfacing has remained the gold standard for treating photodamage and acne scars since the development of the first CO(2) lasers. CO(2) and Er:YAG lasers emit infrared light, which targets water resulting in tissue contraction and collagen formation. The first ablative laser systems created significant thermal damage resulting in unacceptably high rates of scarring and prolonged healing. Newer devices, such as high-energy pulsed lasers and fractional ablative lasers, are capable of achieving significant improvements with fewer side effects and shorter recovery times. While ablative resurfacing has become safer, careful patient selection is still important to avoid post-treatment scarring, dyspigmentation, and infections. Clinicians utilizing ablative devices need to be aware of possible side effects in order to maximize results and patient satisfaction. This chapter reviews the background of ablative lasers including the types of ablative lasers, mechanism of action, indications for ablative resurfacing, and possible side effects.

  8. Ablative therapies for small renal tumours.

    PubMed

    Castro, Arturo; Jenkins, Lawrence C; Salas, Nelson; Lorber, Gideon; Leveillee, Raymond J

    2013-05-01

    Improvements in imaging technology have resulted in an increase in detection of small renal masses (SRMs). Minimally invasive ablation modalities, including cryoablation, radiofrequencey ablation, microwave ablation and irreversible electroporation, are currently being used to treat SRMs in select groups of patients. Cryoablation and radiofrequency ablation have been extensively studied. Presently, cryoablation is gaining popularity because the resulting ice ball can be visualized easily using ultrasonography. Tumour size and location are strong predictors of outcome of radiofrequency ablation. One of the main benefits of microwave ablation is that microwaves can propagate through all types of tissue, including desiccated and charred tissue, as well as water vapour, which might be formed during the ablation. Irreversible electroporation has been shown in animal studies to affect only the cell membrane of undesirable target tissues and to spare adjacent structures; however, clinical studies that depict the efficacy and safety of this treatment modality in humans are still sparse. As more experience is gained in the future, ablation modalities might be utilized in all patients with tumours <4 cm in diameter, rather than just as an alternative treatment for high-risk surgical patients.

  9. Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis.

    PubMed

    Lin, Wensheng; Lin, Yifeng; Li, Jin; Fenstermaker, Ali G; Way, Sharon W; Clayton, Benjamin; Jamison, Stephanie; Harding, Heather P; Ron, David; Popko, Brian

    2013-04-03

    There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the development of the demyelinating disorder multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Therefore, approaches designed to protect oligodendrocytes would likely have therapeutic value. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum (ER) stress increases cell survival under various cytotoxic conditions. Moreover, there is evidence that PERK signaling is activated in oligodendrocytes within demyelinating lesions in multiple sclerosis and EAE. Our previous study demonstrated that CNS delivery of the inflammatory cytokine interferon-γ before EAE onset protected mice against EAE, and this protection was dependent on PERK signaling. In our current study, we sought to elucidate the role of PERK signaling in oligodendrocytes during EAE. We generated transgenic mice that allow for temporally controlled activation of PERK signaling, in the absence of ER stress, specifically in oligodendrocytes. We demonstrated that persistent activation of PERK signaling was not deleterious to oligodendrocyte viability or the myelin of adult animals. Importantly, we found that enhanced activation of PERK signaling specifically in oligodendrocytes significantly attenuated EAE disease severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. This effect was not the result of an altered degree of the inflammatory response in EAE mice. Our results provide direct evidence that activation of PERK signaling in oligodendrocytes is cytoprotective, protecting mice against EAE.

  10. Severe Convulsions and Dysmyelination in Both Jimpy and Cx32/47 (-/-) Mice may Associate Astrocytic L-Channel Function with Myelination and Oligodendrocytic Connexins with Internodal Kv Channels.

    PubMed

    Chaban, Y H Gerald; Chen, Ye; Hertz, Elna; Hertz, Leif

    2017-02-18

    The Jimpy mouse illustrates the importance of interactions between astrocytes and oligodendrocytes. It has a mutation in Plp coding for proteolipid protein and DM20. Its behavior is normal at birth but from the age of ~2 weeks it shows severe convulsions associated with oligodendrocyte/myelination deficits and early death. A normally occurring increase in oxygen consumption by highly elevated K(+) concentrations is absent in Jimpy brain slices and cultured astrocytes, reflecting that Plp at early embryonic stages affects common precursors as also shown by the ability of conditioned medium from normal astrocytes to counteract histological abnormalities. This metabolic response is now known to reflect opening of L-channels for Ca(2+). The resulting deficiency in Ca(2+) entry has many consequences, including lack of K(+)-stimulated glycogenolysis and release of gliotransmitter ATP. Lack of purinergic stimulation compromises oligodendrocyte survival and myelination and affects connexins and K(+) channels. Mice lacking the oligodendrocytic connexins Cx32 and 47 show similar neurological dysfunction as Jimpy. This possibly reflects that K(+) released by intermodal axonal Kv channels is transported underneath a loosened myelin sheath instead of reaching the extracellular space via connexin-mediated transport to oligodendrocytes, followed by release and astrocytic Na(+),K(+)-ATPase-driven uptake with subsequent Kir4.1-facilitated release and neuronal uptake.

  11. Learning disability and oligodendrocyte myelin glycoprotein (OMGP) gene in neurofibromatosis type 1.

    PubMed

    Terzi, Yunus Kasim; Oğuzkan-Balci, Sibel; Anlar, Banu; Erdoğan-Bakar, Emel; Ayter, Sükriye

    2011-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disease where phenotypic heterogeneity is explained by the effect of modifier genes. Thirty to 65% of patients have learning disability. The oligodendrocyte myelin glycoprotein (OMGP) gene located within the neurofibromatosis type 1 (NF1) gene might affect the phenotype of learning disability because it is expressed in the brain, and OMGP gene mutations have been associated with cognitive disturbances. We analyzed the OMGP gene in NF1 patients with and without learning disability (n = 50 each) and healthy controls (n = 100). The allele distribution of OMGP62 polymorphism was not significantly different between the groups (p = 0.447). These results do not support a relationship between the OMGP gene and the learning disability phenotype observed in NF1. Other modifying genes, post-translational modifications or receptor interactions might be involved in the phenotypic variability of NF1.

  12. Enhanced coupling of optical energy during liquid-confined metal ablation

    SciTech Connect

    Kang, Hyun Wook; Welch, Ashley J.

    2015-10-21

    Liquid-confined laser ablation was investigated with various metals of indium, aluminum, and nickel. Ablation threshold and rate were characterized in terms of surface deformation, transient acoustic responses, and plasma emissions. The surface condition affected the degree of ablation dynamics due to variations in reflectance. The liquid confinement yielded up to an order of larger ablation crater along with stronger acoustic transients than dry ablation. Enhanced ablation performance resulted possibly from effective coupling of optical energy at the interface during explosive vaporization, plasma confinement, and cavitation. The deposition of a liquid layer can induce more efficient ablation for laser metal processing.

  13. Conditional Ablation of Neuroprogenitor Cells in Adult Mice Impedes Recovery of Poststroke Cognitive Function and Reduces Synaptic Connectivity in the Perforant Pathway

    PubMed Central

    Sun, Chongran; Sun, Hui; Wu, Steven; Lee, Chih Cheng; Akamatsu, Yosuke; Wang, Ruikang K.; Kernie, Steven G.

    2013-01-01

    The causal relationship between neurogenesis and the recovery of poststroke cognitive function has not been properly explored. The current study aimed to determine whether depleting neuroprogenitor cells (NPCs) affects poststroke functional outcome in nestin-δ-HSV-TK-EGFP transgenic mice, in which the expression of a truncated viral thymidine kinase gene and EGFP was restricted to nestin-expressing NPCs. Ganciclovir (GCV; 200 mg/kg/d) or saline was continuously administered via osmotic pumps in mice for 4 weeks before the induction of experimental stroke. Both baseline and stroke-induced type 1 and type 2 NPCs were conditionally ablated. GCV eliminated NPCs in a duration-dependent fashion, but it did not attenuate the genesis of astroglia or oligodendrocytes in the peri-infarct cortex, nor did it affect infarct size or cerebral blood reperfusion after stroke. Transgenic stroke mice given GCV displayed impaired spatial learning and memory in the Barnes maze test compared with saline control or wild-type stroke mice given GCV, suggesting a contributing role of stroke-induced neurogenesis in the recovery of cognitive function. However, there was no significant difference in poststroke motor function between transgenic mice treated with GCV and those treated with vehicle, despite a significant ablation of NPCs in the subventricular zone of the former. Furthermore, nestin-δ-HSV-TK-EGFP mice treated with GCV had fewer retrogradely labeled neurons in the entorhinal cortex (EC) when injected with the polysynaptic viral marker PRV614 in the dentate gyrus (DG), suggesting that there might be reduced synaptic connectivity between the DG and EC following ablation of NPCs, which may contribute to impaired poststroke memory function. PMID:24174664

  14. Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelination

    PubMed Central

    Linden, Jennifer R.; Ma, Yinghua; Zhao, Baohua; Harris, Jason Michael; Rumah, Kareem Rashid; Schaeren-Wiemers, Nicole

    2015-01-01

    ABSTRACT Clostridium perfringens epsilon toxin (ε-toxin) is responsible for a devastating multifocal central nervous system (CNS) white matter disease in ruminant animals. The mechanism by which ε-toxin causes white matter damage is poorly understood. In this study, we sought to determine the molecular and cellular mechanisms by which ε-toxin causes pathological changes to white matter. In primary CNS cultures, ε-toxin binds to and kills oligodendrocytes but not astrocytes, microglia, or neurons. In cerebellar organotypic culture, ε-toxin induces demyelination, which occurs in a time- and dose-dependent manner, while preserving neurons, astrocytes, and microglia. ε-Toxin specificity for oligodendrocytes was confirmed using enriched glial culture. Sensitivity to ε-toxin is developmentally regulated, as only mature oligodendrocytes are susceptible to ε-toxin; oligodendrocyte progenitor cells are not. ε-Toxin sensitivity is also dependent on oligodendrocyte expression of the proteolipid myelin and lymphocyte protein (MAL), as MAL-deficient oligodendrocytes are insensitive to ε-toxin. In addition, ε-toxin binding to white matter follows the spatial and temporal pattern of MAL expression. A neutralizing antibody against ε-toxin inhibits oligodendrocyte death and demyelination. This study provides several novel insights into the action of ε-toxin in the CNS. (i) ε-Toxin causes selective oligodendrocyte death while preserving all other neural elements. (ii) ε-Toxin-mediated oligodendrocyte death is a cell autonomous effect. (iii) The effects of ε-toxin on the oligodendrocyte lineage are restricted to mature oligodendrocytes. (iv) Expression of the developmentally regulated proteolipid MAL is required for the cytotoxic effects. (v) The cytotoxic effects of ε-toxin can be abrogated by an ε-toxin neutralizing antibody. PMID:26081637

  15. Oligodendrocytes and the control of myelination in vivo: new insights from the rat anterior medullary velum.

    PubMed

    Butt, A M; Berry, M

    2000-02-15

    The rat anterior medullary velum (AMV) is representative of the brain and spinal cord, overall, and provides an almost two-dimensional preparation for investigating axon-glial interactions in vivo. Here, we review some of our findings on axon-oligodendrocyte unit relations in our adult, development, and injury paradigms: (1) adult oligodendrocytes are phenotypically heterogeneous, conforming to Del Rio Hortega's types I-IV, whereby differences in oligodendrocyte morphology, metabolism, myelin sheath radial and longitudinal dimensions, and biochemistry correlate with the diameters of axons in the unit; (2) oligodendrocytes derive from a common premyelinating oligodendrocyte phenotype, and divergence of types I-IV is related to the age they emerge and the presumptive diameter of axons in the unit; (3) during myelination, axon-oligodendrocyte units progress through a sequence of maturation phases, related to axon contact, ensheathment, establishment of internodal myelin sheaths, and finally the radial growth and compaction of the myelin sheath; (4) we provide direct in vivo evidence that platelet-derived growth factor-AA (PDGF-AA), fibroblast growth factor (FGF-2), and insulin-like growth factor-I (IGF-I) differentially regulate these events, by injecting the growth factors into the cerebrospinal fluid of neonatal rat pups; (5) in lesioned adult AMV, transected central nervous system (CNS) axons regenerate through the putatively inhibitory environment of the glial scar, but remyelination by oligodendrocytes is incomplete, indicating that axon-oligodendrocyte interactions are defective; and (6) in the adult AMV, cells expressing the NG2 chondroitin sulphate have a presumptive adult oligodendrocyte progenitor antigenic phenotype, but are highly complex cells and send processes to contact axolemma at nodes of Ranvier, suggesting they subserve a specific perinodal function. Thus, axons and oligodendrocyte lineage cells form interdependent functional units, but

  16. In vivo and in vitro models of demyelinating disease: activation of the adenylate cyclase system influences JHM virus expression in explanted rat oligodendrocytes.

    PubMed Central

    Beushausen, S; Narindrasorasak, S; Sanwal, B D; Dales, S

    1987-01-01

    The specificity of JHM virus (JHMV) tropism for rat oligodendrocytes, as one of the primary host cells in the central nervous system, is maintained after explanation (S. Beushausen and S. Dales, Virology 141:89-101, 1985). The temporal correlation between onset of resistance to JHMV infection in vivo, completion of myelination, and maturation of the central nervous system can be simulated in vitro by inducers of oligodendrocyte differentiation (Beushausen and Dales, Virology, 1985). Stimulation of differentiation through the elevation of intracellular cyclic AMP (cAMP) levels suggests a possible connection between activation of the adenylate cyclase system and coronavirus expression. Chromatographic analysis of cAMP-dependent protein kinase activity in cytosol extracts prepared from astrocytes or oligodendrocytes revealed that both glial cell types were deficient in protein kinase I, indicating that expression of coronavirus in differentiated cells was not contingent upon the presence of protein kinase I. However, treatment with N6,2'-O-dibutyryladenosine-3',5'-cyclic monophosphate (dbcAMP) resulted in a severalfold enhancement of the free regulatory subunit (RI) in oligodendrocytes but not in astrocytes. The RII subunit in both neural cell types was relatively unaffected. Rapid increase in RI due to dbcAMP treatment was correlated with inhibition of JHMV expression. Other differentiation inducers, including 8-Br cAMP and forskolin which, by contrast, caused a decrease in detectable RI, also blocked JHMV expression. This apparent anomaly can be attributed to an increased turnover of RI due to destabilization of the molecule which occurs upon site-specific binding of the cyclic nucleotides. On the basis of these observations, we conclude that the state of oligodendrocyte differentiation manifested with the modulation of RI regulates JHMV expression. The differentiation process did not affect either virus adsorption or sequestration but appeared to inhibit the

  17. Astrocytes in Oligodendrocyte Lineage Development and White Matter Pathology.

    PubMed

    Li, Jiasi; Zhang, Lei; Chu, Yongxin; Namaka, Michael; Deng, Benqiang; Kong, Jiming; Bi, Xiaoying

    2016-01-01

    White matter is primarily composed of myelin and myelinated axons. Structural and functional completeness of myelin is critical for the reliable and efficient transmission of information. White matter injury has been associated with the development of many demyelinating diseases. Despite a variety of scientific advances aimed at promoting re-myelination, their benefit has proven at best to be marginal. Research suggests that the failure of the re-myelination process may be the result of an unfavorable microenvironment. Astrocytes, are the most ample and diverse type of glial cells in central nervous system (CNS) which display multiple functions for the cells of the oligodendrocytes lineage. As such, much attention has recently been drawn to astrocyte function in terms of white matter myelin repair. They are different in white matter from those in gray matter in specific regards to development, morphology, location, protein expression and other supportive functions. During the process of demyelination and re-myelination, the functions of astrocytes are dynamic in that they are able to change functions in accordance to different time points, triggers or reactive pathways resulting in vastly different biologic effects. They have pivotal effects on oligodendrocytes and other cell types in the oligodendrocyte lineage by serving as an energy supplier, a participant of immunological and inflammatory functions, a source of trophic factors and iron and a sustainer of homeostasis. Astrocytic impairment has been shown to be directly linked to the development of neuromyelities optica (NMO). In addition, astroctyes have also been implicated in other white matter conditions such as psychiatric disorders and neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Inhibiting specifically detrimental signaling pathways in astrocytes while preserving their beneficial functions may be a promising approach for

  18. Astrocytes in Oligodendrocyte Lineage Development and White Matter Pathology

    PubMed Central

    Li, Jiasi; Zhang, Lei; Chu, Yongxin; Namaka, Michael; Deng, Benqiang; Kong, Jiming; Bi, Xiaoying

    2016-01-01

    White matter is primarily composed of myelin and myelinated axons. Structural and functional completeness of myelin is critical for the reliable and efficient transmission of information. White matter injury has been associated with the development of many demyelinating diseases. Despite a variety of scientific advances aimed at promoting re-myelination, their benefit has proven at best to be marginal. Research suggests that the failure of the re-myelination process may be the result of an unfavorable microenvironment. Astrocytes, are the most ample and diverse type of glial cells in central nervous system (CNS) which display multiple functions for the cells of the oligodendrocytes lineage. As such, much attention has recently been drawn to astrocyte function in terms of white matter myelin repair. They are different in white matter from those in gray matter in specific regards to development, morphology, location, protein expression and other supportive functions. During the process of demyelination and re-myelination, the functions of astrocytes are dynamic in that they are able to change functions in accordance to different time points, triggers or reactive pathways resulting in vastly different biologic effects. They have pivotal effects on oligodendrocytes and other cell types in the oligodendrocyte lineage by serving as an energy supplier, a participant of immunological and inflammatory functions, a source of trophic factors and iron and a sustainer of homeostasis. Astrocytic impairment has been shown to be directly linked to the development of neuromyelities optica (NMO). In addition, astroctyes have also been implicated in other white matter conditions such as psychiatric disorders and neurodegenerative diseases such as Alzheimer’s disease (AD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Inhibiting specifically detrimental signaling pathways in astrocytes while preserving their beneficial functions may be a promising approach for

  19. Fibroblast growth factor receptor 3 signaling regulates the onset of oligodendrocyte terminal differentiation.

    PubMed

    Oh, Luke Y S; Denninger, Adam; Colvin, Jennifer S; Vyas, Aditee; Tole, Shubha; Ornitz, David M; Bansal, Rashmi

    2003-02-01

    Fibroblast growth factor receptor (FGFR) signaling is essential for nervous system development. We have shown that, in the normal postnatal brain, the spatial and temporal expression pattern of FGFR3 parallels the appearance of differentiated oligodendrocytes and that in culture FGFR3 is expressed maximally at the critical stage in the lineage at which oligodendrocyte late progenitors (Pro-OLs) enter terminal differentiation. Therefore, FGFR3 expression is positioned ideally to have an impact on oligodendrocyte differentiation. In support of this we show that, during the onset and active phase of myelination in FGFR3-deficient mice, there are reduced numbers of differentiated oligodendrocytes in the forebrain, cerebellum, hindbrain, and spinal cord. Furthermore, myelination is delayed in parallel. Delay of oligodendrocyte differentiation also is observed in primary cell culture from this mutant. On the other hand, no differences are observed in the survival or proliferation of oligodendrocyte progenitors. This suggests that the decrease in the number of differentiated oligodendrocytes is attributable to a delay in the timing of their differentiation process. Astrocytes also express FGFR3, and in mice lacking FGFR3 there is an enhancement of the astrocytic marker glial fibrillary acidic protein expression in a region-specific manner. Thus our findings suggest that there are cell type- and region-specific functions for FGFR3 signaling and in particular emphasize a prominent role for FGFR3 as part of a system regulating the onset of oligodendrocyte terminal differentiation.

  20. Axon-to-Glia Interaction Regulates GABAA Receptor Expression in Oligodendrocytes.

    PubMed

    Arellano, Rogelio O; Sánchez-Gómez, María Victoria; Alberdi, Elena; Canedo-Antelo, Manuel; Chara, Juan Carlos; Palomino, Aitor; Pérez-Samartín, Alberto; Matute, Carlos

    2016-01-01

    Myelination requires oligodendrocyte-neuron communication, and both neurotransmitters and contact interactions are essential for this process. Oligodendrocytes are endowed with neurotransmitter receptors whose expression levels and properties may change during myelination. However, only scant information is available about the extent and timing of these changes or how they are regulated by oligodendrocyte-neuron interactions. Here, we used electrophysiology to study the expression of ionotropic GABA, glutamate, and ATP receptors in oligodendrocytes derived from the optic nerve and forebrain cultured either alone or in the presence of dorsal root ganglion neurons. We observed that oligodendrocytes from both regions responded to these transmitters at 1 day in culture. After the first day in culture, however, GABA sensitivity diminished drastically to less than 10%, while that of glutamate and ATP remained constant. In contrast, the GABA response amplitude was sustained and remained stable in oligodendrocytes cocultured with dorsal root ganglion neurons. Immunochemistry and pharmacological properties of the responses indicated that they were mediated by distinctive GABAA receptors and that in coculture with neurons, the oligodendrocytes bearing the receptors were those in direct contact with axons. These results reveal that GABAA receptor regulation in oligodendrocytes is driven by axonal cues and that GABA signaling may play a role in myelination and/or during axon-glia recognition.

  1. Insulin-like growth factor I/somatomedin C: a potent inducer of oligodendrocyte development

    SciTech Connect

    McMorris, F.A.; Smith, T.M.; DeSalvo, S.; Furlanetto, R.W.

    1986-02-01

    Cell cultures established from cerebrum of 1-day-old rats were used to investigate hormonal regulation of the development of oligodendrocytes, which synthesize myelin in the central nervous system. The number of oligodendrocytes that developed was preferentially increased by insulin, or by insulin-like growth factor I (IGF-I), also known as somatomedin C. High concentrations of insulin were required for substantial induction of oligodendrocyte development, whereas only 3.3 ng of IGF-I per ml was needed for a 2-fold increase in oligodendrocyte numbers. At an IGF-I concentration of 100 ng/ml, oligodendrocyte numbers were increased 6-fold in cultures grown in the presence of 10% fetal bovine serum, or up to 60-fold in cultures maintained in serum-free medium. IGF-I produced less than a 2-fold increase in the number of nonoligodendroglial cells in the same cultures. Type I IGF receptors were identified on oligodendrocytes and on a putative oligodendrocyte precursor cell population identified by using mouse monoclonal antibody A2B5. Radioligand binding assays were done. These results indicate that IGF-I is a potent inducer of oligodendrocyte development and suggest a possible mechanism based on IGF deficiency for the hypomyelination that results from early postnatal malnutrition.

  2. PERK activation preserves the viability and function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

    PubMed

    Lin, Yifeng; Huang, Guangcun; Jamison, Stephanie; Li, Jin; Harding, Heather P; Ron, David; Lin, Wensheng

    2014-02-01

    Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

  3. Nonequilibrium Ablation of Phenolic Impregnated Carbon Ablator

    NASA Technical Reports Server (NTRS)

    Milos, Frank S.; Chen, Yih K.; Gokcen, Tahir

    2012-01-01

    In previous work, an equilibrium ablation and thermal response model for Phenolic Impregnated Carbon Ablator was developed. In general, over a wide range of test conditions, model predictions compared well with arcjet data for surface recession, surface temperature, in-depth temperature at multiple thermocouples, and char depth. In this work, additional arcjet tests were conducted at stagnation conditions down to 40 W/sq cm and 1.6 kPa. The new data suggest that nonequilibrium effects become important for ablation predictions at heat flux or pressure below about 80 W/sq cm or 10 kPa, respectively. Modifications to the ablation model to account for nonequilibrium effects are investigated. Predictions of the equilibrium and nonequilibrium models are compared with the arcjet data.

  4. Neuron-glia communication in the control of oligodendrocyte function and myelin biogenesis.

    PubMed

    Simons, Mikael; Trajkovic, Katarina

    2006-11-01

    During the development of the central nervous system the reciprocal communication between neurons and oligodendrocytes is essential for the generation of myelin, a multilamellar insulating membrane that ensheathes the axons. Neuron-derived signalling molecules regulate the proliferation, differentiation and survival of oligodendrocytes. Furthermore, neurons control the onset and timing of myelin membrane growth. In turn, signals from oligodendrocytes to neurons direct the assembly of specific subdomains in neurons at the node of Ranvier. Recent work has begun to shed light on the molecules and signaling systems used to coordinate the interaction of neurons and oligodendrocytes. For example, the neuronal signals seem to control the membrane trafficking machinery in oligodendrocytes that leads to myelination. These interconnections at multiple levels show how neurons and glia cooperate to build a complex network during development.

  5. Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model

    PubMed Central

    Romanelli, Elisa; Merkler, Doron; Mezydlo, Aleksandra; Weil, Marie-Theres; Weber, Martin S.; Nikić, Ivana; Potz, Stephanie; Meinl, Edgar; Matznick, Florian E. H.; Kreutzfeldt, Mario; Ghanem, Alexander; Conzelmann, Karl-Klaus; Metz, Imke; Brück, Wolfgang; Routh, Matthew; Simons, Mikael; Bishop, Derron; Misgeld, Thomas; Kerschensteiner, Martin

    2016-01-01

    Oligodendrocyte damage is a central event in the pathogenesis of the common neuroinflammatory condition, multiple sclerosis (MS). Where and how oligodendrocyte damage is initiated in MS is not completely understood. Here, we use a combination of light and electron microscopy techniques to provide a dynamic and highly resolved view of oligodendrocyte damage in neuroinflammatory lesions. We show that both in MS and in its animal model structural damage is initiated at the myelin sheaths and only later spreads to the oligodendrocyte cell body. Early myelin damage itself is characterized by the formation of local myelin out-foldings—‘myelinosomes'—, which are surrounded by phagocyte processes and promoted in their formation by anti-myelin antibodies and complement. The presence of myelinosomes in actively demyelinating MS lesions suggests that oligodendrocyte damage follows a similar pattern in the human disease, where targeting demyelination by therapeutic interventions remains a major open challenge. PMID:27848954

  6. The T3-induced gene KLF9 regulates oligodendrocyte differentiation and myelin regeneration.

    PubMed

    Dugas, Jason C; Ibrahim, Adiljan; Barres, Ben A

    2012-05-01

    Hypothyroidism is a well-described cause of hypomyelination. In addition, thyroid hormone (T3) has recently been shown to enhance remyelination in various animal models of CNS demyelination. What are the ways in which T3 promotes the development and regeneration of healthy myelin? To begin to understand the mechanisms by which T3 drives myelination, we have identified genes regulated specifically by T3 in purified oligodendrocyte precursor cells (OPCs). Among the genes identified by genomic expression analyses were four transcription factors, Kruppel-like factor 9 (KLF9), basic helix-loop-helix family member e22 (BHLHe22), Hairless (Hr), and Albumin D box-binding protein (DBP), all of which were induced in OPCs by both brief and long term exposure to T3. To begin to investigate the role of these genes in myelination, we focused on the most rapidly and robustly induced of these, KLF9, and found it is both necessary and sufficient to promote oligodendrocyte differentiation in vitro. Surprisingly, we found that loss of KLF9 in vivo negligibly affects the formation of CNS myelin during development, but does significantly delay remyelination in cuprizone-induced demyelinated lesions. These experiments indicate that KLF9 is likely a novel integral component of the T3-driven signaling cascade that promotes the regeneration of lost myelin. Future analyses of the roles of KLF9 and other identified T3-induced genes in myelination may lead to novel insights into how to enhance the regeneration of myelin in demyelinating diseases such as multiple sclerosis.

  7. Role of Sonic Hedgehog Signaling in Oligodendrocyte Differentiation.

    PubMed

    Wang, Li-Chun; Almazan, Guillermina

    2016-12-01

    During development, the secreted molecule Sonic Hedgehog (Shh) is required for lineage specification and proliferation of oligodendrocyte progenitors (OLPs), which are the glia cells responsible for the myelination of axons in the central nervous system (CNS). Shh signaling has been implicated in controlling both the generation of oligodendrocytes (OLGs) during embryonic development and their production in adulthood. Although, some evidence points to a role of Shh signaling in OLG development, its involvement in OLG differentiation remains to be fully determined. The objective of this study was to assess whether Shh signaling is involved in OLG differentiation after neural stem cell commitment to the OLG lineage. To address these questions, we manipulated Shh signaling using cyclopamine, a potent inhibitor of Shh signaling activator Smoothened (Smo), alone or combined with the agonist SAG in OLG primary cultures and assessed expression of myelin-specific markers. We found that inactivation of Shh signaling caused a dose-dependent decrease in myelin basic protein (MBP) and myelin associated glycoprotein (MAG) in differentiating OLGs. Co-treatment of the cells with SAG reversed the inhibitory effect of cyclopamine on both myelin-specific protein levels and morphological changes associated with it. Further experiments are required to elucidate the molecular mechanism by which Shh signaling regulates OLG differentiation.

  8. Shh Signaling through the Primary Cilium Modulates Rat Oligodendrocyte Differentiation

    PubMed Central

    Falcón-Urrutia, Paulina; Carrasco, Carlos M.; Lois, Pablo

    2015-01-01

    Primary Cilia (PC) are a very likely place for signal integration where multiple signaling pathways converge. Two major signaling pathways clearly shown to signal through the PC, Sonic Hedgehog (Shh) and PDGF-Rα, are particularly important for the proliferation and differentiation of oligodendrocytes, suggesting that their interaction occurs in or around this organelle. We identified PC in rat oligodendrocyte precursor cells (OPCs) and found that, while easily detectable in early OPCs, PC are lost as these cells progress to terminal differentiation. We confirmed the interaction between these pathways, as cyclopamine inhibition of Hedgehog function impairs both PDGF-mediated OPC proliferation and Shh-dependent cell branching. However, we failed to detect PDGF-Rα localization into the PC. Remarkably, ciliobrevin-mediated disruption of PC and reduction of OPC process extension was counteracted by recombinant Shh treatment, while PDGF had no effect. Therefore, while PDGF-Rα-dependent OPC proliferation and survival most probably does not initiate at the PC, still the integrity of this organelle and cilium-centered pathway is necessary for OPC survival and differentiation. PMID:26218245

  9. Pulmonary ablation: a primer.

    PubMed

    Roberton, Benjamin J; Liu, David; Power, Mark; Wan, John M C; Stuart, Sam; Klass, Darren; Yee, John

    2014-05-01

    Percutaneous image-guided thermal ablation is safe and efficacious in achieving local control and improving outcome in the treatment of both early stage non-small-cell lung cancer and pulmonary metastatic disease, in which surgical treatment is precluded by comorbidity, poor cardiorespiratory reserve, or unfavorable disease distribution. Radiofrequency ablation is the most established technology, but new thermal ablation technologies such as microwave ablation and cryoablation may offer some advantages. The use of advanced techniques, such as induced pneumothorax and the popsicle stick technique, or combining thermal ablation with radiotherapy, widens the treatment options available to the multidisciplinary team. The intent of this article is to provide the reader with a practical knowledge base of pulmonary ablation by concentrating on indications, techniques, and follow-up.

  10. Renal Ablation Update

    PubMed Central

    Khiatani, Vishal; Dixon, Robert G.

    2014-01-01

    Thermal ablative technologies have evolved considerably in the recent past and are now an important component of current clinical guidelines for the treatment of small renal masses. Both radiofrequency ablation and cryoablation have intermediate-term oncologic control that rivals surgical options, with favorable complication profiles. Studies comparing cryoablation and radiofrequency ablation show no significant difference in oncologic control or complication profile between the two modalities. Early data from small series with microwave ablation have shown similar promising results. Newer technologies including irreversible electroporation and high-intensity–focused ultrasound have theoretical advantages, but will require further research before becoming a routine part of the ablation armamentarium. The purpose of this review article is to discuss the current ablative technologies available, briefly review their mechanisms of action, discuss technical aspects of each, and provide current data supporting their use. PMID:25049445

  11. Radiofrequency Ablation of Cancer

    SciTech Connect

    Friedman, Marc; Mikityansky, Igor; Kam, Anthony; Libutti, Steven K.; Walther, McClellan M.; Neeman, Ziv; Locklin, Julia K.; Wood, Bradford J.

    2004-09-15

    Radiofrequency ablation (RFA) has been used for over 18 years for treatment of nerve-related chronic pain and cardiac arrhythmias. In the last 10 years, technical developments have increased ablation volumes in a controllable, versatile, and relatively inexpensive manner. The host of clinical applications for RFA have similarly expanded. Current RFA equipment, techniques, applications, results, complications, and research avenues for local tumor ablation are summarized.

  12. Lung Ablation: Whats New?

    PubMed

    Xiong, Lillian; Dupuy, Damian E

    2016-07-01

    Lung cancer had an estimated incidence of 221,200 in 2015, making up 13% of all cancer diagnoses. Tumor ablation is an important treatment option for nonsurgical lung cancer and pulmonary metastatic patients. Radiofrequency ablation has been used for over a decade with newer modalities, microwave ablation, cryoablation, and irreversible electroporation presenting as additional and possibly improved treatment options for patients. This minimally invasive therapy is best for small primary lesions or favorably located metastatic tumors. These technologies can offer palliation and sometimes cure of thoracic malignancies. This article discusses the current available technologies and techniques available for tumor ablation.

  13. Ablative Thermal Protection System Fundamentals

    NASA Technical Reports Server (NTRS)

    Beck, Robin A. S.

    2013-01-01

    This is the presentation for a short course on the fundamentals of ablative thermal protection systems. It covers the definition of ablation, description of ablative materials, how they work, how to analyze them and how to model them.

  14. Demyelination precedes oligodendrocyte loss in canine distemper virus-induced encephalitis.

    PubMed

    Schobesberger, M; Zurbriggen, A; Doherr, M G; Weissenböck, H; Vandevelde, M; Lassmann, H; Griot, C

    2002-01-01

    Canine distemper virus (CDV), a negative-stranded RNA morbillivirus, causes a persistent infection within the central nervous system resulting in a progressive, multifocal demyelinating disease. Demyelination is thought to be caused by a selective alteration of the myelin-producing oligodendrocytes. Metabolic impairment and morphological changes of the oligodendrocytes after CDV infection have previously been observed in vitro as well as in vivo. Until now it has been suggested that the oligodendrocytes completely disappear from CDV-induced demyelinating lesions. However, ultrastructural analysis in brain tissue sections and immunohistochemical examination of oligodendrocytes in dog brain cell cultures contradicted these observations. In this study oligodendrocytes from different categories of CDV-induced lesions were examined by in situ hybridization for proteolipid protein mRNA and--as a new tool employed on canine brain tissue sections--by immunohistochemistry using a monoclonal antibody against 2',3'-cyclic nucleotide 3'-phosphodiesterase, a myelin-specific enzyme. A down-regulation in the myelin gene transcription was detected already before demyelination occurred. However, a decrease in the number of oligodendrocytes was not observed until demyelination became evident. Although there was further depletion of oligodendrocytes in plaques with progressive demyelination, we demonstrated for the first time that these cells were still present in a significant amount even in chronic, completely demyelinated distemper lesions.

  15. Endogenous GABA controls oligodendrocyte lineage cell number, myelination, and CNS internode length

    PubMed Central

    Clarke, Laura E.; Arancibia‐Carcamo, I. Lorena; Kougioumtzidou, Eleni; Matthey, Moritz; Káradóttir, Ragnhildur; Whiteley, Louise; Bergersen, Linda H.; Richardson, William D.; Attwell, David

    2016-01-01

    Adjusting the thickness and internodal length of the myelin sheath is a mechanism for tuning the conduction velocity of axons to match computational needs. Interactions between oligodendrocyte precursor cells (OPCs) and developing axons regulate the formation of myelin around axons. We now show, using organotypic cerebral cortex slices from mice expressing eGFP in Sox10‐positive oligodendrocytes, that endogenously released GABA, acting on GABAA receptors, greatly reduces the number of oligodendrocyte lineage cells. The decrease in oligodendrocyte number correlates with a reduction in the amount of myelination but also an increase in internode length, a parameter previously thought to be set by the axon diameter or to be a property intrinsic to oligodendrocytes. Importantly, while TTX block of neuronal activity had no effect on oligodendrocyte lineage cell number when applied alone, it was able to completely abolish the effect of blocking GABAA receptors, suggesting that control of myelination by endogenous GABA may require a permissive factor to be released from axons. In contrast, block of AMPA/KA receptors had no effect on oligodendrocyte lineage cell number or myelination. These results imply that, during development, GABA can act as a local environmental cue to control myelination and thus influence the conduction velocity of action potentials within the CNS. GLIA 2017;65:309–321 PMID:27796063

  16. Cellular iron status influences the functional relationship between microglia and oligodendrocytes.

    PubMed

    Zhang, X; Surguladze, N; Slagle-Webb, B; Cozzi, A; Connor, J R

    2006-12-01

    Previously, we have reported that there is a spatiotemporal relationship between iron accumulation in microglia and oligodendrocytes during normal development and in remyelination following injury. This in vivo observation has prompted us to develop a cell culture model to test the relationship between iron status of microglia and survival of oligodendrocytes. We found that conditioned media from iron-loaded microglia increases the survival of oligodendrocytes; but conditioned media from iron loaded activated microglia is toxic to oligodendrocytes. In the trophic condition, one of the proteins released by iron-loaded microglia is H-ferritin, and transfecting the microglia with siRNA for H-ferritin blocks the trophic response on oligodendrocytes. Lipopolysaccharide (LPS) activation decreases the amount of H-ferritin that is released from microglia and increases the release of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. LPS activation of iron-enriched microglia results in the activation of NF-kB and greater release of cytokines when compared with that of control microglia; whereas treating microglia with an iron chelator is associated with less NF-kB activation and less release of cytokines. These results indicate that microglia play an important role in iron homoeostasis and that their iron status can influence how microglia influence growth and survival of oligodendrocytes. The results further indicate that ferritin, released by microglia, is a significant source of iron for oligodendrocytes.

  17. Endogenous GABA controls oligodendrocyte lineage cell number, myelination, and CNS internode length.

    PubMed

    Hamilton, Nicola B; Clarke, Laura E; Arancibia-Carcamo, I Lorena; Kougioumtzidou, Eleni; Matthey, Moritz; Káradóttir, Ragnhildur; Whiteley, Louise; Bergersen, Linda H; Richardson, William D; Attwell, David

    2017-02-01

    Adjusting the thickness and internodal length of the myelin sheath is a mechanism for tuning the conduction velocity of axons to match computational needs. Interactions between oligodendrocyte precursor cells (OPCs) and developing axons regulate the formation of myelin around axons. We now show, using organotypic cerebral cortex slices from mice expressing eGFP in Sox10-positive oligodendrocytes, that endogenously released GABA, acting on GABAA receptors, greatly reduces the number of oligodendrocyte lineage cells. The decrease in oligodendrocyte number correlates with a reduction in the amount of myelination but also an increase in internode length, a parameter previously thought to be set by the axon diameter or to be a property intrinsic to oligodendrocytes. Importantly, while TTX block of neuronal activity had no effect on oligodendrocyte lineage cell number when applied alone, it was able to completely abolish the effect of blocking GABAA receptors, suggesting that control of myelination by endogenous GABA may require a permissive factor to be released from axons. In contrast, block of AMPA/KA receptors had no effect on oligodendrocyte lineage cell number or myelination. These results imply that, during development, GABA can act as a local environmental cue to control myelination and thus influence the conduction velocity of action potentials within the CNS. GLIA 2017;65:309-321.

  18. IκB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-κB in the central nervous system

    PubMed Central

    Raasch, Jenni; Zeller, Nicolas; van Loo, Geert; Merkler, Doron; Mildner, Alexander; Erny, Daniel; Knobeloch, Klaus-Peter; Bethea, John R.; Waisman, Ari; Knust, Markus; Del Turco, Domenico; Deller, Thomas; Blank, Thomas; Priller, Josef; Brück, Wolfgang

    2011-01-01

    The IκB kinase complex induces nuclear factor kappa B activation and has recently been recognized as a key player of autoimmunity in the central nervous system. Notably, IκB kinase/nuclear factor kappa B signalling regulates peripheral myelin formation by Schwann cells, however, its role in myelin formation in the central nervous system during health and disease is largely unknown. Surprisingly, we found that brain-specific IκB kinase 2 expression is dispensable for proper myelin assembly and repair in the central nervous system, but instead plays a fundamental role for the loss of myelin in the cuprizone model. During toxic demyelination, inhibition of nuclear factor kappa B activation by conditional ablation of IκB kinase 2 resulted in strong preservation of central nervous system myelin, reduced expression of proinflammatory mediators and a significantly attenuated glial response. Importantly, IκB kinase 2 depletion in astrocytes, but not in oligodendrocytes, was sufficient to protect mice from myelin loss. Our results reveal a crucial role of glial cell-specific IκB kinase 2/nuclear factor kappa B signalling for oligodendrocyte damage during toxic demyelination. Thus, therapies targeting IκB kinase 2 function in non-neuronal cells may represent a promising strategy for the treatment of distinct demyelinating central nervous system diseases. PMID:21310728

  19. Sprayable lightweight ablative coating

    NASA Technical Reports Server (NTRS)

    Simpson, William G. (Inventor); Sharpe, Max H. (Inventor); Hill, William E. (Inventor)

    1991-01-01

    An improved lightweight, ablative coating is disclosed that may be spray applied and cured without the development of appreciable shrinkage cracks. The ablative mixture consists essentially of phenolic microballoons, hollow glass spheres, glass fibers, ground cork, a flexibilized resin binder, and an activated colloidal clay.

  20. The relationship between developing oligodendrocyte units and maturing axons during myelinogenesis in the anterior medullary velum of neonatal rats.

    PubMed

    Butt, A M; Ibrahim, M; Berry, M

    1997-05-01

    Myelinogenesis was investigated in whole-mounted anterior medullary vela from rats aged postnatal day (P) 10-12, using double immunofluorescence labelling with Rip and anti-neurofilament 200 (NF200) antibodies, to identify oligodendrocytes and axons, respectively. A number of discrete phases of maturation of oligodendrocyte units were recognised. (1) Promyelinating oligodendrocytes co-expressed Rip and Myelin basic Protein and formed axonal associations, prior to ensheathment. (2) Transitional oligodendrocytes contained both ensheathing and non-ensheating processes. (3) Myelinating oligodendrocytes were established after a period of remodelling (in which non-ensheathing processes were lost), appearing as oligodendrocyte unit morphological phenotypes with a definitive number of incipient myelin sheaths. (4) Maturation of myelinating oligodendrocytes was defined as the establishment of internodal sheath lengths and the redistrubution of myelin basic protein from the cell somata and radial processes into the myelin sheaths only. Myelination was probably related to the maturational state of the axons, since it was initiated when the latter had attained a critical diameter of between approximately 0.2 and 0.4 micron, coincident with the expression of NF200. Oligodendrocyte differentiation and myelination of the AMV were asynchronous and multifocal, and at P10: (1) axons which were destined to be of the largest calibre in the adult AMV were already myelinated by early developing oligodendrocytes, whilst those which were destined to be the smallest calibre in the adult were unmyelinated, but ultimately became ensheathed by late developing oligoendrocytes; (2) axons were sequentially ensheathed by early developing myelinating oligodendrocytes and late developing promyelinating oligodendrocytes; (3) all axons were small calibre; (4) oligodendrocyte units exhibited polymorphism. Thus, the development of oligodendrocyte morphological phenotypes was not related solely to

  1. Migrating Oligodendrocyte Progenitor Cells Swell Prior to Soma Dislocation

    PubMed Central

    Happel, Patrick; Möller, Kerstin; Schwering, Nina K.; Dietzel, Irmgard D.

    2013-01-01

    The migration of oligodendrocyte progenitor cells (OPCs) to the white matter is an indispensable requirement for an intact brain function. The mechanism of cell migration in general is not yet completely understood. Nevertheless, evidence is accumulating that besides the coordinated rearrangement of the cytoskeleton, a finetuned interplay of ion and water fluxes across the cell membrane is essential for cell migration. One part of a general hypothesis is that a local volume increase towards the direction of movement triggers a mechano-activated calcium influx that regulates various procedures at the rear end of a migrating cell. Here, we investigated cell volume changes of migrating OPCs using scanning ion conductance microscopy. We found that during accelerated migration OPCs undergo an increase in the frontal cell body volume. These findings are supplemented with time lapse calcium imaging data that hint an increase in calcium content the frontal part of the cell soma. PMID:23657670

  2. Excitability and synaptic communication within the oligodendrocyte lineage.

    PubMed

    De Biase, Lindsay M; Nishiyama, Akiko; Bergles, Dwight E

    2010-03-10

    The mammalian CNS contains an abundant, widely distributed population of glial cells that serve as oligodendrocyte progenitors. It has been reported that these NG2-immunoreactive cells (NG2(+) cells) form synapses and generate action potentials, suggesting that neural-evoked excitation of these progenitors may regulate oligodendrogenesis. However, recent studies also suggest that NG2(+) cells are comprised of functionally distinct groups that differ in their ability to respond to neuronal activity, undergo differentiation, and experience injury following ischemia. To better define the physiological properties of NG2(+) cells, we used transgenic mice that allowed an unbiased sampling of this population and unambiguous identification of cells in discrete states of differentiation. Using acute brain slices prepared from developing and mature mice, we found that NG2(+) cells in diverse brain regions share a core set of physiological properties, including expression of voltage-gated Na(+) (NaV) channels and ionotropic glutamate receptors, and formation of synapses with glutamatergic neurons. Although small amplitude Na(+) spikes could be elicited in some NG2(+) cells during the first postnatal week, they were not capable of generating action potentials. Transition of these progenitors to the premyelinating stage was accompanied by the rapid removal of synaptic input, as well as downregulation of AMPA and NMDA receptors and NaV channels. Thus, prior reports of physiological heterogeneity among NG2(+) cells may reflect analysis of cells in later stages of maturation. These results suggest that NG2(+) cells are uniquely positioned within the oligodendrocyte lineage to monitor the firing patterns of surrounding neurons.

  3. Tumor Ablation and Nanotechnology

    PubMed Central

    Manthe, Rachel L.; Foy, Susan P.; Krishnamurthy, Nishanth; Sharma, Blanka; Labhasetwar, Vinod

    2010-01-01

    Next to surgical resection, tumor ablation is a commonly used intervention in the treatment of solid tumors. Tumor ablation methods include thermal therapies, photodynamic therapy, and reactive oxygen species (ROS) producing agents. Thermal therapies induce tumor cell death via thermal energy and include radiofrequency, microwave, high intensity focused ultrasound, and cryoablation. Photodynamic therapy and ROS producing agents cause increased oxidative stress in tumor cells leading to apoptosis. While these therapies are safe and viable alternatives when resection of malignancies is not feasible, they do have associated limitations that prevent their widespread use in clinical applications. To improve the efficacy of these treatments, nanoparticles are being studied in combination with nonsurgical ablation regimens. In addition to better thermal effect on tumor ablation, nanoparticles can deliver anticancer therapeutics that show synergistic anti-tumor effect in the presence of heat and can also be imaged to achieve precision in therapy. Understanding the molecular mechanism of nanoparticle-mediated tumor ablation could further help engineer nanoparticles of appropriate composition and properties to synergize the ablation effect. This review aims to explore the various types of nonsurgical tumor ablation methods currently used in cancer treatment and potential improvements by nanotechnology applications. PMID:20866097

  4. Ablation of the ability to control the right-to-left cardiac shunt does not affect oxygen uptake, specific dynamic action or growth in the rattlesnake Crotalus durissus.

    PubMed

    Leite, Cleo A C; Taylor, Edwin W; Wang, Tobias; Abe, Augusto S; de Andrade, Denis O V

    2013-05-15

    The morphologically undivided ventricle of the heart in non-crocodilian reptiles permits the mixing of oxygen-rich blood returning from the lungs and oxygen-poor blood from the systemic circulation. A possible functional significance for this intra-cardiac shunt has been debated for almost a century. Unilateral left vagotomy rendered the single effective pulmonary artery of the South American rattlesnake, Crotalus durissus, unable to adjust the magnitude of blood flow to the lung. The higher constant perfusion of the lung circulation and the incapability of adjusting the right-left shunt in left-denervated snakes persisted over time, providing a unique model for investigation of the long-term consequences of cardiac shunting in a squamate. Oxygen uptake recorded at rest and during spontaneous and forced activity was not affected by removing control of the cardiac shunt. Furthermore, metabolic rate and energetic balance during the post-prandial metabolic increment, plus the food conversion efficiency and growth rate, were all similarly unaffected. These results show that control of cardiac shunting is not associated with a clear functional advantage in adjusting metabolic rate, effectiveness of digestion or growth rates.

  5. The Anti-Aging and Tumor Suppressor Protein Klotho Enhances Differentiation of a Human Oligodendrocytic Hybrid Cell Line

    PubMed Central

    Chen, Ci-Di; Liang, Jennifer; Hixson, Kathryn; Zeldich, Ella; Abraham, Carmela R.

    2016-01-01

    Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats, and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here, we examined the signaling pathways induced by Klotho in MO3.13, a human oligodendrocytic hybrid cell line. We show that exogenous Klotho affects the ERK and Akt signaling pathways, decreases the proliferative abilities and enhances differentiation of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80 % of the differentially expressed genes being downregulated. Using gene set enrichment analysis, we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging, and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain and other malignancies. PMID:24907942

  6. A zinc finger protein that regulates oligodendrocyte specification, migration and myelination in zebrafish

    PubMed Central

    Sidik, Harwin; Talbot, William S.

    2015-01-01

    Precise control of oligodendrocyte migration and development is crucial for myelination of axons in the central nervous system (CNS), but important questions remain unanswered about the mechanisms controlling these processes. In a zebrafish screen for myelination mutants, we identified a mutation in zinc finger protein 16-like (znf16l). znf16l mutant larvae have reduced myelin basic protein (mbp) expression and reduced CNS myelin. Marker, time-lapse and ultrastructural studies indicated that oligodendrocyte specification, migration and myelination are disrupted in znf16l mutants. Transgenic studies indicated that znf16l acts autonomously in oligodendrocytes. Expression of Zfp488 from mouse rescued mbp expression in znf16l mutants, indicating that these homologs have overlapping functions. Our results defined the function of a new zinc finger protein with specific function in oligodendrocyte specification, migration and myelination in the developing CNS. PMID:26459222

  7. Transcription factor–mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells

    PubMed Central

    Najm, Fadi J.; Lager, Angela M.; Zaremba, Anita; Wyatt, Krysta; Caprariello, Andrew V.; Factor, Daniel C.; Karl, Robert T.; Maeda, Tadao; Miller, Robert H.; Tesar, Paul J.

    2013-01-01

    Cell-based therapies for myelin disorders, such as multiple sclerosis and leukodystrophies, require technologies to generate functional oligodendrocyte progenitor cells. Here we describe direct conversion of mouse embryonic and lung fibroblasts to “induced” oligodendrocyte progenitor cells (iOPCs) using sets of either eight or three defined transcription factors. iOPCs exhibit a bipolar morphology and global gene expression profile consistent with bona fide OPCs. They can be expanded in vitro for at least five passages while retaining the ability to differentiate into multiprocessed oligodendrocytes. When transplanted to hypomyelinated mice, iOPCs are capable of ensheathing host axons and generating compact myelin. Lineage conversion of somatic cells to expandable iOPCs provides a strategy to study the molecular control of oligodendrocyte lineage identity and may facilitate neurological disease modeling and autologous remyelinating therapies. PMID:23584611

  8. Excitotoxic oligodendrocyte death and axonal damage induced by glutamate transporter inhibition.

    PubMed

    Domercq, María; Etxebarria, Estibaliz; Pérez-Samartín, Alberto; Matute, Carlos

    2005-10-01

    Glutamate uptake is crucial to terminate glutamate signaling and to prevent excitotoxicity. The present study describes the expression of functional glutamate transporters GLAST and GLT-1 in oligodendrocytes by means of electrophysiology, uptake assays, and immunocytochemistry. Inhibition of glutamate uptake, both in oligodendrocyte cultures and in isolated optic nerves, increases glutamate levels and causes oligodendrocyte excitotoxicity, which is prevented by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptor antagonists. Furthermore, glutamate transporter inhibitors or antisense oligonucleotides applied onto the optic nerve in vivo lead to oligodendroglial loss, massive demyelination, and severe axonal damage. Overall, these results demonstrate that the integrity of oligodendrocytes and white matter depends on proper glutamate transporter function. Deregulated transporter activity may contribute to acute and chronic white matter damage.

  9. Ablation of CBP in forebrain principal neurons causes modest memory and transcriptional defects and a dramatic reduction of histone acetylation but does not affect cell viability.

    PubMed

    Valor, Luis M; Pulopulos, Matias M; Jimenez-Minchan, Maria; Olivares, Roman; Lutz, Beat; Barco, Angel

    2011-02-02

    Rubinstein-Taybi syndrome (RSTS) is an inheritable disease associated with mutations in the gene encoding the CREB (cAMP response element-binding protein)-binding protein (CBP) and characterized by growth impairment, learning disabilities, and distinctive facial and skeletal features. Studies in mouse models for RSTS first suggested a direct role for CBP and histone acetylation in cognition and memory. Here, we took advantage of the genetic tools for generating mice in which the CBP gene is specifically deleted in postmitotic principal neurons of the forebrain to investigate the consequences of the loss of CBP in the adult brain. In contrast to the conventional CBP knock-out mice, which exhibit very early embryonic lethality, postnatal forebrain-restricted CBP mutants were viable and displayed no overt abnormalities. We identified the dimer of histones H2A and H2B as the preferred substrate of the histone acetyltransferase domain of CBP. Surprisingly, the loss of CBP and subsequent histone hypoacetylation had a very modest impact in the expression of a number of immediate early genes and did not affect neuronal viability. In addition, the behavioral characterization of these mice dissociated embryonic and postnatal deficits caused by impaired CBP function, narrowed down the anatomical substrate of specific behavioral defects, and confirmed the special sensitivity of object recognition memory to CBP deficiency. Overall, our study provides novel insights into RSTS etiology and clarifies some of the standing questions concerning the role of CBP and histone acetylation in activity-driven gene expression, memory formation, and neurodegeneration.

  10. Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination.

    PubMed

    Dutta, Dipankar J; Zameer, Andleeb; Mariani, John N; Zhang, Jingya; Asp, Linnea; Huynh, Jimmy; Mahase, Sean; Laitman, Benjamin M; Argaw, Azeb Tadesse; Mitiku, Nesanet; Urbanski, Mateusz; Melendez-Vasquez, Carmen V; Casaccia, Patrizia; Hayot, Fernand; Bottinger, Erwin P; Brown, Chester W; John, Gareth R

    2014-06-01

    In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLP-neuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb(-/-) embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3(-/-) mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation.

  11. IKAP/hELP1 deficiency in the cerebrum of familial dysautonomia patients results in down regulation of genes involved in oligodendrocyte differentiation and in myelination.

    PubMed

    Cheishvili, David; Maayan, Channa; Smith, Yoav; Ast, Gil; Razin, Aharon

    2007-09-01

    The gene affected in the congenital neuropathy familial dysautonomia (FD) is IKBKAP that codes for the IKAP/hELP1 protein. Several different functions have been suggested for this protein, but none of them have been verified in vivo or shown to have some link with the FD phenotype. In an attempt to elucidate the involvement of IKAP/hELP1 in brain function, we searched for IKAP/hELP1 target genes associated with neuronal function. In a microarray expression analysis using RNA extracted from the cerebrum of two FD patients as well as sex and age matched controls, no genes were found to be upregulated in the FD cerebrum. However, 25 genes were downregulated more than 2-fold in the cerebrum of both the male FD child and female FD mature woman. Thirteen of them are known to be involved in oligodendrocyte development and myelin formation. The down regulation of all these genes was verified by real-time PCR. Four of these genes were also confirmed to be downregulated at the protein level. These results are statistically significant and have high biological relevance, since seven of the downregulated genes in the cerebrum of the FD patients were shown by others to be upregulated during oligodendrocyte differentiation in vitro. Our results therefore suggest that IKAP/hELP1 may play a role in oligodendrocyte differentiation and/or myelin formation.

  12. Thermal ablation for hepatocellular carcinoma.

    PubMed

    Head, Hayden W; Dodd, Gerald D

    2004-11-01

    Thermal ablation, as a form of minimally invasive therapy for hepatocellular carcinoma (HCC), has become an important treatment modality. Because of the limitations of surgery, the techniques of thermal ablation have become standard therapies for HCC in some situations. This article reviews 4 thermal ablation techniques-radiofrequency (RF) ablation, microwave ablation, laser ablation, and cryoablation. Each of these techniques may have a role in treating HCC, and the mechanisms, equipment, patient selection, results, and complications of each are considered. Furthermore, combined therapies consisting of thermal ablation and adjuvant chemotherapy also show promise for enhancing these techniques. Important areas of research into thermal ablation remain, including improving the ability of ablation to treat larger tumors, determining the indications for each thermal ablation modality, optimizing image guidance, and obtaining good outcome data on the efficacy of these techniques.

  13. Developmental cuprizone exposure impairs oligodendrocyte lineages differentially in cortical and white matter tissues and suppresses glutamatergic neurogenesis signals and synaptic plasticity in the hippocampal dentate gyrus of rats.

    PubMed

    Abe, Hajime; Saito, Fumiyo; Tanaka, Takeshi; Mizukami, Sayaka; Hasegawa-Baba, Yasuko; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

    2016-01-01

    Developmental cuprizone (CPZ) exposure impairs rat hippocampal neurogenesis. Here, we captured the developmental neurotoxicity profile of CPZ using a region-specific expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex and cerebellar vermis of rat offspring exposed to 0, 0.1, or 0.4% CPZ in the maternal diet from gestation day 6 to postnatal day (PND) 21. Transcripts of those genes identified as altered were subjected to immunohistochemical analysis on PNDs 21 and 77. Our results showed that transcripts for myelinogenesis-related genes, including Cnp, were selectively downregulated in the cerebral cortex by CPZ at ≥0.1% or 0.4% on PND 21. CPZ at 0.4% decreased immunostaining intensity for 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) and CNPase(+) and OLIG2(+) oligodendrocyte densities in the cerebral cortex, whereas CNPase immunostaining intensity alone was decreased in the corpus callosum. By contrast, a striking transcript upregulation for Klotho gene and an increased density of Klotho(+) oligodendrocytes were detected in the corpus callosum at ≥0.1%. In the dentate gyrus, CPZ at ≥0.1% or 0.4% decreased the transcript levels for Gria1, Grin2a and Ptgs2, genes related to the synapse and synaptic transmission, and the number of GRIA1(+) and GRIN2A(+) hilar γ-aminobutyric acid (GABA)-ergic interneurons and cyclooxygenase-2(+) granule cells. All changes were reversed at PND 77. Thus, developmental CPZ exposure reversibly decreased mature oligodendrocytes in both cortical and white matter tissues, and Klotho protected white matter oligodendrocyte growth. CPZ also reversibly targeted glutamatergic signals of GABAergic interneuron to affect dentate gyrus neurogenesis and synaptic plasticity in granule cells.

  14. Neurobehavioral and cytotoxic effects of vanadium during oligodendrocyte maturation: a protective role for erythropoietin.

    PubMed

    Mustapha, Oluwaseun; Oke, Bankole; Offen, Nils; Sirén, Anna-Leena; Olopade, James

    2014-07-01

    Vanadium exposure has been known to lead to lipid peroxidation, demyelination and oligodendrocytes depletion. We investigated behaviour and glial reactions in juvenile mice after early neonatal exposure to vanadium, and examined the direct effects of vanadium in oligodendrocyte progenitor cultures from embryonic mice. Neonatal pups exposed to vanadium via lactation for 15 and 22 days all had lower body weights. Behavioural tests showed in most instances a reduction in locomotor activity and negative geotaxis. Brain analyses revealed astrocytic activation and demyelination in the vanadium exposed groups compared to the controls. In cell culture, exposure of oligodendrocytes to 300 μM sodium metavanadate significantly increased cell death. Expression of the oligodendrocyte specific proteins, 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and oligodendrocyte specific protein (OSP/Claudin) were reduced upon vanadium treatment while simultaneous administration of erythropoietin (EPO; 4-12 U/ml) counteracted vanadium-toxicity. The data suggest that oligodendrocyte damage may explain the increased vulnerability of the juvenile brain to vanadium and support a potential for erythropoietin as a protective agent against vanadium-toxicity during perinatal brain development and maturation.

  15. Oligodendrocyte-microglia cross-talk in the central nervous system.

    PubMed

    Peferoen, Laura; Kipp, Markus; van der Valk, Paul; van Noort, Johannes M; Amor, Sandra

    2014-03-01

    Communication between the immune system and the central nervous system (CNS) is exemplified by cross-talk between glia and neurons shown to be essential for maintaining homeostasis. While microglia are actively modulated by neurons in the healthy brain, little is known about the cross-talk between oligodendrocytes and microglia. Oligodendrocytes, the myelin-forming cells in the CNS, are essential for the propagation of action potentials along axons, and additionally serve to support neurons by producing neurotrophic factors. In demyelinating diseases such as multiple sclerosis, oligodendrocytes are thought to be the victims. Here, we review evidence that oligodendrocytes also have strong immune functions, express a wide variety of innate immune receptors, and produce and respond to chemokines and cytokines that modulate immune responses in the CNS. We also review evidence that during stress events in the brain, oligodendrocytes can trigger a cascade of protective and regenerative responses, in addition to responses that elicit progressive neurodegeneration. Knowledge of the cross-talk between microglia and oligodendrocytes may continue to uncover novel pathways of immune regulation in the brain that could be further exploited to control neuroinflammation and degeneration.

  16. In vitro and in vivo induction and activation of nNOS by LPS in oligodendrocytes

    PubMed Central

    Yao, SY.; Ljunggren-Rose, A.; Chandramohan, N.; Whetsell, W.O.; Sriram, S.

    2014-01-01

    There are currently four known isoforms of nitric oxide synthase (NOS). Of these, neuronal NOS (nNOS) is known to be present exclusively in neurons, endothelial NOS (eNOS) in vascular endothelium, while the inducible form of NOS (iNOS) is known to be activated in oligodendrocytes, astrocytes and microglia. The fourth isoform, mitochondrial NOS (mtNOS), represents a post translational modification of nNOS. Using western blotting and real time-PCR, we show induction and activation of nNOS following culture of oligodendrocyte progenitor cells (OPC) with lipopolysaccharide (LPS). Activation of nNOS results in accumulation of peroxynitrite and tyrosine nitration of proteins in oligodendrocytes resulting in reduced cell viability. Injection of LPS in vivo into the corpus callosum of rats leads to the development of extensive demyelination of the white matter tracts. Immunostaining of regions close to the injection site shows the presence of nNOS, but not iNOS, in oligodendrocytes. Neither iNOS nor nNOS was seen in astrocytes in areas of demyelination. These studies suggest that activation of nNOS in oligodendrocytes leads to oligodendrocyte injury resulting in demyelination. PMID:20724006

  17. Axon-myelin sheath relations of oligodendrocyte unit phenotypes in the adult rat anterior medullary velum.

    PubMed

    Butt, A M; Ibrahim, M; Berry, M

    1998-04-01

    Axon-oligodendrocyte relations of Rip-immunolabelled and dye-injected oligodendrocyte units are characterised in the adult rat anterior medullary velum (AMV). Each oligodendrocyte unit comprised the oligodendrocyte cell body, processes and the internodal myelin segments they support. Oligodendrocyte units corresponded to classically described type I/II or type III/IV unit phenotypes which respectively myelinated discrete populations of small and large diameter axons, delineated by a myelinated fire diameter of 2-4 microns (diameter of the axon plus its myelin sheath). Within units, mean fibre diameter was directly related to mean internodal length and inversely related to the number of myelin sheaths in the unit. The relationship between fibre diameter and internodal length was retained in units which myelinated axons of different diameters, indicating that axon diameter was an important determinant of the longitudinal dimensions of myelin sheaths. We also show that type III/IV units maintained a far greater volume of myelin than type I/II units. It was concluded that type I/II and III/IV oligodendrocytes represent two functionally and morphologically distinct phenotypes whose distribution densities were determined by the diameter and spatial dispersion of axons.

  18. Ablative skin resurfacing.

    PubMed

    Agrawal, Nidhi; Smith, Greg; Heffelfinger, Ryan

    2014-02-01

    Ablative laser resurfacing has evolved as a safe and effective treatment for skin rejuvenation. Although traditional lasers were associated with significant thermal damage and lengthy recovery, advances in laser technology have improved safety profiles and reduced social downtime. CO2 lasers remain the gold standard of treatment, and fractional ablative devices capable of achieving remarkable clinical improvement with fewer side effects and shorter recovery times have made it a more practical option for patients. Although ablative resurfacing has become safer, careful patient selection and choice of suitable laser parameters are essential to minimize complications and optimize outcomes. This article describes the current modalities used in ablative laser skin resurfacing and examines their efficacy, indications, and possible side effects.

  19. Moldable cork ablation material

    NASA Technical Reports Server (NTRS)

    1977-01-01

    A successful thermal ablative material was manufactured. Moldable cork sheets were tested for density, tensile strength, tensile elongation, thermal conductivity, compression set, and specific heat. A moldable cork sheet, therefore, was established as a realistic product.

  20. Endometrial Ablation for Menorrhagia

    PubMed Central

    Sanders, Barry H.

    1992-01-01

    Endometrial ablation is a relatively new treatment for patients with persistent menorrhagia. The procedure can be performed by either laser photocoagulation or electrocoagulation; both have a very low risk of complication. Generally, less than 24 hours of hospitalization is required and return to normal activities, including work, is almost immediate. Endometrial ablation is likely to become a mainstay of treatment for menorrhagia as the technology and training become more readily available. PMID:21229128

  1. TLR4 Deficiency Impairs Oligodendrocyte Formation in the Injured Spinal Cord

    PubMed Central

    Church, Jamie S.; Kigerl, Kristina A.; Lerch, Jessica K.; Popovich, Phillip G.

    2016-01-01

    Acute oligodendrocyte (OL) death after traumatic spinal cord injury (SCI) is followed by robust neuron–glial antigen 2 (NG2)-positive OL progenitor proliferation and differentiation into new OLs. Inflammatory mediators are prevalent during both phases and can influence the fate of NG2 cells and OLs. Specifically, toll-like receptor (TLR) 4 signaling induces OL genesis in the naive spinal cord, and lack of TLR4 signaling impairs white matter sparing and functional recovery after SCI. Therefore, we hypothesized that TLR4 signaling may regulate oligodendrogenesis after SCI. C3H/HeJ (TLR4-deficient) and control (C3H/HeOuJ) mice received a moderate midthoracic spinal contusion. TLR4-deficient mice showed worse functional recovery and reduced OL numbers compared with controls at 24 h after injury through chronic time points. Acute OL loss was accompanied by reduced ferritin expression, which is regulated by TLR4 and needed for effective iron storage. TLR4-deficient injured spinal cords also displayed features consistent with reduced OL genesis, including reduced NG2 expression, fewer BrdU-positive OLs, altered BMP4 signaling and inhibitor of differentiation 4 (ID4) expression, and delayed myelin phagocytosis. Expression of several factors, including IGF-1, FGF2, IL-1β, and PDGF-A, was altered in TLR4-deficient injured spinal cords compared with wild types. Together, these data show that TLR4 signaling after SCI is important for OL lineage cell sparing and replacement, as well as in regulating cytokine and growth factor expression. These results highlight new roles for TLR4 in endogenous SCI repair and emphasize that altering the function of a single immune-related receptor can dramatically change the reparative responses of multiple cellular constituents in the injured CNS milieu. SIGNIFICANCE STATEMENT Myelinating cells of the CNS [oligodendrocytes (OLs)] are killed for several weeks after traumatic spinal cord injury (SCI), but they are replaced by resident

  2. FGF-2 signal promotes proliferation of cerebellar progenitor cells and their oligodendrocytic differentiation at early postnatal stage

    SciTech Connect

    Naruse, Masae; Shibasaki, Koji; Ishizaki, Yasuki

    2015-08-07

    The origins and developmental regulation of cerebellar oligodendrocytes are largely unknown, although some hypotheses of embryonic origins have been suggested. Neural stem cells exist in the white matter of postnatal cerebellum, but it is unclear whether these neural stem cells generate oligodendrocytes at postnatal stages. We previously showed that cerebellar progenitor cells, including neural stem cells, widely express CD44 at around postnatal day 3. In the present study, we showed that CD44-positive cells prepared from the postnatal day 3 cerebellum gave rise to neurospheres, while CD44-negative cells prepared from the same cerebellum did not. These neurospheres differentiated mainly into oligodendrocytes and astrocytes, suggesting that CD44-positive neural stem/progenitor cells might generate oligodendrocytes in postnatal cerebellum. We cultured CD44-positive cells from the postnatal day 3 cerebellum in the presence of signaling molecules known as mitogens or inductive differentiation factors for oligodendrocyte progenitor cells. Of these, only FGF-2 promoted survival and proliferation of CD44-positive cells, and these cells differentiated into O4+ oligodendrocytes. Furthermore, we examined the effect of FGF-2 on cerebellar oligodendrocyte development ex vivo. FGF-2 enhanced proliferation of oligodendrocyte progenitor cells and increased the number of O4+ and CC1+ oligodendrocytes in slice cultures. These results suggest that CD44-positive cells might be a source of cerebellar oligodendrocytes and that FGF-2 plays important roles in their development at an early postnatal stage. - Highlights: • CD44 is expressed in cerebellar neural stem/progenitor cells at postnatal day 3 (P3). • FGF-2 promoted proliferation of CD44-positive progenitor cells from P3 cerebellum. • FGF-2 promoted oligodendrocytic differentiation of CD44-positive progenitor cells. • FGF-2 increased the number of oligodendrocytes in P3 cerebellar slice culture.

  3. The developing oligodendrocyte: key cellular target in brain injury in the premature infant.

    PubMed

    Volpe, Joseph J; Kinney, Hannah C; Jensen, Frances E; Rosenberg, Paul A

    2011-06-01

    Brain injury in the premature infant, a problem of enormous importance, is associated with a high risk of neurodevelopmental disability. The major type of injury involves cerebral white matter and the principal cellular target is the developing oligodendrocyte. The specific phase of the oligodendroglial lineage affected has been defined from study of both human brain and experimental models. This premyelinating cell (pre-OL) is vulnerable because of a series of maturation-dependent events. The pathogenesis of pre-OL injury relates to operation of two upstream mechanisms, hypoxia-ischemia and systemic infection/inflammation, both of which are common occurrences in premature infants. The focus of this review and of our research over the past 15-20 years has been the cellular and molecular bases for the maturation-dependent vulnerability of the pre-OL to the action of the two upstream mechanisms. Three downstream mechanisms have been identified, i.e., microglial activation, excitotoxicity and free radical attack. The work in both experimental models and human brain has identified a remarkable confluence of maturation-dependent factors that render the pre-OL so exquisitely vulnerable to these downstream mechanisms. Most importantly, elucidation of these factors has led to delineation of a series of potential therapeutic interventions, which in experimental models show marked protective properties. The critical next step, i.e., clinical trials in the living infant, is now on the horizon.

  4. Ceramide and neurodegeneration: Susceptibility of neurons and oligodendrocytes to cell damage and death

    PubMed Central

    Jana, Arundhati; Hogan, Edward L.; Pahan, Kalipada

    2009-01-01

    Neurodegenerative disorders are marked by extensive neuronal apoptosis and gliosis. Although several apoptosis-inducing agents have been described, understanding of the regulatory mechanisms underlying modes of cell death is incomplete. A major breakthrough in delineation of the mechanism of cell death came from elucidation of the sphingomyelin (SM)-ceramide pathway that has received worldwide attention in recent years. The SM pathway induces apoptosis, differentiation, proliferation, and growth arrest depending upon cell and receptor types, and on downstream targets. Sphingomyelin, a plasma membrane constituent, is abundant in mammalian nervous system, and ceramide, its primary catabolic product released by activation of either neutral or acidic sphingomyelinase, serves as a potential lipid second messenger or mediator molecule modulating diverse cellular signaling pathways. Neutral sphingomyelinase (NSMase) is a key enzyme in the regulated activation of the SM cycle and is particularly sensitive to oxidative stress. In a context of increasing clarification of the mechanisms of neurodegeneration, we thought that it would be useful to review details of recent findings that we and others have made concerning different pro-apoptotic neurotoxins including proinflammatory cytokines, hypoxia-induced SM hydrolysis and ceramide production that induce cell death in human primary neurons and primary oligodendrocytes: redox sensitive events. What has and is emerging is a vista of therapeutically important ceramide regulation affecting a variety of different neurodegenerative and neuroinflammatory disorders. PMID:19147160

  5. Neonatal Hyperoxia Exposure Disrupts Axon-Oligodendrocyte Integrity in the Sub-Cortical White Matter

    PubMed Central

    Ritter, Jonathan; Schmitz, Thomas; Chew, Li-Jin; Bührer, Christoph; Möbius, Wiebke; Zonouzi, Marzieh; Gallo, Vittorio

    2013-01-01

    The pathological mechanisms underlying neurological deficits observed in individuals born pre-maturely are not completely understood. A common form of injury in the pre-term population is periventricular white matter injury (PWMI), a pathology associated with impaired brain development. To mitigate or eliminate white matter injury, there is an urgent need to understand the pathological mechanism(s) involved on a neurobiological, structural and functional level. Recent clinical data suggests that a percentage of pre-mature infants experience relative hyperoxia. Using a hyperoxic model of pre-mature brain injury, we have previously demonstrated that neonatal hyperoxia exposure in the mouse disrupts development of the white matter (WM) by delaying the maturation of the oligodendroglial lineage. In the present study, we address the question of how hyperoxia-induced alterations in WM development affect overall WM integrity and axonal function. We show that neonatal hyperoxia causes ultra-structural changes, including i) myelination abnormalities (reduced myelin thickness and abnormal extra myelin loops) and ii) axonopathy (altered neurofilament phosphorylation, paranodal defects and changes in node of Ranvier number and structure). This disruption of axon-oligodendrocyte integrity results in the lasting impairment of conduction properties in the adult WM. Understanding the pathology of pre-mature PWMI injury will allow for the development of interventional strategies to preserve WM integrity and function. PMID:23699510

  6. Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries.

    PubMed

    Glezer, Isaias; Lapointe, Amelie; Rivest, Serge

    2006-04-01

    Regarded as a damaging reaction, innate immune response can either improve or worsen brain outcome after injury. Hence, inflammatory molecules might modulate cell susceptibility or healing events. The remyelination that follows brain lesions is dependent on the recruitment of oligodendrocyte progenitor cells (OPCs) and expression of genes controlling differentiation and myelin production, such as Olig1 and Olig2 bHLH transcription factors. We aimed to determine how innate immunity affects these processes. Here we report that lipopolysaccharide (LPS) infusion triggered OPC reactivity. Acute inflammation changed the distribution of Olig1- and Olig2-expressing cells following chemical demyelination, enhanced reappearance of transcription signals linked to remyelination and rapidly cleared myelin debris. Although cells expressing Olig1, Olig2, and proteolipid protein were attracted to demyelinated sites in the course of chronic inflammation, myelin loss was not associated with the effects of inflammation on OPC reactivity. In addition, the beneficial properties of brain immunity are broadened to an aggressive model of injury, wherein LPS through Toll-like receptor 4 (TLR4) reduced surfactant-mediated damage while anti-inflammatory treatment enlarged the lesion. In conclusion, TLR4 activation in microglia is a powerful mechanism for improving repair at the remyelination level and protecting the cerebral tissue in presence of agents with strong cytolytic properties.

  7. HIV-1 Tat Inhibits Autotaxin Lysophospholipase D Activity and Modulates Oligodendrocyte Differentiation

    PubMed Central

    Wheeler, Natalie A.; Fuss, Babette; Knapp, Pamela E.

    2016-01-01

    White matter injury has been frequently reported in HIV+ patients. Previous studies showed that HIV-1 Tat (transactivator of transcription), a viral protein that is produced and secreted by HIV-infected cells, is toxic to young, immature oligodendrocytes (OLGs). Adding Tat to the culture medium reduced the viability of immature OLGs, and the surviving OLGs exhibited reduced process networks. OLGs produce and secrete autotaxin (ATX), an ecto-enzyme containing a lysophospholipase D (lysoPLD) activity that converts lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a lipid signaling molecule that stimulates OLG differentiation. We hypothesized that Tat affects OLG development by interfering with the ATX-LPA signaling pathway. Our data show that Tat treatment leads to changes in the expression of OLG differentiation genes and the area of OLG process networks, both of which can be rescued by LPA. Tat-treated OLGs showed no change in LPA receptor expression but significantly decreased extracellular ATX levels and lysoPLD activity. In Tat transgenic mice, expression of Tat in vivo leads to decreased OLG ATX secretion. Furthermore, co-immunoprecipitation experiments revealed a potential physical interaction between Tat and ATX. Together, these data strongly suggest two functional implications of Tat blocking ATX’s lysoPLD activity. On one hand, it attenuates OLG differentiation, and on the other hand it interferes with the protective effects of LPA on OLG process morphology. PMID:27659560

  8. Functional identification of neural stem cell-derived oligodendrocytes.

    PubMed

    Grade, Sofia; Agasse, Fabienne; Bernardino, Liliana; Malva, João O

    2012-01-01

    Directing neural stem cells (NSCs) differentiation towards oligodendroglial cell lineage is a crucial step in the endeavor of developing cell replacement-based therapies for demyelinating diseases. Evaluation of NSCs differentiation is mostly performed by methodologies that use fixed cells, like immunocytochemistry, or lysates, like Western blot. On the other hand, electrophysiology allows differentiation studies on living cells, but it is highly time-consuming and endowed with important limitations concerning population studies. Herein, we describe a functional method, based on single cell calcium imaging, which accurately and rapidly distinguishes cell types among NSCs progeny, in living cultures prepared from the major reservoir of NSCs in the postnatal mouse brain, the subventricular zone (SVZ). Indeed, by applying a rational sequence of three stimuli-KCl, histamine, and thrombin-to the heterogeneous SVZ cell population, one can identify each cell phenotype according to its unique calcium signature. Mature oligodendrocytes, the myelin-forming cells of the central nervous system, are the thrombin-responsive cells in SVZ cell culture and display no intracellular calcium increase upon KCl or histamine perfusion. On the other hand, KCl and histamine stimulate neurons and immature cells, respectively. The method described in this chapter is a valuable tool to identify novel pro-oligodendrogenic compounds, which may play an important role in the design of future treatments for demyelinating disorders such as multiple sclerosis.

  9. Nerve growth factor signal transduction in mature pig oligodendrocytes.

    PubMed

    Althaus, H H; Hempel, R; Klöppner, S; Engel, J; Schmidt-Schultz, T; Kruska, L; Heumann, R

    1997-12-01

    It has previously been shown that nerve growth factor (NGF) is of functional significance for mature pig oligodendrocytes (OLs) in culture. The present data give evidence for the expression of TrkA, the so-called high-affinity NGF receptor, and of p75NTR, the so-called low-affinity NGF receptor. TrkA is upregulated during culturing, in contrast to the p75 receptor. Exposure of OLs to NGF induces an autophosphorylation of TrkA via its intrinsic tyrosine kinase. K-252a inhibits the TrkA autophosphorylation, which reduces the OL process formation to control levels. To the tyrosine-phosphorylated sites of TrkA several proteins, such as phospholipase C-gamma1, the adaptor protein SHC, the phosphotyrosine phosphatase SH-PTP2 (SYP) associate via their SH2 phosphotase SH-PTP2 domain. The association of SHC to TrkA is shown by co-immunoprecipitation. Indirect evidence for a possible activation of PLC-gamma1 is given by an NGF-induced increase of oligodendroglial [Ca2+]i. Downstream from TrkA, a mitogen-activated protein kinase cascade, which includes Erk1 and Erk2, is operating. An in-gel myelin basic protein kinase assay revealed that NGF activates predominantly Erk1. Finally, it is shown that NGF stimulates expression of c-fos.

  10. Apcdd1 stimulates oligodendrocyte differentiation after white matter injury

    PubMed Central

    Lee, Hyun Kyoung; Laug, Dylan; Zhu, Wenyi; Patel, Jay M; Ung, Kevin; Arenkiel, Benjamin R; Fancy, Stephen PJ; Mohila, Carrie; Deneen, Benjamin

    2015-01-01

    Wnt signaling plays an essential role in developmental and regenerative myelination of the CNS, therefore it is critical to understand how the factors associated with the various regulatory layers of this complex pathway contribute to these processes. Recently, Apcdd1 was identified as a negative regulator of proximal Wnt signaling, however its role in oligodendrodcyte (OL) differentiation and reymelination in the CNS remain undefined. Analysis of Apcdd1 expression revealed dynamic expression during OL development, where its expression is upregulated during differentiation. Functional studies using ex vivo and in vitro OL systems, revealed that Apcdd1 promotes OL differentiation, suppresses Wnt signaling, and associates with β-catenin. Application of these findings to white matter injury (WMI) models revealed that Apcdd1 similarly promotes OL differentiation after gliotoxic injury in vivo and acute hypoxia ex vivo. Examination of Apcdd1 expression in white matter lesions from neonatal WMI and adult Multiple Sclerosis revealed its expression in subsets of oligodendrocyte precursors. These studies describe, for the first time, the role of Apcdd1 in OLs after WMI and reveal that negative regulators of the proximal Wnt pathway can influence regenerative myelination, suggesting a new therapeutic strategy for modulating Wnt signaling and stimulating repair after WMI. PMID:25946682

  11. Oligodendrocyte progenitor programming and reprogramming: Toward myelin regeneration.

    PubMed

    Lopez Juarez, Alejandro; He, Danyang; Richard Lu, Q

    2016-05-01

    Demyelinating diseases such as multiple sclerosis (MS) are among the most disabling and cost-intensive neurological disorders. The loss of myelin in the central nervous system, produced by oligodendrocytes (OLs), impairs saltatory nerve conduction, leading to motor and cognitive deficits. Immunosuppression therapy has a limited efficacy in MS patients, arguing for a paradigm shift to strategies that target OL lineage cells to achieve myelin repair. The inhibitory microenvironment in MS lesions abrogates the expansion and differentiation of resident OL precursor cells (OPCs) into mature myelin-forming OLs. Recent studies indicate that OPCs display a highly plastic ability to differentiate into alternative cell lineages under certain circumstances. Thus, understanding the mechanisms that maintain and control OPC fate and differentiation into mature OLs in a hostile, non-permissive lesion environment may open new opportunities for regenerative therapies. In this review, we will focus on 1) the plasticity of OPCs in terms of their developmental origins, distribution, and differentiation potentials in the normal and injured brain; 2) recent discoveries of extrinsic and intrinsic factors and small molecule compounds that control OPC specification and differentiation; and 3) therapeutic potential for motivation of neural progenitor cells and reprogramming of differentiated cells into OPCs and their likely impacts on remyelination. OL-based therapies through activating regenerative potentials of OPCs or cell replacement offer exciting opportunities for innovative strategies to promote remyelination and neuroprotection in devastating demyelinating diseases like MS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only).

  12. Simulated microgravity enhances oligodendrocyte mitochondrial function and lipid metabolism.

    PubMed

    Espinosa-Jeffrey, Araceli; Nguyen, Kevin; Kumar, Shalini; Toshimasa, Ochiai; Hirose, Ryuji; Reue, Karen; Vergnes, Laurent; Kinchen, Jason; Vellis, Jean de

    2016-12-01

    The primary energy sources of mammalian cells are proteins, fats, and sugars that are processed by well-known biochemical mechanisms that have been discovered and studied in 1G (terrestrial gravity). Here we sought to determine how simulated microgravity (sim-µG) impacts both energy and lipid metabolism in oligodendrocytes (OLs), the myelin-forming cells in the central nervous system. We report increased mitochondrial respiration and increased glycolysis 24 hr after exposure to sim-µG. Moreover, examination of the secretome after 3 days' exposure of OLs to sim-µG increased the Krebs cycle (Krebs and Weitzman, ) flux in sim-µG. The secretome study also revealed a significant increase in the synthesis of fatty acids and complex lipids such as 1,2-dipalmitoyl-GPC (5.67); lysolipids like 1-oleoyl-GPE (4.48) were also increased by microgravity. Although longer-chain lipids were not observed in this study, it is possible that at longer time points OLs would have continued moving forward toward the synthesis of lipids that constitute myelin. For centuries, basic developmental biology research has been the pillar of an array of discoveries that have led to clinical applications; we believe that studies using microgravity will open new avenues to our understanding of the brain in health and disease-in particular, to the discovery of new molecules and mechanisms impossible to unveil while in 1G. © 2016 Wiley Periodicals, Inc.

  13. Laser ablated hard coating for microtools

    DOEpatents

    McLean, W. II; Balooch, M.; Siekhaus, W.J.

    1998-05-05

    Wear-resistant coatings composed of laser ablated hard carbon films, are deposited by pulsed laser ablation using visible light, on instruments such as microscope tips and micro-surgical tools. Hard carbon, known as diamond-like carbon (DLC), films produced by pulsed laser ablation using visible light enhances the abrasion resistance, wear characteristics, and lifetimes of small tools or instruments, such as small, sharp silicon tips used in atomic probe microscopy without significantly affecting the sharpness or size of these devices. For example, a 10--20 nm layer of diamond-like carbon on a standard silicon atomic force microscope (AFM) tip, enables the useful operating life of the tip to be increased by at least twofold. Moreover, the low inherent friction coefficient of the DLC coating leads to higher resolution for AFM tips operating in the contact mode. 12 figs.

  14. Laser ablated hard coating for microtools

    DOEpatents

    McLean, II, William; Balooch, Mehdi; Siekhaus, Wigbert J.

    1998-05-05

    Wear-resistant coatings composed of laser ablated hard carbon films, are deposited by pulsed laser ablation using visible light, on instruments such as microscope tips and micro-surgical tools. Hard carbon, known as diamond-like carbon (DLC), films produced by pulsed laser ablation using visible light enhances the abrasion resistance, wear characteristics, and lifetimes of small tools or instruments, such as small, sharp silicon tips used in atomic probe microscopy without significantly affecting the sharpness or size of these devices. For example, a 10-20 nm layer of diamond-like carbon on a standard silicon atomic force microscope (AFM) tip, enables the useful operating life of the tip to be increased by at least twofold. Moreover, the low inherent friction coefficient of the DLC coating leads to higher resolution for AFM tips operating in the contact mode.

  15. Infrared laser bone ablation

    SciTech Connect

    Nuss, R.C.; Fabian, R.L.; Sarkar, R.; Puliafito, C.A.

    1988-01-01

    The bone ablation characteristics of five infrared lasers, including three pulsed lasers (Nd:YAG, lambda = 1064 micron; Hol:YSGG, lambda = 2.10 micron; and Erb:YAG, lambda = 2.94 micron) and two continuous-wave lasers (Nd:YAG, lambda = 1.064 micron; and CO/sub 2/, lambda = 10.6 micron), were studied. All laser ablations were performed in vitro, using moist, freshly dissected calvarium of guinea pig skulls. Quantitative etch rates of the three pulsed lasers were calculated. Light microscopy of histologic sections of ablated bone revealed a zone of tissue damage of 10 to 15 micron adjacent to the lesion edge in the case of the pulsed Nd:YAG and the Erb:YAG lasers, from 20 to 90 micron zone of tissue damage for bone ablated by the Hol:YSGG laser, and 60 to 135 micron zone of tissue damage in the case of the two continuous-wave lasers. Possible mechanisms of bone ablation and tissue damage are discussed.

  16. Ba2+- and bupivacaine-sensitive background K+ conductances mediate rapid EPSP attenuation in oligodendrocyte precursor cells.

    PubMed

    Chan, Chu-Fang; Kuo, Tzu-Wei; Weng, Ju-Yun; Lin, Yen-Chu; Chen, Ting-Yu; Cheng, Jen-Kun; Lien, Cheng-Chang

    2013-10-01

    Glutamatergic transmission onto oligodendrocyte precursor cells (OPCs) may regulate OPC proliferation, migration and differentiation. Dendritic integration of excitatory postsynaptic potentials (EPSPs) is critical for neuronal functions, and mechanisms regulating dendritic propagation and summation of EPSPs are well understood. However, little is known about EPSP attenuation and integration in OPCs. We developed realistic OPC models for synaptic integration, based on passive membrane responses of OPCs obtained by simultaneous dual whole-cell patch-pipette recordings. Compared with neurons, OPCs have a very low value of membrane resistivity, which is largely mediated by Ba(2+)- and bupivacaine-sensitive background K(+) conductances. The very low membrane resistivity not only leads to rapid EPSP attenuation along OPC processes but also sharpens EPSPs and narrows the temporal window for EPSP summation. Thus, background K(+) conductances regulate synaptic responses and integration in OPCs, thereby affecting activity-dependent neuronal control of OPC development and function.

  17. A selective thyroid hormone β receptor agonist enhances human and rodent oligodendrocyte differentiation.

    PubMed

    Baxi, Emily G; Schott, Jason T; Fairchild, Amanda N; Kirby, Leslie A; Karani, Rabia; Uapinyoying, Prech; Pardo-Villamizar, Carlos; Rothstein, Jeffrey R; Bergles, Dwight E; Calabresi, Peter A

    2014-09-01

    Nerve conduction within the mammalian central nervous system is made efficient by oligodendrocyte-derived myelin. Historically, thyroid hormones have a well described role in regulating oligodendrocyte differentiation and myelination during development; however, it remains unclear which thyroid hormone receptors are required to drive these effects. This is a question with clinical relevance since nonspecific thyroid receptor stimulation can produce deleterious side-effects. Here we report that GC-1, a thyromimetic with selective thyroid receptor β action and a potentially limited side-effect profile, promotes in vitro oligodendrogenesis from both rodent and human oligodendrocyte progenitor cells. In addition, we used in vivo genetic fate tracing of oligodendrocyte progenitor cells via PDGFαR-CreER;Rosa26-eYFP double-transgenic mice to examine the effect of GC-1 on cellular fate and find that treatment with GC-1 during developmental myelination promotes oligodendrogenesis within the corpus callosum, occipital cortex and optic nerve. GC-1 was also observed to enhance the expression of the myelin proteins MBP, CNP and MAG within the same regions. These results indicate that a β receptor selective thyromimetic can enhance oligodendrocyte differentiation in vitro and during developmental myelination in vivo and warrants further study as a therapeutic agent for demyelinating models.

  18. Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendrocyte death

    PubMed Central

    Veto, Sara; Acs, Peter; Bauer, Jan; Lassmann, Hans; Berente, Zoltan; Setalo, Gyorgy; Borgulya, Gabor; Sumegi, Balazs; Komoly, Samuel; Gallyas, Ferenc; Illes, Zsolt

    2010-01-01

    Oligodendrocyte loss and demyelination are major pathological hallmarks of multiple sclerosis. In pattern III lesions, inflammation is minor in the early stages, and oligodendrocyte apoptosis prevails, which appears to be mediated at least in part through mitochondrial injury. Here, we demonstrate poly(ADP-ribose) polymerase activation and apoptosis inducing factor nuclear translocation within apoptotic oligodendrocytes in such multiple sclerosis lesions. The same morphological and molecular pathology was observed in an experimental model of primary demyelination, induced by the mitochondrial toxin cuprizone. Inhibition of poly(ADP-ribose) polymerase in this model attenuated oligodendrocyte depletion and decreased demyelination. Poly(ADP-ribose) polymerase inhibition suppressed c-Jun N-terminal kinase and p38 mitogen-activated protein kinase phosphorylation, increased the activation of the cytoprotective phosphatidylinositol-3 kinase-Akt pathway and prevented caspase-independent apoptosis inducing factor-mediated apoptosis. Our data indicate that poly(ADP-ribose) polymerase activation plays a crucial role in the pathogenesis of pattern III multiple sclerosis lesions. Since poly(ADP-ribose) polymerase inhibition was also effective in the inflammatory model of multiple sclerosis, it may target all subtypes of multiple sclerosis, either by preventing oligodendrocyte death or attenuating inflammation. PMID:20157013

  19. Knockdown of Lingo1b protein promotes myelination and oligodendrocyte differentiation in zebrafish.

    PubMed

    Yin, Wu; Hu, Bing

    2014-01-01

    Demyelinating diseases include multiple sclerosis, which is a neurodegenerative disease characterized by immune attacks on the central nervous system (CNS), resulting in myelin sheath damage and axonal loss. Leucine-rich repeat and immunoglobulin domain-containing neurite outgrowth inhibitory protein (Nogo) receptor-interacting protein-1 (LINGO-1) have been identified as a negative regulator of oligodendrocytes differentiation. Targeted LINGO-1 inhibition promotes neuron survival, axon regeneration, oligodendrocyte differentiation, and remyelination in diverse animal models. Although studies in rodent models have extended our understanding of LINGO-1, its roles in neural development and myelination in zebrafish (Danio rerio) are not yet clear. In this study, we cloned the zebrafish homolog of the human LINGO-1 and found that lingo1b regulated myelination and oligodendrocyte differentiation. The expression of lingo1b started 1 (mRNA) and 2 (protein) days post-fertilization (dpf) in the CNS. Morpholino oligonucleotide knockdown of lingo1b resulted in developmental abnormalities, including less dark pigment, small eyes, and a curly spinal cord. The lack of lingo1b enhanced myelination and oligodendrocyte differentiation during embryogenesis. Furthermore, immunohistochemistry and movement analysis showed that lingo1b was involved in the axon development of primary motor neurons. These results suggested that Lingo1b protein functions as a negative regulator of myelination and oligodendrocyte differentiation during zebrafish development.

  20. Nogo-A and myelin-associated glycoprotein differently regulate oligodendrocyte maturation and myelin formation.

    PubMed

    Pernet, Vincent; Joly, Sandrine; Christ, Franziska; Dimou, Leda; Schwab, Martin E

    2008-07-16

    Nogo-A is one of the most potent oligodendrocyte-derived inhibitors for axonal regrowth in the injured adult CNS. However, the physiological function of Nogo-A in development and in healthy oligodendrocytes is still unknown. In the present study, we investigated the role of Nogo-A for myelin formation in the developing optic nerve. By quantitative real-time PCR, we found that the expression of Nogo-A increased faster in differentiating oligodendrocytes than that of the major myelin proteins MBP (myelin basic protein), PLP (proteolipid protein)/DM20, and CNP (2',3'-cyclic nucleotide 3'-phosphodiesterase). The analysis of optic nerves and cerebella of mice deficient for Nogo-A (Nogo-A(-/-)) revealed a marked delay of oligodendrocyte differentiation, myelin sheath formation, and axonal caliber growth within the first postnatal month. The combined deletion of Nogo-A and MAG caused a more severe transient hypomyelination. In contrast to MAG(-/-) mice, Nogo-A(-/-) mutants did not present abnormalities in the structure of myelin sheaths and Ranvier nodes. The common binding protein for Nogo-A and MAG, NgR1, was exclusively upregulated in MAG(-/-) animals, whereas the level of Lingo-1, a coreceptor, remained unchanged. Together, our results demonstrate that Nogo-A and MAG are differently involved in oligodendrocyte maturation in vivo, and suggest that Nogo-A may influence also remyelination in pathological conditions such as multiple sclerosis.

  1. Is cell migration or proliferation dominant in the formation of linear arrays of oligodendrocytes?

    PubMed

    Walsh, Darragh M; Röth, Philipp T; Holmes, William R; Landman, Kerry A; Merson, Tobias D; Hughes, Barry D

    2016-10-07

    Oligodendrocytes are the myelin-producing cells of the central nervous system that are responsible for electrically insulating axons to speed the propagation of electrical impulses. A striking feature of oligodendrocyte development within white matter is that the cell bodies of many oligodendrocyte progenitor cells become organised into discrete linear arrays of three or more cells before they differentiate into myelin-producing oligodendrocytes. These linear arrays align parallel to the direction of the axons within white matter tracts and are believed to play an important role in the co-ordination of myelination. Guided by experimental data on the abundance and composition of linear arrays in the corpus callosum of the postnatal mouse brain, we construct discrete and continuous models of linear array generation to specifically investigate the relative influence of cell migration, proliferation, differentiation and death of oligodendroglia upon the genesis of linear arrays during early postnatal development. We demonstrate that only models that incorporate significant cell migration can replicate all of the experimental observations on number of arrays, number of cells in arrays and total cell count of oligodendroglia within a given area of the corpus callosum. These models are also necessary to accurately reflect experimental data on the abundance of linear arrays composed of oligodendrocytes that derive from progenitors of different clonal origins.

  2. Enhancement of oligodendrocyte differentiation from murine embryonic stem cells by an activator of gp130 signaling.

    PubMed

    Zhang, Peilin; Chebath, Judith; Lonai, Peter; Revel, Michel

    2004-01-01

    Embryonic stem (ES) cells derived from the inner cell mass of blastocyst-stage embryos are a potential large scale source of oligodendrocytes and of their progenitors for transplantation into the central nervous system for the repair of demyelinating lesions. We found previously that interleukin-6 (IL-6) fused to its soluble receptor (IL-6R), a potent activator of the gp130 receptor, induces myelin gene expression in Schwann cells of embryonic dorsal root ganglia. Like leukemia inhibitory factor, IL-6R/IL-6 inhibits the differentiation of murine ES cells into embryoid bodies. In the present study, we show that this recombinant cytokine may be efficiently used to stimulate the differentiation of oligodendrocytes if added to ES cell-derived neural precursors. IL-6R/IL-6 leads to an increase in early chondroitin sulfate proteoglycan positive and late O4 positive progenitors and to a stimulation of maturation into O1 and myelin basic protein expressing oligodendrocytes. Expression of the genes for transcription factor genes Olig-1 and Sox10, which appear early in the oligodendrocyte lineage, was stimulated by IL-6R/IL-6 addition. We conclude that this cytokine can significantly enhance the derivation of oligodendrocytes from ES cells.

  3. Movement and structure of mitochondria in oligodendrocytes and their myelin sheaths.

    PubMed

    Rinholm, Johanne E; Vervaeke, Koen; Tadross, Michael R; Tkachuk, Ariana N; Kopek, Benjamin G; Brown, Timothy A; Bergersen, Linda H; Clayton, David A

    2016-05-01

    Mitochondria play several crucial roles in the life of oligodendrocytes. During development of the myelin sheath they are essential providers of carbon skeletons and energy for lipid synthesis. During normal brain function their consumption of pyruvate will be a key determinant of how much lactate is available for oligodendrocytes to export to power axonal function. Finally, during calcium-overload induced pathology, as occurs in ischemia, mitochondria may buffer calcium or induce apoptosis. Despite their important functions, very little is known of the properties of oligodendrocyte mitochondria, and mitochondria have never been observed in the myelin sheaths. We have now used targeted expression of fluorescent mitochondrial markers to characterize the location and movement of mitochondria within oligodendrocytes. We show for the first time that mitochondria are able to enter and move within the myelin sheath. Within the myelin sheath the highest number of mitochondria was in the cytoplasmic ridges along the sheath. Mitochondria moved more slowly than in neurons and, in contrast to their behavior in neurons and astrocytes, their movement was increased rather than inhibited by glutamate activating NMDA receptors. By electron microscopy we show that myelin sheath mitochondria have a low surface area of cristae, which suggests a low ATP production. These data specify fundamental properties of the oxidative phosphorylation system in oligodendrocytes, the glial cells that enhance cognition by speeding action potential propagation and provide metabolic support to axons.

  4. Retinoic acid regulates the development of oligodendrocyte precursor cells in vitro.

    PubMed

    Laeng, P; Décimo, D; Pettmann, B; Janet, T; Labourdette, G

    1994-12-15

    Cultures of oligodendrocyte precursor cells can be grown from brain hemispheres of newborn rats. These cells, also called O-2A progenitor cells, can differentiate in vitro into oligodendrocytes or type 2 astrocytes. Basic FGF and PDGF are known to stimulate their proliferation and delay their differentiation. Lack or excess of retinoic acid (RA) has been known for a long time to alter brain development suggesting that this compound is involved in normal brain development. Here we report that RA partially inhibits both the proliferation and the differentiation of oligodendrocyte precursor cells. It also down-regulates the mitogenic effect of bFGF on these cells while keeping them in an immature stage. RA is more effective than bFGF in inhibiting myelin basic protein mRNA expression in these cells, and like bFGF, it preserves their bipotential character. RA nuclear receptors RAR-alpha and their transcripts are expressed in oligodendrocyte precursor cells as seen by Western blot, Northern blot and in situ hybridization. The expression of RAR-alpha transcripts is stimulated transiently by RA alone or associated to bFGF. The expression of RAR-beta transcripts is not constitutive and is induced by RA alone or associated to bFGF and to a lesser extent by bFGF alone. These results suggest that retinoids participate in the control of the development of glial cells of the oligodendrocyte lineage.

  5. Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

    PubMed Central

    Ossola, Bernardino; Zhao, Chao; Compston, Alastair; Pluchino, Stefano; Franklin, Robin J. M.

    2015-01-01

    Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471 PMID:26576485

  6. Shuttle subscale ablative nozzle tests

    NASA Technical Reports Server (NTRS)

    Powers, L. B.; Bailey, R. L.

    1980-01-01

    Recent subscale nozzle tests have identified new and promising carbon phenolic nozzle ablatives which utilize staple rayon, PAN, and pitch based carbon cloth. A 4-inch throat diameter submerged test nozzle designed for the 48-inch Jet Propulsion Laboratory char motor was used to evaluate five different designs incorporating 20 candidate ablatives. Test results indicate that several pitch and PAN-based carbon phenolic ablatives can provide erosion and char performance equivalent or superior to the present continuous rayon-based SRM ablative.

  7. Oligodendrocytes regulate formation of nodes of Ranvier via the recognition molecule OMgp

    PubMed Central

    NIE, DU-YU; MA, QUAN-HONG; LAW, JANICE W.S.; CHIA, CHERN-PANG; DHINGRA, NARENDER K.; SHIMODA, YASUSHI; YANG, WU-LIN; GONG, NENG; CHEN, QING-WEN; XU, GANG; HU, QI-DONG; CHOW, PIERCE K.H.; NG, YEE-KONG; LING, ENG-ANG; WATANABE, KAZUTADA; XU, TIAN-LE; HABIB, AMYN A.; SCHACHNER, MELITTA; XIAO, ZHI-CHENG

    2006-01-01

    The molecular mechanisms underlying the involvement of oligodendrocytes in formation of the nodes of Ranvier (NORs) remain poorly understood. Here we show that oligodendrocyte-myelin glycoprotein (OMgp) aggregates specifically at NORs. Nodal location of OMgp does not occur along demyelinated axons of either Shiverer or proteolipid protein (PLP) transgenic mice. Over-expression of OMgp in OLN-93 cells facilitates process outgrowth. In transgenic mice in which expression of OMgp is down-regulated, myelin thickness declines, and lateral oligodendrocyte loops at the node-paranode junction are less compacted and even join together with the opposite loops, which leads to shortened nodal gaps. Notably, each of these structural abnormalities plus modest down-regulation of expression of Na+ channel α subunit result in reduced conduction velocity in the spinal cords of the mutant mice. Thus, OMgp that is derived from glia has distinct roles in regulating nodal formation and function during CNS myelination. PMID:17364021

  8. Oligodendrocyte, Astrocyte, and Microglia Crosstalk in Myelin Development, Damage, and Repair

    PubMed Central

    Domingues, Helena S.; Portugal, Camila C.; Socodato, Renato; Relvas, João B.

    2016-01-01

    Oligodendrocytes are the myelinating glia of the central nervous system. Myelination of axons allows rapid saltatory conduction of nerve impulses and contributes to axonal integrity. Devastating neurological deficits caused by demyelinating diseases, such as multiple sclerosis, illustrate well the importance of the process. In this review, we focus on the positive and negative interactions between oligodendrocytes, astrocytes, and microglia during developmental myelination and remyelination. Even though many lines of evidence support a crucial role for glia crosstalk during these processes, the nature of such interactions is often neglected when designing therapeutics for repair of demyelinated lesions. Understanding the cellular and molecular mechanisms underlying glial cell communication and how they influence oligodendrocyte differentiation and myelination is fundamental to uncover novel therapeutic strategies for myelin repair. PMID:27551677

  9. Disturbance of oligodendrocyte function plays a key role in the pathogenesis of schizophrenia and major depressive disorder.

    PubMed

    Miyata, Shingo; Hattori, Tsuyoshi; Shimizu, Shoko; Ito, Akira; Tohyama, Masaya

    2015-01-01

    The major psychiatric disorders such as schizophrenia (SZ) and major depressive disorder (MDD) are thought to be multifactorial diseases related to both genetic and environmental factors. However, the genes responsible and the molecular mechanisms underlying the pathogenesis of SZ and MDD remain unclear. We previously reported that abnormalities of disrupted-in-Schizophrenia-1 (DISC1) and DISC1 binding zinc finger (DBZ) might cause major psychiatric disorders such as SZ. Interestingly, both DISC and DBZ have been further detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 negatively regulates the differentiation of oligodendrocytes, whereas DBZ plays a positive regulatory role in oligodendrocyte differentiation. We have reported that repeated stressful events, one of the major risk factors of MDD, can induce sustained upregulation of plasma corticosterone levels and serum/glucocorticoid regulated kinase 1 (Sgk1) mRNA expression in oligodendrocytes. Repeated stressful events can also activate the SGK1 cascade and cause excess arborization of oligodendrocyte processes, which is thought to be related to depressive-like symptoms. In this review, we discuss the expression of DISC1, DBZ, and SGK1 in oligodendrocytes, their roles in the regulation of oligodendrocyte function, possible interactions of DISC1 and DBZ in relation to SZ, and the activation of the SGK1 signaling cascade in relation to MDD.

  10. Disturbance of Oligodendrocyte Function Plays a Key Role in the Pathogenesis of Schizophrenia and Major Depressive Disorder

    PubMed Central

    Ito, Akira; Tohyama, Masaya

    2015-01-01

    The major psychiatric disorders such as schizophrenia (SZ) and major depressive disorder (MDD) are thought to be multifactorial diseases related to both genetic and environmental factors. However, the genes responsible and the molecular mechanisms underlying the pathogenesis of SZ and MDD remain unclear. We previously reported that abnormalities of disrupted-in-Schizophrenia-1 (DISC1) and DISC1 binding zinc finger (DBZ) might cause major psychiatric disorders such as SZ. Interestingly, both DISC and DBZ have been further detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 negatively regulates the differentiation of oligodendrocytes, whereas DBZ plays a positive regulatory role in oligodendrocyte differentiation. We have reported that repeated stressful events, one of the major risk factors of MDD, can induce sustained upregulation of plasma corticosterone levels and serum/glucocorticoid regulated kinase 1 (Sgk1) mRNA expression in oligodendrocytes. Repeated stressful events can also activate the SGK1 cascade and cause excess arborization of oligodendrocyte processes, which is thought to be related to depressive-like symptoms. In this review, we discuss the expression of DISC1, DBZ, and SGK1 in oligodendrocytes, their roles in the regulation of oligodendrocyte function, possible interactions of DISC1 and DBZ in relation to SZ, and the activation of the SGK1 signaling cascade in relation to MDD. PMID:25705664

  11. Ischemic damage and subsequent proliferation of oligodendrocytes in focal cerebral ischemia.

    PubMed

    Mandai, K; Matsumoto, M; Kitagawa, K; Matsushita, K; Ohtsuki, T; Mabuchi, T; Colman, D R; Kamada, T; Yanagihara, T

    1997-04-01

    In order to achieve a better understanding of the pathophysiology of ischemic white matter lesions, oligodendrocytic degeneration and subsequent proliferation were examined in the mouse model of middle cerebral artery occlusion. In situ hybridization histochemistry for proteolipid protein messenger RNA was employed as a sensitive and specific marker of oligodendrocytes, and immunohistochemistry for myelin basic protein was used as a compact myelin marker. Immunohistochemistry for microtubule-associated protein 2 and albumin was employed to monitor neuronal degeneration and the breakdown of the blood brain barrier, respectively. In the ischemic core of the caudoputamen, the immunoreactivity for microtubule-associated protein 2 disappeared and massive albumin extravasation occurred several hours after vessel occlusion, while proteolipid protein messenger RNA signals remained relatively strong at this time. The messenger RNA signals began to attenuate 12 h after ischemia and were hardly detectable 24 h after ischemia in the whole ischemic lesion. In situ end-labeling of fragmented DNA showed some cells with proteolipid protein messenger RNAs to have DNA fragmentation at this period. In contrast to proteolipid protein messenger RNA signals, the immunoreactivity for myelin basic protein was detected as long as five days after ischemia. An apparent increase in the cells possessing strong proteolipid protein messenger RNA signals was found five days after ischemia, mainly in the corpus callosum and the cortex bordering the infarcted areas. A double simultaneous procedure with in situ hybridization for proteolipid protein messenger RNA and immunohistochemistry for glial fibrillary acid protein or lectin histochemistry for macrophages/microglia showed proliferating oligodendrocytes to be co-localized with reactive astrocytes and macrophages/microglia. These findings show that oligodendrocytic damage occurred following ischemic neuronal damage and the breakdown of the blood

  12. Fluoxetine prevents oligodendrocyte cell death by inhibiting microglia activation after spinal cord injury.

    PubMed

    Lee, Jee Y; Kang, So R; Yune, Tae Y

    2015-05-01

    Oligodendrocyte cell death and axon demyelination after spinal cord injury (SCI) are known to be important secondary injuries contributing to permanent neurological disability. Thus, blocking oligodendrocyte cell death should be considered for therapeutic intervention after SCI. Here, we demonstrated that fluoxetine, an antidepressant drug, alleviates oligodendrocyte cell death by inhibiting microglia activation after SCI. After injury at the T9 level with a Precision Systems and Instrumentation (Lexington, KY) device, fluoxetine (10 mg/kg, intraperitoneal) was administered once a day for the indicated time points. Immunostaining with CD11b (OX-42) antibody and quantification analysis showed that microglia activation was significantly inhibited by fluoxetine at 5 days after injury. Fluoxetine also significantly inhibited activation of p38 mitogen-activated protein kinase (p38-MAPK) and expression of pro-nerve growth factor (pro-NGF), which is known to mediate oligodendrocyte cell death through the p75 neurotrophin receptor after SCI. In addition, fluoxetine attenuated activation of Ras homolog gene family member A and decreased the level of phosphorylated c-Jun and, ultimately, alleviated caspase-3 activation and significantly reduced cell death of oligodendrocytes at 5 days after SCI. Further, the decrease of myelin basic protein, myelin loss, and axon loss in white matter was also significantly blocked by fluoxetine, as compared to vehicle control. These results suggest that fluoxetine inhibits oligodendrocyte cell death by inhibiting microglia activation and p38-MAPK activation, followed by pro-NGF production after SCI, and provide a potential usage of fluoxetine for a therapeutic agent after acute SCI in humans.

  13. ST8SIA2 promotes oligodendrocyte differentiation and the integrity of myelin and axons

    PubMed Central

    Szewczyk, Lukasz Mateusz; Brozko, Nikola; Nagalski, Andrzej; Röckle, Iris; Werneburg, Sebastian; Hildebrandt, Herbert

    2016-01-01

    ST8SIA2 is a polysialyltransferase that attaches polysialic acid to the glycoproteins NCAM1 and CADM1. Polysialylation is involved in brain development and plasticity. ST8SIA2 is a schizophrenia candidate gene, and St8sia2 −/− mice exhibit schizophrenia‐like behavior. We sought to identify new pathological consequences of ST8SIA2 deficiency. Our proteomic analysis suggested myelin impairment in St8sia2 −/− mice. Histological and immune staining together with Western blot revealed that the onset of myelination was not delayed in St8sia2 −/− mice, but the content of myelin was lower. Ultrastructure analysis of the corpus callosum showed thinner myelin sheaths, smaller and irregularly shaped axons, and white matter lesions in adult St8sia2 −/− mice. Then we evaluated oligodendrocyte differentiation in vivo and in vitro. Fewer OLIG2+ cells in the cortex and corpus callosum, together with the higher percentage of undifferentiated oligodenroglia in St8sia2 −/− mice suggested an impairment in oligodendrocyte generation. Experiment on primary cultures of oligodendrocyte precursor cells (OPCs) confirmed a cell‐autonomous effect of ST8SIA2 in oligodendroglia, and demonstrated that OPC to oligodendrocyte transition is inhibited in St8sia2 −/− mice. Concluding, ST8SIA2‐mediated polysialylation influences on oligodendrocyte differentiation, and oligodendrocyte deficits in St8sia2 mice are a possible cause of the demyelination and degeneration of axons, resembling nerve fiber alterations in schizophrenia. GLIA 2016;65:34–49 PMID:27534376

  14. Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury.

    PubMed

    Shindo, Akihiro; Liang, Anna C; Maki, Takakuni; Miyamoto, Nobukazu; Tomimoto, Hidekazu; Lo, Eng H; Arai, Ken

    2016-01-01

    Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.

  15. LINGO-1 regulates oligodendrocyte differentiation by inhibiting ErbB2 translocation and activation in lipid rafts.

    PubMed

    Lee, Xinhua; Shao, Zhaohui; Sheng, Guoqing; Pepinsky, Blake; Mi, Sha

    2014-05-01

    Oligodendrocyte differentiation is negatively regulated by LINGO-1 and positively regulated by the ErbB2 receptor tyrosine kinase. In wild-type oligodendrocytes, inhibition of ErbB2 blocks differentiation, whereas activation of ErbB2 promotes differentiation. In LINGO-1(-/-) oligodendrocytes, inhibition of ErbB2 blocks oligodendrocyte differentiation; whereas activation of ErbB2 does not enhance differentiation. Biological and biochemical evidence showing that LINGO-1 can directly bind to ErbB2, block ErbB2 translocation into lipid rafts, and inhibit its phosphorylation for activation. The study demonstrates a novel regulatory mechanism of ErbB2 function whereby LINGO-1 suppresses oligodendrocyte differentiation by inhibiting ErbB2 translocation and activation in lipid rafts.

  16. Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

    PubMed Central

    Shindo, Akihiro; Liang, Anna C; Maki, Takakuni; Miyamoto, Nobukazu; Tomimoto, Hidekazu; Lo, Eng H

    2016-01-01

    Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury. PMID:25920960

  17. NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration

    PubMed Central

    Kang, Shin H.; Fukaya, Masahiro; Yang, Jason K.; Rothstein, Jeffrey D.; Bergles, Dwight E.

    2010-01-01

    SUMMARY The mammalian CNS contains a ubiquitous population of glial progenitors known as NG2+ cells that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although it has been reported that NG2+ cells are multipotent, their fate in health and disease remains controversial. Here, we generated PDGFαR-CreER transgenic mice and followed their fate in vivo in the developing and adult CNS. These studies revealed that NG2+ cells in the postnatal CNS generate myelinating oligodendrocytes, but not astrocytes or neurons. In regions of neurodegeneration in the spinal cord of ALS mice, NG2+ cells exhibited enhanced proliferation and accelerated differentiation into oligodendrocytes, but remained committed to the oligodendrocyte lineage. These results indicate that NG2+ cells in the normal CNS are oligodendrocyte precursors with restricted lineage potential, and that cell loss and gliosis are not sufficient to alter the lineage potential of these progenitors in ALS mice. PMID:21092857

  18. Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitors Aid in Functional Recovery of Sensory Pathways following Contusive Spinal Cord Injury

    PubMed Central

    All, Angelo H.; Bazley, Faith A.; Gupta, Siddharth; Pashai, Nikta; Hu, Charles; Pourmorteza, Amir; Kerr, Candace

    2012-01-01

    Background Transplantations of human stem cell derivatives have been widely investigated in rodent models for the potential restoration of function of neural pathways after spinal cord injury (SCI). Studies have already demonstrated cells survival following transplantation in SCI. We sought to evaluate survival and potential therapeutic effects of transplanted human embryonic stem (hES) cell-derived oligodendrocyte progenitor cells (OPCs) in a contusive injury in rats. Bioluminescence imaging was utilized to verify survivability of cells up to 4 weeks, and somatosensory evoked potential (SSEPs) were recorded at the cortex to monitor function of sensory pathways throughout the 6-week recovery period. Principal Findings hES cells were transduced with the firefly luciferase gene and differentiated into OPCs. OPCs were transplanted into the lesion epicenter of rat spinal cords 2 hours after inducing a moderate contusive SCI. The hES-treatment group showed improved SSEPs, including increased amplitude and decreased latencies, compared to the control group. The bioluminescence of transplanted OPCs decreased by 97% in the injured spinal cord compared to only 80% when injected into an uninjured spinal cord. Bioluminescence increased in both experimental groups such that by week 3, no statistical difference was detected, signifying that the cells survived and proliferated independent of injury. Post-mortem histology of the spinal cords showed integration of human cells expressing mature oligodendrocyte markers and myelin basic protein without the expression of markers for astrocytes (GFAP) or pluripotent cells (OCT4). Conclusions hES-derived OPCs transplanted 2 hours after contusive SCI survive and differentiate into OLs that produce MBP. Treated rats demonstrated functional improvements in SSEP amplitudes and latencies compared to controls as early as 1 week post-injury. Finally, the hostile injury microenvironment at 2 hours post-injury initially caused increased cell

  19. Molecular dynamics investigation of mechanisms of femtosecond laser ablation

    NASA Astrophysics Data System (ADS)

    Cheng, Changrui

    Laser micro-machining has been widely applied for material processing in many industries. A phenomenon called "laser ablation" is usually involved in the laser micro-machining process. Laser ablation is the process of material removal after the irradiation of a laser beam onto the material. It is commonly characterized by small temporal and spatial scales, extremely high material temperature and pressure, and strong non-equilibrium thermodynamic state. In this work, molecular dynamics (MD) simulation is conducted to study the femtosecond laser ablation of metals (nickel and copper) and dielectrics (fused silica, or glass). The laser heating and the ablation processes are numerically modeled, and the computation is accelerated by parallel processing technique. Both the pair-wise Morse potential and the many-body EAM (Embedded-Atom Method) potential are employed for metals. In the simulation of fused silica, the BKS (van Beest, Kramer and van Santen) potential is used, and the generation of free electrons, the energy transport from laser beam to free electrons and energy coupling between electrons and the lattice are considered. The main goal of this work is to illustrate the detailed processes of femtosecond laser ablation and to study its mechanisms. From the MD results, it is found that the mechanism of femtosecond laser ablation is strongly dependent on the laser fluences. For metals, low fluence laser ablation is mainly through phase explosion (homogeneous gas bubble nucleation), while spinodal decomposition is responsible for high fluence ablation. Ablation mechanism is determined by whether or not the material (liquid) temperature exceeds the critical temperature. For fused silica, the generation and existence of free electrons are found to affect ablation significantly, especially at low fluence, where Coulomb explosion is found to play an important role in material separation.

  20. Percutaneous ablation of adrenal tumors.

    PubMed

    Venkatesan, Aradhana M; Locklin, Julia; Dupuy, Damian E; Wood, Bradford J

    2010-06-01

    Adrenal tumors comprise a broad spectrum of benign and malignant neoplasms and include functional adrenal adenomas, pheochromocytomas, primary adrenocortical carcinoma, and adrenal metastases. Percutaneous ablative approaches that have been described and used in the treatment of adrenal tumors include percutaneous radiofrequency ablation, cryoablation, microwave ablation, and chemical ablation. Local tumor ablation in the adrenal gland presents unique challenges, secondary to the adrenal gland's unique anatomic and physiological features. The results of clinical series employing percutaneous ablative techniques in the treatment of adrenal tumors are reviewed in this article. Clinical and technical considerations unique to ablation in the adrenal gland are presented, including approaches commonly used in our practices, and risks and potential complications are discussed.

  1. Ablation of skeletal metastases: current status.

    PubMed

    Kurup, A Nicholas; Callstrom, Matthew R

    2010-08-01

    Image-guided percutaneous ablation of bone metastases is an effective, minimally invasive alternative to conventional therapies in the palliation of pain from metastatic disease. Ablative technologies applied in the treatment of skeletal metastases include radiofrequency ablation, cryoablation, microwave ablation, laser ablation, ethanol ablation, and, most recently, focused ultrasound. These ablative methods may be performed in combination with percutaneous cementoplasty to provide support and stabilization for metastases in weight-bearing bones at risk for pathologic fracture.

  2. Increased Cx32 expression in spinal cord TrkB oligodendrocytes following peripheral axon injury.

    PubMed

    Coulibaly, Aminata P; Isaacson, Lori G

    2016-08-03

    Following injury to motor axons in the periphery, retrograde influences from the injury site lead to glial cell plasticity in the vicinity of the injured neurons. Following the transection of peripherally located preganglionic axons of the cervical sympathetic trunk (CST), a population of oligodendrocyte (OL) lineage cells expressing full length TrkB, the cognate receptor for brain derived neurotrophic factor (BDNF), is significantly increased in number in the spinal cord. Such robust plasticity in OL lineage cells in the spinal cord following peripheral axon transection led to the hypothesis that the gap junction communication protein connexin 32 (Cx32), which is specific to OL lineage cells, was influenced by the injury. Following CST transection, Cx32 expression in the spinal cord intermediolateral cell column (IML), the location of the parent cell bodies, was significantly increased. The increased Cx32 expression was localized specifically to TrkB OLs in the IML, rather than other cell types in the OL cell lineage, with the population of Cx32/TrkB cells increased by 59%. Cx32 expression in association with OPCs was significantly decreased at one week following the injury. The results of this study provide evidence that peripheral axon injury can differentially affect the gap junction protein expression in OL lineage cells in the adult rat spinal cord. We conclude that the retrograde influences originating from the peripheral injury site elicit dramatic changes in the CNS expression of Cx32, which in turn may mediate the plasticity of OL lineage cells observed in the spinal cord following peripheral axon injury.

  3. Channel-mediated and carrier-mediated uptake of K+ into cultured ovine oligodendrocytes

    SciTech Connect

    Hertz, L.; Soliven, B.; Hertz, E.; Szuchet, S.; Nelson, D.J. )

    1990-01-01

    Uptake of radioactive K+ by mature ovine oligodendrocytes (OLGs) maintained in primary culture was measured under steady-state conditions, i.e., in cells maintained in a normal tissue culture medium (5.4 mM K+), and in cells after depletion of intracellular K+ to less than 15% of its normal value by pre-incubation in K(+)-free medium. The latter value is dominated by an active, carrier-mediated uptake (although it may include some diffusional uptake), whereas the former, in addition to active uptake, also reflects passive K+ diffusion through ion selective channels and possible self-exchange between extracellular and intracellular K+, which may be carrier-mediated. The total uptake rate was 144 +/- 10 nmol/min/mg protein, and the uptake after K+ depletion was 60 +/- 2 nmol/min/mg protein, much lower rates than previously observed in astrocytes. The uptake into K(+)-depleted cells was inhibited by about 80% in the presence of ouabain (1 mM) and about 30% in the presence of furosemide (2 mM). Activators of protein kinase C (phorbol esters) and cAMP-dependent protein kinase (forskolin) have been shown to alter the myelinogenic metabolism as well as outward K+ current in cultured OLGs. The present study demonstrates that K+ homeostasis in OLGs is modulated through similar second messenger pathways. Active uptake was inhibited by about 60% in the presence of active phorbol esters (100 nM) but was not affected by forskolin (100 nM). Forskolin likewise had no effect on total uptake, whereas phorbol esters caused a much larger inhibition than expected from their effect on carrier-mediated uptake alone, suggesting that channel-mediated uptake was also reduced.

  4. Anesthetic Management in Radiofrequency Catheter Ablation of Ventricular Tachycardia

    PubMed Central

    Naeini, Payam S.; Razavi, Mehdi; Collard, Charles D.; Tolpin, Daniel A.; Anton, James M.

    2016-01-01

    Radiofrequency catheter ablation is increasingly being used to treat patients who have ventricular tachycardia, and anesthesiologists frequently manage their perioperative care. This narrative review is intended to familiarize anesthesiologists with preprocedural, intraprocedural, and postprocedural implications of this ablation. Ventricular tachycardia typically arises from structural heart disease, most often from scar tissue after myocardial infarction. Many patients thus affected will benefit from radiofrequency catheter ablation in the electrophysiology laboratory to ablate the foci of arrhythmogenesis. The pathophysiology of ventricular tachycardia is complex, as are the technical aspects of mapping and ablating these arrhythmias. Patients often have substantial comorbidities and tenuous hemodynamic status, necessitating pharmacologic and mechanical cardiopulmonary support. General anesthesia and monitored anesthesia care, when used for sedation during ablation, can lead to drug interactions and side effects in the presence of ventricular tachycardia, so anesthesiologists should also be aware of potential perioperative complications. We discuss variables that can help anesthesiologists safely guide patients through the challenges of radiofrequency catheter ablation of ventricular tachycardia. PMID:28100967

  5. Cartilage ablation studies using mid-IR free electron laser

    NASA Astrophysics Data System (ADS)

    Youn, Jong-In; Peavy, George M.; Venugopalan, Vasan

    2005-04-01

    The ablation rate of articular cartilage and fibrocartilage (meniscus), were quantified to examine wavelength and tissue-composition dependence of ablation efficiency for selected mid-infrared wavelengths. The wavelengths tested were 2.9 um (water dominant absorption), 6.1 (protein and water absorption) and 6.45 um (protein dominant absorption) generated by the Free Electron Laser (FEL) at Vanderbilt University. The measurement of tissue mass removal using a microbalance during laser ablation was conducted to determine the ablation rates of cartilage. The technique can be accurate over methods such as profilometer and histology sectioning where tissue surface and the crater morphology may be affected by tissue processing. The ablation efficiency was found to be dependent upon the wavelength. Both articular cartilage and meniscus (fibrocartilage) ablations at 6.1 um were more efficient than those at the other wavelengths evaluated. We observed the lowest ablation efficiency of both types of cartilage with the 6.45 um wavelength, possibly due to the reduction in water absorption at this wavelength in comparison to the other wavelengths that were evaluated.

  6. Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model.

    PubMed

    Jaramillo-Merchán, J; Jones, J; Ivorra, J L; Pastor, D; Viso-León, M C; Armengól, J A; Moltó, M D; Geijo-Barrientos, E; Martínez, S

    2013-08-29

    Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain's white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrow-derived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft.

  7. Rab35, acting through ACAP2 switching off Arf6, negatively regulates oligodendrocyte differentiation and myelination

    PubMed Central

    Miyamoto, Yuki; Yamamori, Natsuki; Torii, Tomohiro; Tanoue, Akito; Yamauchi, Junji

    2014-01-01

    Oligodendrocyte precursor cells differentiate to produce myelin sheaths that insulate axons to ensure fast propagation of action potentials. Many aspects of differentiation are regulated by multiple extracellular signals. However, their intracellular signalings remain elusive. We show that Rab35 and its effector, ACAP2, a GTPase-activating protein that switches off Arf6 activity, negatively regulate oligodendrocyte morphological differentiation. Knockdown of Rab35 or ACAP2 with their respective small interfering RNAs promotes differentiation. As differentiation initiates, the activities of Rab35 and ACAP2 are down-regulated. The activity of Arf6, in contrast, is up-regulated. Arf6 knockdown inhibits differentiation, indicating that Rab35 and ACAP2 negatively regulate differentiation by down-regulating Arf6. Importantly, as differentiation proceeds, the activity of cytohesin-2, a guanine nucleotide exchange factor that switches on Arf6 activity, is up-regulated. Pharmacological inhibition of cytohesin-2 inhibits differentiation, suggesting that cytohesin-2 promotes differentiation by activating Arf6. Furthermore, using oligodendrocyte-neuronal cocultures, we find that knockdown of Rab35 or ACAP2 promotes myelination, whereas inhibition of cytohesin-2 or knockdown of Arf6 inhibits myelination. Thus Rab35/ACAP2 and cytohesin-2 antagonistically control oligodendrocyte differentiation and myelination through Arf6 regulation, presenting a unique small GTPase on/off switching mechanism. PMID:24600047

  8. Brain-derived neurotrophic factor promotes central nervous system myelination via a direct effect upon oligodendrocytes.

    PubMed

    Xiao, Junhua; Wong, Agnes W; Willingham, Melanie M; van den Buuse, Maarten; Kilpatrick, Trevor J; Murray, Simon S

    2010-01-01

    The extracellular factors that are responsible for inducing myelination in the central nervous system (CNS) remain elusive. We investigated whether brain-derived neurotrophic factor (BDNF) is implicated, by first confirming that BDNF heterozygous mice exhibit delayed CNS myelination during early postnatal development. We next established that the influence of BDNF upon myelination was direct, by acting on oligodendrocytes, using co-cultures of dorsal root ganglia neurons and oligodendrocyte precursor cells. Importantly, we found that BDNF retains its capacity to enhance myelination of neurons or by oligodendrocytes derived from p75NTR knockout mice, indicating the expression of p75NTR is not necessary for BDNF-induced myelination. Conversely, we observed that phosphorylation of TrkB correlated with myelination, and that inhibiting TrkB signalling also inhibited the promyelinating effect of BDNF, suggesting that BDNF enhances CNS myelination via activating oligodendroglial TrkB-FL receptors. Together, our data reveal a previously unknown role for BDNF in potentiating the normal development of CNS myelination, via signalling within oligodendrocytes.

  9. Viral Vector Reprogramming of Adult Resident Striatal Oligodendrocytes into Functional Neurons.

    PubMed

    Weinberg, Marc S; Criswell, Hugh E; Powell, Sara K; Bhatt, Aadra P; McCown, Thomas J

    2017-04-05

    Recent advances suggest that in vivo reprogramming of endogenous cell populations provides a viable alternative for neuron replacement. Astrocytes and oligodendrocyte precursor cells can be induced to transdifferentiate into neurons in the CNS, but, in these instances, reprogramming requires either transgenic mice or retroviral-mediated gene expression. We developed a microRNA (miRNA)-GFP construct that in vitro significantly reduced the expression of polypyrimidine tract-binding protein, and, subsequently, we packaged this construct in a novel oligodendrocyte preferring adeno-associated virus vector. Ten days after rat striatal transduction, the vast majority of the GFP-positive cells were oligodendrocytes, but 6 weeks to 6 months later, the majority of GFP-positive cells exhibited neuronal morphology and co-localized with the neuronal marker NeuN. Patch-clamp studies on striatal slices established that the GFP-positive cells exhibited electrophysiological properties indicative of mature neurons, such as spontaneous action potentials and spontaneous inhibitory postsynaptic currents. Also, 3 months after striatal vector administration, GFP-positive terminals in the ipsilateral globus pallidus or substantia nigra retrogradely transported fluorescent beads back to GFP-positive striatal cell bodies, indicating the presence of functional presynaptic terminals. Thus, this viral vector approach provides a potential means to harness resident oligodendrocytes as an endogenous source for in vivo neuronal replacement.

  10. Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model

    PubMed Central

    Jaramillo-Merchán, J; Jones, J; Ivorra, J L; Pastor, D; Viso-León, M C; Armengól, J A; Moltó, M D; Geijo-Barrientos, E; Martínez, S

    2013-01-01

    Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain's white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrow-derived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft. PMID:23990019

  11. The microglial reaction in spinal cords of jimpy mice is related to apoptotic oligodendrocytes.

    PubMed

    Vela, J M; Dalmau, I; González, B; Castellano, B

    1996-03-11

    Jimpy is a shortened life-span murine mutant whose genetic disorder results in a severe hypomyelination in the central neruons system associated with a variety of glial abnormalities, including oligodendrocyte death. In this study, we report that oligodendrocyte death in jimpy occurs through an apoptotic mechanism, as demonstrated by in situ labeling of nuclear DNA fragmentation. Compared to those of normal littermates, the spinal cords of jimpy mice showed a significantly higher number of apoptotic cells. Our observations also corroborate that specific glial cell death in jimpy is restricted to oligodendrocytes, as evidenced by double labeling for DNA fragmentation and MBP immunocytochemistry. Cells labeled for DNA fragmentation were always negative for astroglial or microglial markers. Apoptotic oligodendrocytes were not aggregated into clusters and were ubiquitously distributed throughout the jimpy spinal cord, although were more numerous in white matter than in gray matter. We found no physical association between astrocytes and dying cells in jimpy. Microglial cells, however, were found closely attached to and even surrounding apoptotic cells. The possible role of microglial cells in relation to apoptotsis is discussed.

  12. Noscapine protects OLN-93 oligodendrocytes from ischemia-reperfusion damage: Calcium and nitric oxide involvement.

    PubMed

    Nadjafi, S; Ebrahimi, S-A; Rahbar-Roshandel, N

    2015-12-01

    This study was carried out to evaluate the effects of noscapine, a benzylisoquinoline alkaloid from opium poppy, on oligodendrocyte during ischemia/reperfusion-induced excitotoxic injury. Changes in intracellular calcium levels due to chemical ischemia and nitric oxide (NO) production during ischemia/reperfusion were evaluated as the hallmarks of ischemia-derived excitotoxic event. OLN-93 cell line (a permanent immature rat oligodendrocyte) was used as a model of oligodendrocyte. 30- or 60-minute-oxygen-glucose deprivation/24 hours reperfusion were used to induce excitotoxicity. MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay was used to evaluate cell viability. Ratiometric fluorescence microscopy using Ca(2+)-sensitive indicator Fura-2/AM was utilized to assess intracellular calcium levels. NO production was evaluated by Griess method. Noscapine (4 μM) significantly attenuated intracellular Ca(2+) elevation (P < 0.001). Also, noscapine significantly decreased NO production during a 30-minute oxygen-glucose deprivation/reperfusion (P < 0.01). The inhibitory effect of noscapine (4 μM) on intracellular Ca(2+) was greater than ionotropic glutamate receptors antagonists. Noscapine is protective against ischemia/reperfusion-induced excitotoxic injury in OLN-93 oligodendrocyte. This protective effect seems to be related to attenuation of intracellular Ca(2+) overload and NO production.

  13. Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination

    PubMed Central

    Chong, S. Y. Christin; Rosenberg, Sheila S.; Fancy, Stephen P. J.; Zhao, Chao; Shen, Yun-An A.; Hahn, Angela T.; McGee, Aaron W.; Xu, Xiaomei; Zheng, Binhai; Zhang, Li I.; Rowitch, David H.; Franklin, Robin J. M.; Lu, Q. Richard; Chan, Jonah R.

    2012-01-01

    A requisite component of nervous system development is the achievement of cellular recognition and spatial segregation through competition-based refinement mechanisms. Competition for available axon space by myelinating oligodendrocytes ensures that all relevant CNS axons are myelinated properly. To ascertain the nature of this competition, we generated a transgenic mouse with sparsely labeled oligodendrocytes and establish that individual oligodendrocytes occupying similar axon tracts can greatly vary the number and lengths of their myelin internodes. Here we show that intercellular interactions between competing oligodendroglia influence the number and length of myelin internodes, referred to as myelinogenic potential, and identify the amino-terminal region of Nogo-A, expressed by oligodendroglia, as necessary and sufficient to inhibit this process. Exuberant and expansive myelination/remyelination is detected in the absence of Nogo during development and after demyelination, suggesting that spatial segregation and myelin extent is limited by microenvironmental inhibition. We demonstrate a unique physiological role for Nogo-A in the precise myelination of the developing CNS. Maximizing the myelinogenic potential of oligodendrocytes may offer an effective strategy for repair in future therapies for demyelination. PMID:22160722

  14. Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination.

    PubMed

    Chong, S Y Christin; Rosenberg, Sheila S; Fancy, Stephen P J; Zhao, Chao; Shen, Yun-An A; Hahn, Angela T; McGee, Aaron W; Xu, Xiaomei; Zheng, Binhai; Zhang, Li I; Rowitch, David H; Franklin, Robin J M; Lu, Q Richard; Chan, Jonah R

    2012-01-24

    A requisite component of nervous system development is the achievement of cellular recognition and spatial segregation through competition-based refinement mechanisms. Competition for available axon space by myelinating oligodendrocytes ensures that all relevant CNS axons are myelinated properly. To ascertain the nature of this competition, we generated a transgenic mouse with sparsely labeled oligodendrocytes and establish that individual oligodendrocytes occupying similar axon tracts can greatly vary the number and lengths of their myelin internodes. Here we show that intercellular interactions between competing oligodendroglia influence the number and length of myelin internodes, referred to as myelinogenic potential, and identify the amino-terminal region of Nogo-A, expressed by oligodendroglia, as necessary and sufficient to inhibit this process. Exuberant and expansive myelination/remyelination is detected in the absence of Nogo during development and after demyelination, suggesting that spatial segregation and myelin extent is limited by microenvironmental inhibition. We demonstrate a unique physiological role for Nogo-A in the precise myelination of the developing CNS. Maximizing the myelinogenic potential of oligodendrocytes may offer an effective strategy for repair in future therapies for demyelination.

  15. Do the Purkinje cells have a special type of oligodendrocyte as satellites?

    PubMed Central

    Monteiro, R A

    1983-01-01

    Two types of oligodendrocytes considered to be a constant feature in the cerebellar cortex of the rat are described. One cell type (I) exhibits rounded or elliptical nuclei, whereas the other type (II) presents more irregular nuclear and cellular contours and wider perinuclear cisternae. The latter cell type shows a more electron-dense cytoplasm with more heavily clumped heterochromatin, contrasting strongly with the euchromatin; also long and parallel cisternae of rough endoplasmic reticulum are more frequent. The percentages of both types of oligodendrocytes in relation to the total population of common glial cell types were calculated in the cortical layers and at several levels in these layers. The distribution of oligodendrocytes in the associated white matter was also carried out for purposes of comparison. The results provide evidence the the Purkinje cells may have a special kind of oligodendrocyte (Type II) as satellites. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 PMID:6630036

  16. Protracted abstinence from chronic ethanol exposure alters the structure of neurons and expression of oligodendrocytes and myelin in the medial prefrontal cortex

    PubMed Central

    Navarro, Alvaro I.; Mandyam, Chitra D.

    2015-01-01

    In rodents, chronic intermittent ethanol vapor exposure (CIE) produces alcohol dependence, alters the structure and activity of pyramidal neurons and decreases the number of oligodendroglial progenitors in the medial prefrontal cortex (mPFC). In this study, adult Wistar rats were exposed to seven weeks of CIE and were withdrawn from CIE for 21 days (protracted abstinence; PA) and tissue enriched in the mPFC was processed for Western blot analysis and Golgi-Cox staining to investigate the long-lasting effects of CIE on structure of mPFC neurons and levels of myelin associated proteins. PA increased dendritic arborization within apical dendrites of pyramidal neurons and these changes occurred concurrently with hypophosphorylation of the NMDA receptor 2B (NR2B) at Tyr-1472. PA increased myelin basic protein (MBP) levels that occurred concurrently with hypophosphorylation of the premyelinating oligodendrocyte bHLH transcription factor Olig2 in the mPFC. Given that PA is associated with increased sensitivity to stress and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and stress alters oligodendrocyte expression as a function of glucocorticoid receptor (GR) activation, the levels of total GR and phosphorylated GR were also evaluated. PA produces hypophosphorylation of the GR at Ser-232 without affecting expression of total protein. These findings demonstrate persistent and compensatory effects of ethanol in the mPFC long after cessation of CIE, including enhanced myelin production and impaired GR function. Collectively, these results suggest a novel relationship between oligodendrocytes and GR in the mPFC, in which stress may alter frontal cortex function in alcohol dependent subjects by promoting hypermyelination, thereby altering the cellular composition and white matter structure in the mPFC. PMID:25732140

  17. [Ablative and fractional lasers].

    PubMed

    Beylot, C; Grognard, C; Michaud, T

    2009-10-01

    The use of pulsed or scanning Carbon Dioxide, and pulsed Erbium-YAG lasers allows the programmable and reproducible photocoagulation of thin layers of the epidermis and superficial dermis. Thermal damage depends on the type of laser and is greater with CO(2) lasers. The degree of neocollagenesis is proportional to the thermal damage and is better with CO(2) lasers. Their main indication is the correction of photoaged facial skin but they can also be used for corrective dermatology, e.g. for scars and genodermatosis. Results are highly satisfactory but the technique is invasive and the patient experiences a social hindrance of around two weeks. Fractionated techniques treat 25% of the defective skin area at each session in noncontiguous microzones; four sessions are therefore necessary to treat the entire cutaneous surface. The treatment is given under topical anesthesia and is much less invasive, particularly with nonablative fractional laser treatment in which photothermolysis does not penetrate below the epidermis and/or the effects are slight, with no or very little social isolation. However, the results are much less satisfactory than the results of ablative laser and there is no firming effect. Other zones than the face can be treated. With the fractional CO(2) and Erbium ablative lasers, which have multiplied over the past 2 years, the much wider impacts cause perforation of the epidermis and there is a zone of ablation by laser photovaporization, with a zone of thermal damage below. The results are better in correcting photoaging of the face, without, however, achieving the efficacy of ablative lasers, which remain the reference technique. However, the effects are not insignificant, requiring at least 5 days of social isolation.

  18. Femtosecond laser for cavity preparation in enamel and dentin: ablation efficiency related factors

    PubMed Central

    Chen, H.; Li, H.; Sun, YC.; Wang, Y.; Lü, PJ.

    2016-01-01

    To study the effects of laser fluence (laser energy density), scanning line spacing and ablation depth on the efficiency of a femtosecond laser for three-dimensional ablation of enamel and dentin. A diode-pumped, thin-disk femtosecond laser (wavelength 1025 nm, pulse width 400 fs) was used for the ablation of enamel and dentin. The laser spot was guided in a series of overlapping parallel lines on enamel and dentin surfaces to form a three-dimensional cavity. The depth and volume of the ablated cavity was then measured under a 3D measurement microscope to determine the ablation efficiency. Different values of fluence, scanning line spacing and ablation depth were used to assess the effects of each variable on ablation efficiency. Ablation efficiencies for enamel and dentin were maximized at different laser fluences and number of scanning lines and decreased with increases in laser fluence or with increases in scanning line spacing beyond spot diameter or with increases in ablation depth. Laser fluence, scanning line spacing and ablation depth all significantly affected femtosecond laser ablation efficiency. Use of a reasonable control for each of these parameters will improve future clinical application. PMID:26864679

  19. Femtosecond laser for cavity preparation in enamel and dentin: ablation efficiency related factors

    NASA Astrophysics Data System (ADS)

    Chen, H.; Li, H.; Sun, Yc.; Wang, Y.; Lü, Pj.

    2016-02-01

    To study the effects of laser fluence (laser energy density), scanning line spacing and ablation depth on the efficiency of a femtosecond laser for three-dimensional ablation of enamel and dentin. A diode-pumped, thin-disk femtosecond laser (wavelength 1025 nm, pulse width 400 fs) was used for the ablation of enamel and dentin. The laser spot was guided in a series of overlapping parallel lines on enamel and dentin surfaces to form a three-dimensional cavity. The depth and volume of the ablated cavity was then measured under a 3D measurement microscope to determine the ablation efficiency. Different values of fluence, scanning line spacing and ablation depth were used to assess the effects of each variable on ablation efficiency. Ablation efficiencies for enamel and dentin were maximized at different laser fluences and number of scanning lines and decreased with increases in laser fluence or with increases in scanning line spacing beyond spot diameter or with increases in ablation depth. Laser fluence, scanning line spacing and ablation depth all significantly affected femtosecond laser ablation efficiency. Use of a reasonable control for each of these parameters will improve future clinical application.

  20. Numerical study of the thermal ablation of wet solids by ultrashort laser pulses

    SciTech Connect

    Perez, Danny; Beland, Laurent Karim; Deryng, Delphine; Lewis, Laurent J.; Meunier, Michel

    2008-01-01

    The ablation by ultrashort laser pulses at relatively low fluences (i.e., in the thermal regime) of solids wetted by a thin liquid film is studied using a generic numerical model. In comparison with dry targets, the liquid is found to significantly affect ablation by confining the solid and slowing down the expansion of the laser-heated material. These factors affect the relative efficiency of the various ablation mechanisms, leading, in particular, to the complete inhibition of phase explosion at lower fluences, a reduced ablation yield, and significant changes in the composition of the plume. As a consequence, at fluences above the ablation threshold, the size of the ejected nanoclusters is lower in presence of the liquid. Our results provide a qualitative understanding of the effect of wetting layers on the ablation process.

  1. LINGO-1 Regulates Oligodendrocyte Differentiation through the Cytoplasmic Gelsolin Signaling Pathway.

    PubMed

    Shao, Zhaohui; Lee, Xinhua; Huang, Guanrong; Sheng, Guoqing; Henderson, Christopher E; Louvard, Daniel; Sohn, Jiho; Pepinsky, Blake; Mi, Sha

    2017-03-22

    Differentiation and maturation of oligodendrocyte progenitor cells (OPCs) involve the assembly and disassembly of actin microfilaments. However, how actin dynamics are regulated during this process remains poorly understood. Leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1 (LINGO-1) is a negative regulator of OPC differentiation. We discovered that anti-LINGO-1 antibody-promoted OPC differentiation was accompanied by upregulation of cytoplasmic gelsolin (cGSN), an abundant actin-severing protein involved in the depolymerization of actin filaments. Treating rat OPCs with cGSN siRNA reduced OPC differentiation, whereas overexpression of cGSN promoted OPC differentiation in vitro and remyelination in vivo Furthermore, coexpression of cGSN and LINGO-1 blocked the inhibitory effect of LINGO-1. Our study demonstrates that cGSN works downstream of LINGO-1 signaling pathway, which enhances actin dynamics and is essential for OPC morphogenesis and differentiation. This finding may lead to novel therapeutic approaches for the treatment of demyelinating diseases such as multiple sclerosis (MS).SIGNIFICANCE STATEMENT Myelin loss and subsequent axon degeneration contributes to a variety of neurological diseases, such as multiple sclerosis (MS). Understanding the regulation of myelination by oligodendrocytes is therefore critical for developing therapies for the treatment of MS. We previously demonstrated that leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1 (LINGO-1) is a negative regulator of oligodendrocyte differentiation and that anti-LINGO-1 promotes remyelination in preclinical animal models for MS and in a phase II acute optic neuritis clinical trial (RENEW). The mechanism by which LINGO-1 regulates oligodendrocyte differentiation is unknown. Here, we demonstrate that LINGO-1 regulates oligodendrocyte differentiation and maturation through the cytoplasmic gelsolin signaling pathway, providing new

  2. Alpha-synuclein mRNA expression in oligodendrocytes in MSA.

    PubMed

    Asi, Yasmine T; Simpson, Julie E; Heath, Paul R; Wharton, Stephen B; Lees, Andrew J; Revesz, Tamas; Houlden, Henry; Holton, Janice L

    2014-06-01

    Multiple system atrophy (MSA) is a progressive neurodegenerative disease presenting clinically with parkinsonian, cerebellar, and autonomic features. α-Synuclein (αsyn), encoded by the gene SNCA, is the main constituent of glial cytoplasmic inclusion (GCI) found in oligodendrocytes in MSA, but the methods of its accumulation have not been established. The aim of this study is to investigate alterations in regional and cellular SNCA mRNA expression in MSA as a possible substrate for GCI formation. Quantitative reverse transcription polymerase chain reaction (qPCR) was performed on postmortem brain samples from 15 MSA, 5 IPD, and 5 control cases to investigate regional expression in the frontal and occipital regions, dorsal putamen, pontine base, and cerebellum. For cellular expression analysis, neurons and oligodendrocytes were isolated by laser-capture microdissection from five MSA and five control cases. SNCA mRNA expression was not significantly different between the MSA, IPD and control cases in all regions (multilevel model, P = 0.14). After adjusting for group effect, the highest expression was found in the occipital cortex while the lowest was in the putamen (multilevel model, P < 0.0001). At the cellular level, MSA oligodendrocytes expressed more SNCA than control oligodendrocytes and expression in MSA neurons was slightly lower than that in controls, however, these results did not reach statistical significance. We have demonstrated regional variations in SNCA expression, which is higher in cortical than subcortical regions. This study is the first to demonstrate SNCA mRNA expression by oligodendrocytes in human postmortem tissue using qPCR and, although not statistically significant, could suggest that this may be increased in MSA compared to controls.

  3. Myelin and oligodendrocyte lineage cells in white matter pathology and plasticity after traumatic brain injury.

    PubMed

    Armstrong, Regina C; Mierzwa, Amanda J; Sullivan, Genevieve M; Sanchez, Maria A

    2016-11-01

    Impact to the head or rapid head acceleration-deceleration can cause traumatic brain injury (TBI) with a characteristic pathology of traumatic axonal injury (TAI) and secondary damage in white matter tracts. Myelin and oligodendrocyte lineage cells have significant roles in the progression of white matter pathology after TBI and in the potential for plasticity and subsequent recovery. The myelination pattern of specific brain regions, such as frontal cortex, may also increase susceptibility to neurodegeneration and psychiatric symptoms after TBI. White matter pathology after TBI depends on the extent and distribution of axon damage, microhemorrhages and/or neuroinflammation. TAI occurs in a pattern of damaged axons dispersed among intact axons in white matter tracts. TAI accompanied by bleeding and/or inflammation produces focal regions of overt tissue destruction, resulting in loss of both axons and myelin. White matter regions with TAI may also exhibit demyelination of intact axons. Demyelinated axons that remain viable have the potential for remyelination and recovery of function. Indeed, animal models of TBI have demonstrated demyelination that is associated with evidence of remyelination, including oligodendrocyte progenitor cell proliferation, generation of new oligodendrocytes, and formation of thinner myelin. Changes in neuronal activity that accompany TBI may also involve myelin remodeling, which modifies conduction efficiency along intact myelinated fibers. Thus, effective remyelination and myelin remodeling may be neurobiological substrates of plasticity in neuronal circuits that require long-distance communication. This perspective integrates findings from multiple contexts to propose a model of myelin and oligodendrocyte lineage cell relevance in white matter injury after TBI. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.

  4. Apoptosis and proliferation of oligodendrocyte progenitor cells in the irradiated rodent spinal cord

    SciTech Connect

    Atkinson, Shelley L.; Li Yuqing; Wong, C. Shun . E-mail: shun.wong@sw.ca

    2005-06-01

    Purpose: Oligodendrocytes undergo early apoptosis after irradiation. The aim of this study was to determine the relationship between oligodendroglial apoptosis and proliferation of oligodendrocyte progenitor cells (OPC) in the irradiated central nervous system. Methods and Materials: Adult rats and p53 transgenic mice were given single doses of 2 Gy, 8 Gy, or 22 Gy to the cervical spinal cord. Apoptosis was assessed using TUNEL (Tdt-mediated dUTP terminal nick-end labeling) staining or by examining nuclear morphology. Oligodendrocyte progenitor cells were identified with an NG2 antibody or by in situ hybridization for platelet-derived growth factor receptor {alpha}. Proliferation of OPC was assessed by in vivo bromodeoxyuridine (BrdU) labeling and subsequent immunohistochemistry. Because radiation-induced apoptosis of oligodendroglial cells is p53 dependent, p53 transgenic mice were used to study the relationship between apoptosis and cell proliferation. Results: Oligodendrocyte progenitor cells underwent apoptosis within 24 h of irradiation in the rat. That did not result in a change in OPC density at 24 h. Oligodendrocyte progenitor cell density was significantly reduced by 2-4 weeks, but showed recovery by 6 weeks after irradiation. An increase in BrdU-labeled cells was observed at 2 weeks after 8 Gy or 22 Gy, and proliferating cells in the rat spinal cord were immunoreactive for NG2. The mouse spinal cord showed a similar early cell proliferation after irradiation. No difference was observed in the proliferation response in the spinal cord of p53 -/- mice compared with wild type animals. Conclusions: Oligodendroglial cells undergo early apoptosis and OPC undergo early proliferation after ionizing radiation. However, apoptosis is not likely to be the trigger for early proliferation of OPC in the irradiated central nervous system.

  5. Impact of Simulated Microgravity on Oligodendrocyte Development: Implications for Central Nervous System Repair

    PubMed Central

    Espinosa-Jeffrey, Araceli; Paez, Pablo M.; Cheli, Veronica T.; Spreuer, Vilma; Wanner, Ina; de Vellis, Jean

    2013-01-01

    We have recently established a culture system to study the impact of simulated microgravity on oligodendrocyte progenitor cells (OPCs) development. We subjected mouse and human OPCs to a short exposure of simulated microgravity produced by a 3D-Clinostat robot. Our results demonstrate that rodent and human OPCs display enhanced and sustained proliferation when exposed to simulated microgravity as assessed by several parameters, including a decrease in the cell cycle time. Additionally, OPC migration was examined in vitro using time-lapse imaging of cultured OPCs. Our results indicated that OPCs migrate to a greater extent after stimulated microgravity than in normal conditions, and this enhanced motility was associated with OPC morphological changes. The lack of normal gravity resulted in a significant increase in the migration speed of mouse and human OPCs and we found that the average leading process in migrating bipolar OPCs was significantly longer in microgravity treated cells than in controls, demonstrating that during OPC migration the lack of gravity promotes leading process extension, an essential step in the process of OPC migration. Finally, we tested the effect of simulated microgravity on OPC differentiation. Our data showed that the expression of mature oligodendrocyte markers was significantly delayed in microgravity treated OPCs. Under conditions where OPCs were allowed to progress in the lineage, simulated microgravity decreased the proportion of cells that expressed mature markers, such as CC1 and MBP, with a concomitant increased number of cells that retained immature oligodendrocyte markers such as Sox2 and NG2. Development of methodologies aimed at enhancing the number of OPCs and their ability to progress on the oligodendrocyte lineage is of great value for treatment of demyelinating disorders. To our knowledge, this is the first report on the gravitational modulation of oligodendrocyte intrinsic plasticity to increase their progenies. PMID

  6. Ion channel expression by white matter glia: I. Type 2 astrocytes and oligodendrocytes.

    PubMed

    Barres, B A; Chun, L L; Corey, D P

    1988-01-01

    White matter is a compact structure consisting primarily of neuronal axons and glial cells. As in other parts of the nervous system, the function of glial cells in white matter is poorly understood. We have explored the electrophysiological properties of two types of glial cells found predominantly in white matter: type 2 astrocytes and oligodendrocytes. Whole-cells and single-channel patch-clamp techniques were used to study these cell types in postnatal rat optic nerve cultures prepared according to the procedures of Raff et al. (Nature, 303:390-396, 1983b). Type 2 astrocytes in culture exhibit a "neuronal" channel phenotype, expressing at least six distinct ion channel types. With whole-cell recording we observed three inward currents: a voltage-sensitive sodium current qualitatively similar to that found in neurons and both transient and sustained calcium currents. In addition, type 2 astrocytes had two components of outward current: a delayed potassium current which activated at 0 mV and an inactivating calcium-dependent potassium current which activated at -30 mV. Type 2 astrocytes in culture could be induced to fire single regenerative potentials in response to injections of depolarizing current. Single-channel recording demonstrated the presence of an outwardly rectifying chloride channel in both type 2 astrocytes and oligodendrocytes, but this channel could only be observed in excised patches. Oligodendrocytes expressed only one other current: an inwardly rectifying potassium current that is mediated by 30- and 120-pS channels. Because these channels preferentially conduct potassium from outside to inside the cell, and because they are open at the resting potential of the cell, they would be appropriate for removing potassium from the extracellular space; thus it is proposed that oligodendrocytes, besides myelinating axons, play an important role in potassium regulation in white matter. The conductances present in oligodendrocytes suggest a "modulated

  7. OCDR guided laser ablation device

    DOEpatents

    Dasilva, Luiz B.; Colston, Jr., Bill W.; James, Dale L.

    2002-01-01

    A guided laser ablation device. The device includes a mulitmode laser ablation fiber that is surrounded by one or more single mode optical fibers that are used to image in the vicinity of the laser ablation area to prevent tissue damage. The laser ablation device is combined with an optical coherence domain reflectometry (OCDR) unit and with a control unit which initializes the OCDR unit and a high power laser of the ablation device. Data from the OCDR unit is analyzed by the control unit and used to control the high power laser. The OCDR images up to about 3 mm ahead of the ablation surface to enable a user to see sensitive tissue such as a nerve or artery before damaging it by the laser.

  8. Catheter Ablation for Ventricular Arrhythmias

    PubMed Central

    Nof, Eyal; Stevenson, William G; John, Roy M

    2013-01-01

    Catheter ablation has emerged as an important and effective treatment option for many recurrent ventricular arrhythmias. The approach to ablation and the risks and outcomes are largely determined by the nature of the severity and type of underlying heart disease. In patients with structural heart disease, catheter ablation can effectively reduce ventricular tachycardia (VT) episodes and implantable cardioverter defibrillator (ICD) shocks. For VT and symptomatic premature ventricular beats that occur in the absence of structural heart disease, catheter ablation is often effective as the sole therapy. Advances in catheter technology, imaging and mapping techniques have improved success rates for ablation. This review discusses current approaches to mapping and ablation for ventricular arrhythmias. PMID:26835040

  9. Ablation of hard dental tissues with the Er:YAG laser

    NASA Astrophysics Data System (ADS)

    Vickers, Vicki A.; Jacques, Steven L.; Schwartz, Jon A.; Motamedi, Massoud; Rastegar, Sohi; Martin, J. W.

    1992-08-01

    The Er:YAG laser ablation of hard dental tissues and artificial dental stones was studied. The hole depth after ablation was measured as a function of pulse energy and pulse number. The dental gypsum products allowed systematic study of how pulse energy, pulse number, and water content affected ablation. The studies on human teeth compared teeth stored in saline vs teeth stored in formalin.

  10. Radiofrequency Ablation for Liver Cancer.

    PubMed

    Jacobs, Amy

    2015-01-01

    Interventional ablative technologies aided by imaging techniques such as ultrasonography, computed tomography, and magnetic resonance imaging have been crucial in managing patients with primary liver cancer and liver metastases over the past 20 years. Several ablative technologies have been used to treat liver cancer; however, radiofrequency ablation (RFA) has emerged as the most common ablative therapy for hepatic lesions, both in the United States and globally. RFA is the treatment of choice for patients who cannot have surgical resection of the liver. This article focuses on the role of imaging in RFA treatment of primary and metastatic hepatic lesions.

  11. The effects of fat layer on temperature distribution during microwave atrial fibrillation catheter ablation.

    PubMed

    Zhai, Fei; Nan, Qun; Guo, Xuemei

    2016-01-01

    To investigate the effects of fat layer on the temperature distribution during microwave atrial fibrillation catheter ablation in the conditions of different ablation time; 3D finite element models (fat layer and no fat layer) were built, and temperature distribution was obtained based on coupled electromagnetic-thermal analysis at 2.45 GHz and 30 W of microwave power. Results shown: in the endocardial ablation, the existence of the fat layer did not affect the shape of the 50 °C contour before 30 s. The increase speed of depth became quite slowly in the model with fat layer after 30 s. When ablation depth needed fixed, there are no significant effect on effectively ablation depth whether fat layer over or not. However, the existence of fat layer makes the temperature lower in the myocardium, and maximum temperature point closer to the myocardium surface. What is more, in the model with fat layer, effective ablation reach lower maximum temperature and the shallower depth of 50 °C contour. But there are larger ablation axial length and transverse width. In this case, doctor should ensure safety of normal cardiac tissue around the target tissue. In the epicardial ablation, the existence of fat layer seriously affects result of the microwave ablation. The epicardial ablation needs more heating time to create lesion. But epicardial ablation can be better controlled in the shape of effective ablation area because of the slowly increase of target variables after the appearing of 50 °C contour. Doctor can choose endocardial or epicardial ablation in different case of clinic requirement.

  12. Comparison of percutaneous cryoablation with microwave ablation in a porcine liver model.

    PubMed

    Niu, Lizhi; Li, Jialiang; Zeng, Jianying; Zhou, Liang; Wang, Song; Zhou, Xulong; Sheng, Lin; Chen, Jibing; Xu, Kecheng

    2014-04-01

    We compared imaging and pathological changes between argon-helium cryosurgical (AH) and microwave (MW) ablation in a porcine liver model. Immediately after ablation, computed tomography (CT) imaging showed that the area affected by MW ablation was considerably greater than that affected by AH ablation; moreover, the surface area of necrotic tissue was considerably greater in the AH group, whereas the depth of the necrotic area was similar. Seven days after ablation, the affected area had not changed much in the AH group, but it had significantly increased in the MW group; similarly, the surface and depth of the necrotic areas had not changed much in the AH group, but they had increased significantly in the MW group. The pathological findings showed similar definitive areas for both groups at both time points. The findings indicated that long time after both therapies, complete tissue necrosis can be achieved, but the extent and depth of necrosis differ: necrosis foci after AH ablation could be predicted by ice ball under CT image, and necrosis foci after MW ablation will increase obviously. MW ablation might therefore be suitable for tumors with a larger volume and simple anatomical structures, and AH ablation might be suitable for tumors with complex anatomical structures or those located near important organs. These two methods could therefore be used in combination in clinical settings, but details of the procedure need to be studied.

  13. [Atrial fibrillation ablation: application of nurse methodology].

    PubMed

    Ramos-González-Serna, Amelia; Mateos-García, M Dolores

    2011-01-01

    Ablation of pulmonary veins for treatment of atrial fibrillation involves applying radiofrequency energy wave by a catheter that causes a circumferential lesion to achieve electrical isolation and voltage drop in the interior. It is mainly applied when there is resistance to treatment and recurrence of symptoms affecting the quality of life of patients. The nurse is an important part of the multidisciplinary team who care for patients who undergo this procedure. The provision of comprehensive nursing care should include nursing procedures prior to, during, and after treatment to ensure the careful and systematic quality required. The aims of this article are: to provide specialised knowledge on the procedure of atrial fibrillation ablation, to describe the preparation of the electrophysiology laboratory, analyse nursing care and develop a standardized care plan for patients on whom this procedure is performed using the NANDA (North American Nursing Association) taxonomy and NIC (Nursing Intervention Classification).

  14. High temperature ablative foam

    NASA Technical Reports Server (NTRS)

    Liu, Matthew T. (Inventor)

    1992-01-01

    An ablative foam composition is formed of approximately 150 to 250 parts by weight polymeric isocyanate having an isocyanate functionality of 2.6 to 3.2; approximately 15 to 30 parts by weight reactive flame retardant having a hydroxyl number range from 200-260; approximately 10 to 40 parts by weight non-reactive flame retardant; approximately 10 to 40 parts by weight nonhydrolyzable silicone copolymer having a hydroxyl number range from 75-205; and approximately 3 to 16 parts by weight amine initiated polyether resin having an isocyanate functionality greater than or equal to 3.0 and a hydroxyl number range from 400-800.

  15. Matricectomy and nail ablation.

    PubMed

    Baran, Robert; Haneke, Eckart

    2002-11-01

    Matricectomy refers to the complete extirpation of the nail matrix, resulting in permanent nail loss. Usually however, matricectomy is only partial, restricted to one or both lateral horns of the matrix. Nail ablation is the definitive removal of the entire nail organ. The most important common denominator in the successful matricectomy is the total removal or destruction of the matrix tissue. Matricectomy may be indicated for the management of onychauxis, onychogryphosis, congenital nail dystrophies, and chronic painful nail, such as recalcitrant ingrown toenail or split within the medial or lateral one-third of the nail.

  16. Laser ablation in analytical chemistry.

    PubMed

    Russo, Richard E; Mao, Xianglei; Gonzalez, Jhanis J; Zorba, Vassilia; Yoo, Jong

    2013-07-02

    In 2002, we wrote an Analytical Chemistry feature article describing the Physics of Laser Ablation in Microchemical Analysis. In line with the theme of the 2002 article, this manuscript discusses current issues in fundamental research, applications based on detecting photons at the ablation site (LIBS and LAMIS) and by collecting particles for excitation in a secondary source (ICP), and directions for the technology.

  17. The number of cells expressing the myelin-supporting oligodendrocyte marker PLP-exon 3b remains unchanged in Wallerian degeneration.

    PubMed

    Li, G; Blakemore, W F

    2004-08-01

    Following spinal cord trauma there is controversy as to whether myelin-supporting oligodendrocytes at a distance from areas of spinal cord damage undergo apoptosis. To examine the response of oligodendrocytes to axon degeneration, we counted the number of oligodendrocytes and oligodendrocyte precursors in the dorsal funiculi during the course of Wallerian degeneration. Axons were disrupted at T13 and the number of labelled cells in the dorsal funiculi counted at T12, 4 days and 2, 4, and 8 weeks after injury using riboprobes to exon-3b of the PLP gene whose expression is considered to restricted to myelin-supporting oligodendrocytes, PDGFRalpha which is regarded as a marker of oligodendrocyte precursors, and MOG a marker previously used to identify myelin-supporting oligodendrocytes. We found that the number of PLP-exon-3b labelled cells remained constant during the course of Wallerian degeneration while the number of cells labelled with the riboprobes to PDGFRalpha and MOG increased. Significantly the number of MOG-positive cells was increased at times when the number of PDGFRalpha labelled cells was highest. The number of PDGFRalpha labelled cells decreased with time while the number PLP-exon-3b labelled cells remained constant. It is therefore possible that the apoptotic oligodendrocytes identified in previous studies could represent degenerating oligodendrocyte precursors or their progeny rather than degenerating myelin-supporting oligodendrocytes.

  18. Insights into Eyestalk Ablation Mechanism to Induce Ovarian Maturation in the Black Tiger Shrimp

    PubMed Central

    Uawisetwathana, Umaporn; Leelatanawit, Rungnapa; Klanchui, Amornpan; Prommoon, Juthatip; Klinbunga, Sirawut; Karoonuthaisiri, Nitsara

    2011-01-01

    Eyestalk ablation is commonly practiced in crustacean to induce ovarian maturation in captivity. The molecular mechanism of the ablation has not been well understood, preventing a search for alternative measures to induce ovarian maturation in aquaculture. This is the first study to employ cDNA microarray to examine effects of eyestalk ablation at the transcriptomic level and pathway mapping analysis to identify potentially affected biological pathways in the black tiger shrimp (Penaeus monodon). Microarray analysis comparing between gene expression levels of ovaries from eyestalk-intact and eyestalk-ablated brooders revealed 682 differentially expressed transcripts. Based on Hierarchical clustering of gene expression patterns, Gene Ontology annotation, and relevant functions of these differentially expressed genes, several gene groups were further examined by pathway mapping analysis. Reverse-transcriptase quantitative PCR analysis for some representative transcripts confirmed microarray data. Known reproductive genes involved in vitellogenesis were dramatically increased during the ablation. Besides these transcripts expected to be induced by the ablation, transcripts whose functions involved in electron transfer mechanism, immune responses and calcium signal transduction were significantly altered following the ablation. Pathway mapping analysis revealed that the activation of gonadotropin-releasing hormone signaling, calcium signaling, and progesterone-mediated oocyte maturation pathways were putatively crucial to ovarian maturation induced by the ablation. These findings shed light on several possible molecular mechanisms of the eyestalk ablation effect and allow more focused investigation for an ultimate goal of finding alternative methods to replace the undesirable practice of the eyestalk ablation in the future. PMID:21915325

  19. Simulation of Pellet Ablation

    NASA Astrophysics Data System (ADS)

    Parks, P. B.; Ishizaki, Ryuichi

    2000-10-01

    In order to clarify the structure of the ablation flow, 2D simulation is carried out with a fluid code solving temporal evolution of MHD equations. The code includes electrostatic sheath effect at the cloud interface.(P.B. Parks et al.), Plasma Phys. Contr. Fusion 38, 571 (1996). An Eulerian cylindrical coordinate system (r,z) is used with z in a spherical pellet. The code uses the Cubic-Interpolated Psudoparticle (CIP) method(H. Takewaki and T. Yabe, J. Comput. Phys. 70), 355 (1987). that divides the fluid equations into non-advection and advection phases. The most essential element of the CIP method is in calculation of the advection phase. In this phase, a cubic interpolated spatial profile is shifted in space according to the total derivative equations, similarly to a particle scheme. Since the profile is interpolated by using the value and the spatial derivative value at each grid point, there is no numerical oscillation in space, that often appears in conventional spline interpolation. A free boundary condition is used in the code. The possibility of a stationary shock will also be shown in the presentation because the supersonic ablation flow across the magnetic field is impeded.

  20. Molecular dynamic simulation of tungsten ablation under transient high heat flux

    NASA Astrophysics Data System (ADS)

    Yan, Sha; Zhu, Yizhou; Xue, Jianming; Zhang, Jie; Qu, Miao; Le, Xiaoyun

    2015-08-01

    Molecular dynamic (MD) method is used to simulation the tungsten ablation under transient high heat flux generated by energetic ions. A model including 363,600 W atoms was built based on Finnis-Sinclair potential. The results show that the ablation threshold is much lower than the one of boiling. So the ablation effects might be underestimated if using energy threshold of boiling instead of that of ablation. Particle size distribution of ablation products follows a power decay law with an exponent around -2.5, which does not affect by the incident heat flux. The transverse velocities of particles obey normal distribution, and a stream speed is added to the random movement for the longitudinal velocity. As the ablation start up, the recoiled impulse can induce shock wave in remained target, which is supported by experimental pressure wave measurements.

  1. Endothelial cell–oligodendrocyte interactions in small vessel disease and aging

    PubMed Central

    Rajani, Rikesh M.

    2017-01-01

    Cerebral small vessel disease (SVD) is a prevalent, neurological disease that significantly increases the risk of stroke and dementia. The main pathological changes are vascular, in the form of lipohyalinosis and arteriosclerosis, and in the white matter (WM), in the form of WM lesions. Despite this, it is unclear to what extent the key cell types involved–the endothelial cells (ECs) of the vasculature and the oligodendrocytes of the WM–interact. Here, we describe the work that has so far been carried out suggesting an interaction between ECs and oligodendrocytes in SVD. As these interactions have been studied in more detail in other disease states and in development, we explore these systems and discuss the role these mechanisms may play in SVD. PMID:28202749

  2. Non-viable Borrelia burgdorferi induce inflammatory mediators and apoptosis in human oligodendrocytes.

    PubMed

    Parthasarathy, Geetha; Fevrier, Helene B; Philipp, Mario T

    2013-11-27

    In previous studies, exposure to live Borrelia burgdorferi was shown to induce inflammation and apoptosis of human oligodendrocytes. In this study we assessed the ability of non-viable bacteria (heat killed or sonicated) to induce inflammatory mediators and cell death. Both heat-killed and sonicated bacteria induced release of CCL2, IL-6, and CXCL8 from oligodendrocytes in a dose dependent manner. In addition, non-viable B. burgdorferi also induced cell death as evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and another cell viability assay. These results suggest that spirochetal residues left after bacterial demise, due to treatment or otherwise, may continue to be pathogenic to the central nervous system.

  3. Damage to the Optic Chiasm in Myelin Oligodendrocyte Glycoprotein–Experimental Autoimmune Encephalomyelitis Mice

    PubMed Central

    Herrera, Sheryl L; Palmer, Vanessa L; Whittaker, Heather; Smith, Blair Cardigan; Kim, Annie; Schellenberg, Angela E; Thiessen, Jonathan D; Buist, Richard; Del Bigio, Marc R; Martin, Melanie

    2014-01-01

    Optic chiasm lesions in myelin oligodendrocyte glycoprotein (MOG)–experimental autoimmune encephalomyelitis (EAE) mice were characterized using magnetic resonance imaging (MRI) and validated using electron microscopy (EM). MR images were collected from 3 days after induction to remission, approximately 20 days after induction. Hematoxylin and eosin, solochrome cyanin–stained sections, and EM images were obtained from the optic chiasms of some mice approximately 4 days after disease onset when their scores were thought to be the highest. T2-weighted imaging and apparent diffusion coefficient map hyperintensities corresponded to abnormalities in the optic chiasms of EAE mice. Mixed inflammation was concentrated at the lateral surface. Degeneration of oligodendrocytes, myelin, and early axonal damage were also apparent. A marked increase in chiasm thickness was observed. T2-weighted and diffusion-weighted MRI can detect abnormalities in the optic chiasms of MOG-EAE mice. MRI is an important method in the study of this model toward understanding optic neuritis. PMID:25520558

  4. Dynamics of multiple plumes in laser ablation: Modeling of the shielding effect

    NASA Astrophysics Data System (ADS)

    Zinovik, Igor; Povitsky, Alex

    2006-07-01

    The scattering and absorption of laser radiation by previously ablated plumes in laser ablation (known as the shielding effect) dramatically affect the efficiency of laser ablation process. The ablated plumes consisting of water vapor, droplets, and particles are modeled as a gas-particle equilibrium mixture by solution of the Euler equations combined with the transport equation for the ratio of heat capacities. Shielding effect on the overall ablated mass by multiple plumes is studied for a wide range of concentration of particles in vaporized plumes, various laser repetition rates, scattering, and absorption of laser energy. The shielding phenomenon is studied for short sequences of discrete plumes to focus on the shielding effect of individual plumes. The results of numerical modeling were compared to experimental results of laser-induced water explosive vaporization. Ablation rate was calculated for a single ablated plume and for the sequence of six laser pulses at the repetition rates of 0.33 and 1MHz at which gas dynamics interactions between plumes are strong but plumes have not yet form a continuous jet. A single ablated plume has an initial semispherical shape which transforms into mushroomlike cloud with a thin stem and a ring vortex as it was observed in experiments with water and cornea ablation. For the plume with a given ablated mass, the longer ejection of plume with smaller density produces the plume with smaller shielding capacity. For multiple laser pulses, the velocity of ejected mixture increases from the center of the target to its periphery because of the shielding effect. The ablated mass of the current plume depends on the attenuation of the incident laser beam energy caused by the propagation of laser beam through previously ablated plumes. In the case of laser energy absorption, the ablation rate per pulse exceeds 2-2.5 times the rate obtained for the laser energy scattering.

  5. In vitro analysis of the oligodendrocyte lineage in mice during demyelination and remyelination

    SciTech Connect

    Armstrong, R.; Friedrich, V.L. Jr.; Holmes, K.V.; Dubois-Dalcq, M. )

    1990-09-01

    A demyelinating disease induced in C57B1/6N mice by intracranial injection of a coronavirus (murine hepatitis virus strain A59) is followed by functional recovery and efficient CNS myelin repair. To study the biological properties of the cells involved in this repair process, glial cells were isolated and cultured from spinal cords of these young adult mice during demyelination and remyelination. Using three-color immunofluorescence combined with (3H)thymidine autoradiography, we have analyzed the antigenic phenotype and mitotic potential of individual glial cells. We identified oligodendrocytes with an antibody to galactocerebroside, astrocytes with an antibody to glial fibrillary acidic protein, and oligodendrocyte-type 2 astrocyte (O-2A) progenitor cells with the O4 antibody. Cultures from demyelinated tissue differed in several ways from those of age-matched controls: first, the total number of O-2A lineage cells was strikingly increased; second, the O-2A population consisted of a higher proportion of O4-positive astrocytes and cells of mixed oligodendrocyte-astrocyte phenotype; and third, all the cell types within the O-2A lineage showed enhanced proliferation. This proliferation was not further enhanced by adding PDGF, basic fibroblast growth factor (bFGF), or insulin-like growth factor I (IGF-I) to the defined medium. However, bFGF and IGF-I seemed to influence the fate of O-2A lineage cells in cultures of demyelinated tissue. Basic FGF decreased the percentage of cells expressing galactocerebroside. In contrast, IGF-I increased the relative proportion of oligodendrocytes. Thus, O-2A lineage cells from adult mice display greater phenotypic plasticity and enhanced mitotic potential in response to an episode of demyelination. These properties may be linked to the efficient remyelination achieved in this demyelinating disease.

  6. Oligodendrocyte differentiation and signaling after transferrin internalization: a mechanism of action.

    PubMed

    Pérez, María Julia; Fernandez, Natalia; Pasquini, Juana María

    2013-10-01

    Oligodendrocytes are the cells producing the myelin membrane around the axons in the central nervous system and, although apotransferrin (aTf) is required for oligodendrocyte differentiation, the underlying mechanisms are not fully understood. Fyn tyrosine kinase, a member of the Src family of proteins, has been shown to play an important role in myelination by up-regulating the expression of myelin basic protein; however, a molecular link between aTf and Fyn kinase signaling pathway during oligodendrocytes differentiation has not been established yet. Our aim was to investigate whether Fyn kinase, MEK/ERK and PI3K/Akt signaling pathways are required for aTf-stimulation of oligodendrocyte differentiation and also to determine if the transferrin receptor is involved in these mechanisms. Treatment of primary cultures of oligodendroglial precursor cells with aTf leads to Fyn kinase activation by a mechanism that involves transferrin receptor. In turn, Fyn kinase activation promotes MEK-mediated transient phosphorylation of ERK1/2. On the other hand, transferrin receptor internalization also produces rapid and sustained activation of Akt, which involves phosphatidylinositol 3-kinase (PI3K) activation. Finally, aTf incorporated through clathrin-mediated endocytosis increases myelin basic protein, F3-contactin and β-tubulin through Fyn/MEK/ERK pathways, as well as an activation of the PI3K/Akt pathway. Our results also demonstrate that the activation of the pathways necessary for oligodendroglial precursor cell maturation is dependent on AP2 recruitment onto the plasma membrane for clathrin-mediated endocytosis of transferrin receptor.

  7. LINGO-1, a transmembrane signaling protein, inhibits oligodendrocyte differentiation and myelination through intercellular self-interactions.

    PubMed

    Jepson, Scott; Vought, Bryan; Gross, Christian H; Gan, Lu; Austen, Douglas; Frantz, J Daniel; Zwahlen, Jacque; Lowe, Derek; Markland, William; Krauss, Raul

    2012-06-22

    Overcoming remyelination failure is a major goal of new therapies for demyelinating diseases like multiple sclerosis. LINGO-1, a key negative regulator of myelination, is a transmembrane signaling protein expressed in both neurons and oligodendrocytes. In neurons, LINGO-1 is an integral component of the Nogo receptor complex, which inhibits axonal growth via RhoA. Because the only ligand-binding subunit of this complex, the Nogo receptor, is absent in oligodendrocytes, the extracellular signals that inhibit myelination through a LINGO-1-mediated mechanism are unknown. Here we show that LINGO-1 inhibits oligodendrocyte terminal differentiation through intercellular interactions and is capable of a self-association in trans. Consistent with previous reports, overexpression of full-length LINGO-1 inhibited differentiation of oligodendrocyte precursor cells (OPCs). Unexpectedly, treatment with a soluble recombinant LINGO-1 ectodomain also had an inhibitory effect on OPCs and decreased myelinated axonal segments in cocultures with neurons from dorsal root ganglia. We demonstrated LINGO-1-mediated inhibition of OPCs through intercellular signaling by using a surface-bound LINGO-1 construct expressed ectopically in astrocytes. Further investigation showed that the soluble LINGO-1 ectodomain can interact with itself in trans by binding to CHO cells expressing full-length LINGO-1. Finally, we observed that soluble LINGO-1 could activate RhoA in OPCs. We propose that LINGO-1 acts as both a ligand and a receptor and that the mechanism by which it negatively regulates OPC differentiation and myelination is mediated by a homophilic intercellular interaction. Disruption of this protein-protein interaction could lead to a decrease of LINGO-1 inhibition and an increase in myelination.

  8. Thermal response and ablation characteristics of light weight ceramic ablators

    NASA Technical Reports Server (NTRS)

    Tran, Huy K.; Rasky, Daniel J.; Esfahani, Lili

    1993-01-01

    An account is given of the thermal performance and ablation characteristics of the NASA-Ames Lightweight Ceramic Ablators (LCAs) in supersonic, high-enthalpy convective environments, which use low density ceramic or carbon fiber matrices as substrates for main structural support, with organic resin fillers. LCA densities are in the 0.224-1.282 g/cu cm range. In-depth temperature data have been obtained to determine thermal penetration depths and conductivity. The addition of SiC and PPMA is noted to significantly improve the ablation performance of LCAs with silica substrates. Carbon-based LCAs are the most mass-efficient at high flux levels.

  9. p38 Mitogen-Activated Protein Kinase Pathway Regulates Genes during Proliferation and Differentiation in Oligodendrocytes

    PubMed Central

    Haines, Jeffery D.; Fulton, Debra L.; Richard, Stephane; Almazan, Guillermina

    2015-01-01

    We have previously shown that p38 mitogen-activated protein kinase (p38 MAPK) is important for oligodendrocyte (OLG) differentiation and myelination. However, the precise cellular mechanisms by which p38 regulates OLG differentiation remain largely unknown. To determine whether p38 functions in part through transcriptional events in regulating OLG identity, we performed microarray analysis on differentiating oligodendrocyte progenitors (OLPs) treated with a p38 inhibitor. Consistent with a role in OLG differentiation, pharmacological inhibition of p38 down-regulated the transcription of genes that are involved in myelin biogenesis, transcriptional control and cell cycle. Proliferation assays showed that OLPs treated with the p38 inhibitor retained a proliferative capacity which could be induced upon application of mitogens demonstrating that after two days of p38-inhibition OLGs remained poised to continue mitosis. Together, our results suggest that the p38 pathway regulates gene transcription which can coordinate OLG differentiation. Our microarray dataset will provide a useful resource for future studies investigating the molecular mechanisms by which p38 regulates oligodendrocyte differentiation and myelination. PMID:26714323

  10. The Effect of Cellular Differentiation on HSV-1 Infection of Oligodendrocytic Cells

    PubMed Central

    Bello-Morales, Raquel; Crespillo, Antonio Jesús; García, Beatriz; Dorado, Luis Ángel; Martín, Beatriz; Tabarés, Enrique; Krummenacher, Claude; de Castro, Fernando; López-Guerrero, José Antonio

    2014-01-01

    Herpes simplex type 1 (HSV-1) is a neurotropic virus that infects many types of cells. Previous studies have demonstrated that oligodendrocytic cells are highly susceptible to HSV-1 infection. Here we analysed HSV-1 infection of a human oligodendrocytic cell line, HOG, and oligodendrocyte precursor cells (OPCs) cultured under growth or differentiation conditions. In addition to cell susceptibility, the role of the major cell receptors for viral entry was assessed. Our results revealed that OPCs and HOG cells cultured under differentiation conditions became more susceptible to HSV-1. On the other hand, viral infection induced morphological changes corresponding to differentiated cells, suggesting that HSV-1 might be inducing cell differentiation. We also observed colocalization of HVEM and nectin-1 with viral particles, suggesting that these two major HSV-1 receptors are functional in HOG cells. Finally, electron microscopy assays indicated that HSV-1 may be also entering OLs by macropinocytosis depending on their differentiation stage. In addition, vesicles containing intracellular enveloped virions observed in differentiated cells point to an endocytic mechanism of virus entry. All these data are indicative of diverse entry pathways dependent on the maturation stage of OLs. PMID:24551233

  11. A Minimally-invasive Blood-derived Biomarker of Oligodendrocyte Cell-loss in Multiple Sclerosis.

    PubMed

    Olsen, John A; Kenna, Lauren A; Tipon, Regine C; Spelios, Michael G; Stecker, Mark M; Akirav, Eitan M

    2016-08-01

    Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). Minimally invasive biomarkers of MS are required for disease diagnosis and treatment. Differentially methylated circulating-free DNA (cfDNA) is a useful biomarker for disease diagnosis and prognosis, and may offer to be a viable approach for understanding MS. Here, methylation-specific primers and quantitative real-time PCR were used to study methylation patterns of the myelin oligodendrocyte glycoprotein (MOG) gene, which is expressed primarily in myelin-producing oligodendrocytes (ODCs). MOG-DNA was demethylated in O4(+) ODCs in mice and in DNA from human oligodendrocyte precursor cells (OPCs) when compared with other cell types. In the cuprizone-fed mouse model of demyelination, ODC derived demethylated MOG cfDNA was increased in serum and was associated with tissue-wide demyelination, demonstrating the utility of demethylated MOG cfDNA as a biomarker of ODC death. Collected sera from patients with active (symptomatic) relapsing-remitting MS (RRMS) demonstrated a higher signature of demethylated MOG cfDNA when compared with patients with inactive disease and healthy controls. Taken together, these results offer a minimally invasive approach to measuring ODC death in the blood of MS patients that may be used to monitor disease progression.

  12. Vulnerability of premyelinating oligodendrocytes to white-matter damage in neonatal brain injury.

    PubMed

    Liu, Xiao-Bo; Shen, Yan; Plane, Jennifer M; Deng, Wenbin

    2013-04-01

    Premature birth is a significant economic and public health burden, and its incidence is rising. Periventricular leukomalacia (PVL) is the predominant form of brain injury in premature infants and the leading cause of cerebral palsy. PVL is characterized by selective white-matter damage with prominent oligodendroglial injury. The maturation-dependent vulnerability of developing and premyelinating oligodendrocytes to excitotoxic, oxidative, and inflammatory forms of injury is a major factor in the pathogenesis of PVL. Recent studies using mouse models of PVL reveal that synapses between axons and developing oligodendrocytes are quickly and profoundly damaged in immature white matter. Axon-glia synapses are highly vulnerable to white-matter injury in the developing brain, and the loss of synapses between axons and premyelinating oligodendrocytes occurs before any cellular loss in the immature white matter. Microglial activation and astrogliosis play important roles in triggering white-matter injury. Impairment of white-matter development and function in the neonatal period contributes critically to functional and behavioral deficits. Preservation of the integrity of the white matter is likely key in the treatment of PVL and subsequent neurological consequences and disabilities.

  13. NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination.

    PubMed

    Lee, Xinhua; Yang, Zhongshu; Shao, Zhaohui; Rosenberg, Sheila S; Levesque, Melissa; Pepinsky, R Blake; Qiu, Mengsheng; Miller, Robert H; Chan, Jonah R; Mi, Sha

    2007-01-03

    Neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which axons control myelination. Here, we identify LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) as a potent axonal inhibitor of oligodendrocyte differentiation and myelination that is regulated by nerve growth factor and its cognate receptor TrkA in a dose-dependent manner. Whereas LINGO-1 expressed by oligodendrocyte progenitor cells was previously identified as an inhibitor of differentiation, we demonstrate that axonal expression of LINGO-1 inhibits differentiation with equal potency. Disruption of LINGO-1 on either cell type is sufficient to overcome the inhibitory action and promote differentiation and myelination, independent of axon diameter. Furthermore, these results were recapitulated in transgenic mice overexpressing the full length LINGO-1 under the neuronal promoter synapsin. Myelination was greatly inhibited in the presence of enforced axonal LINGO-1. The implications of these results relate specifically to the development of potential therapeutics targeting extrinsic growth factors that may regulate the axonal expression of modulators of oligodendrocyte development.

  14. Erythropoietin (EPO) increases myelin gene expression in CG4 oligodendrocyte cells through the classical EPO receptor.

    PubMed

    Cervellini, Ilaria; Annenkov, Alexander; Brenton, Thomas; Chernajovsky, Yuti; Ghezzi, Pietro; Mengozzi, Manuela

    2013-08-28

    Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in nonhematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein [MOG] and myelin basic protein [MBP]). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by Western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects.

  15. Aorta-derived mesoangioblasts differentiate into the oligodendrocytes by inhibition of the Rho kinase signaling pathway.

    PubMed

    Wang, Lei; Kamath, Anant; Frye, Janie; Iwamoto, Gary A; Chun, Ju Lan; Berry, Suzanne E

    2012-05-01

    Mesoangioblasts are vessel-derived stem cells that differentiate into mesodermal derivatives. We have isolated postnatal aorta-derived mesoangioblasts (ADMs) that differentiate into smooth, skeletal, and cardiac muscle, and adipocytes, and regenerate damaged skeletal muscle in a murine model for Duchenne muscular dystrophy. We report that the marker profile of ADM is similar to that of mesoangioblasts isolated from embryonic dorsal aorta, postnatal bone marrow, and heart, but distinct from mesoangioblasts derived from skeletal muscle. We also demonstrate that ADM differentiate into myelinating glial cells. ADM localize to peripheral nerve bundles in regenerating muscles and exhibit morphology and marker expression of mature Schwann cells, and myelinate axons. In vitro, ADM spontaneously express markers of oligodendrocyte progenitors, including the chondroitin sulphate proteoglycan NG2, nestin, platelet-derived growth factor (PDGF) receptor α, the A2B5 antigen, thyroid hormone nuclear receptor α, and O4. Pharmacological inhibition of Rho kinase (ROCK) initiated process extension by ADM, and when combined with insulin-like growth factor 1, PDGF, and thyroid hormone, enhanced ADM expression of oligodendrocyte precursor markers and maturation into the oligodendrocyte lineage. ADM injected into the right lateral ventricle of the brain migrate to the corpus callosum, and cerebellar white matter, where they express components of myelin. Because ADM differentiate or mature into cell types of both mesodermal and ectodermal origin, they may be useful for treatment of a variety of degenerative diseases, or repair and regeneration of multiple cell types in severely damaged tissue.

  16. THE NG2 PROTEOGLYCAN PROMOTES OLIGODENDROCYTE PROGENITOR PROLIFERATION AND DEVELOPMENTAL MYELINATION

    PubMed Central

    Kucharova, Karolina; Stallcup, William B.

    2010-01-01

    The NG2 proteoglycan has been shown to promote proliferation and motility in a variety of cell types. The presence of NG2 on oligodendrocyte progenitor cells (OPCs) suggests that the proteoglycan may be a factor in expansion of the OPC pool to fill the entire central nervous system prior to OPC differentiation to form myelinating oligodendrocytes. Comparisons of postnatal cerebellar myelination in wild type and NG2 null mice reveal reduced numbers of OPCs in developing white matter of the NG2 null mouse. Quantification of BrdU incorporation shows that reduced proliferation is a key reason for this OPC shortage, with the peak of OPC proliferation delayed by 4-5 days in the absence of NG2. As a result of the subnormal pool of OPCs, there is also a delay in production of mature oligodendrocytes and myelinating processes in the NG2 null cerebellum. NG2 may promote OPC proliferation via enhancement of growth factor signaling or mediation of OPC interaction with unmyelinated axons. PMID:20006679

  17. [New techniques of tumor ablation (microwaves, electroporation)].

    PubMed

    de Baere, T

    2011-09-01

    Since the introduction of radiofrequency tumor ablation of liver tumors in the late 1990s, local destructive therapies have been applied to lung, renal and bone lesions. In addition, new techniques have been introduced to compensate for the limitations of radiofrequency ablation, namely the reduced rate of complete ablation for tumors larger than 3 cm and tumors near vessels larger than 3 mm. Microwave ablation is currently evolving rapidly. While it is a technique based on thermal ablation similar to radiofrequency ablation, there are significant differences between both techniques. Electroporation, of interest because of the non-thermal nature of the ablation process, also is under evaluation.

  18. Ablative heat shield design for space shuttle

    NASA Technical Reports Server (NTRS)

    Seiferth, R. W.

    1973-01-01

    Ablator heat shield configuration optimization studies were conducted for the orbiter. Ablator and reusable surface insulation (RSI) trajectories for design studies were shaped to take advantage of the low conductance of ceramic RSI and high temperature capability of ablators. Comparative weights were established for the RSI system and for direct bond and mechanically attached ablator systems. Ablator system costs were determined for fabrication, installation and refurbishment. Cost penalties were assigned for payload weight penalties, if any. The direct bond ablator is lowest in weight and cost. A mechanically attached ablator using a magnesium subpanel is highly competitive for both weight and cost.

  19. Intracisternal delivery of AAV9 results in oligodendrocyte and motor neuron transduction in the whole central nervous system of cats.

    PubMed

    Bucher, T; Dubreil, L; Colle, M-A; Maquigneau, M; Deniaud, J; Ledevin, M; Moullier, P; Joussemet, B

    2014-05-01

    Systemic and intracerebrospinal fluid delivery of adeno-associated virus serotype 9 (AAV9) has been shown to achieve widespread gene delivery to the central nervous system (CNS). However, after systemic injection, the neurotropism of the vector has been reported to vary according to age at injection, with greater neuronal transduction in newborns and preferential glial cell tropism in adults. This difference has not yet been reported after cerebrospinal fluid (CSF) delivery. The present study analyzed both neuronal and glial cell transduction in the CNS of cats according to age of AAV9 CSF injection. In both newborns and young cats, administration of AAV9-GFP in the cisterna magna resulted in high levels of motor neurons (MNs) transduction from the cervical (84±5%) to the lumbar (99±1%) spinal cord, demonstrating that the remarkable tropism of AAV9 for MNs is not affected by age at CSF delivery. Surprisingly, numerous oligodendrocytes were also transduced in the brain and in the spinal cord white matter of young cats, but not of neonates, indicating that (i) age of CSF delivery influences the tropism of AAV9 for glial cells and (ii) AAV9 intracisternal delivery could be relevant for both the treatment of MN and demyelinating disorders.

  20. Magnetic and robotic navigation for catheter ablation: "joystick ablation".

    PubMed

    Ernst, Sabine

    2008-10-01

    Catheter ablation has become the treatment of choice to cure various arrhythmias in the last decades. The newest advancement of this general concept is made on the navigation ability using remote-controlled ablation catheters. This review summarizes the concept of the two currently available systems, followed by a critical review of the published clinical reports for each system, respectively. Despite the limited amount of data, an attempt to compare the two systems is made.

  1. TPS Ablator Technologies for Interplanetary Spacecraft

    NASA Technical Reports Server (NTRS)

    Curry, Donald M.

    2004-01-01

    This slide presentation reviews the status of Thermal Protection System (TPS) Ablator technologies and the preparation for use in interplanetary spacecraft. NASA does not have adequate TPS ablatives and sufficient selection for planned missions. It includes a comparison of shuttle and interplanetary TPS requirements, the status of mainline TPS charring ablator materials, a summary of JSC SBIR accomplishments in developing advanced charring ablators and the benefits of SBIR Ablator/fabrication technology.

  2. Functional identification of neural stem cell-derived oligodendrocytes by means of calcium transients elicited by thrombin.

    PubMed

    Grade, Sofia; Agasse, Fabienne; Bernardino, Liliana; Silva, Carla G; Cortes, Luísa; Malva, João O

    2010-02-01

    Current immunosuppressive treatments for central nervous system demyelinating diseases fail to prevent long-term motor and cognitive decline in patients. Excitingly, glial cell transplantation arises as a promising complementary strategy to challenge oligodendrocytes loss occurring in myelination disorders. A potential source of new oligodendrocytes is the subventricular zone (SVZ) pool of multipotent neural stem cells. However, this approach has been handicapped by the lack of functional methods for identification and pharmacological analysis of differentiating oligodendrocytes, prior to transplantation. In this study, we questioned whether SVZ-derived oligodendrocytes could be functionally discriminated due to intracellular calcium level ([Ca(2+)](i)) variations following KCl, histamine, and thrombin stimulations. Previously, we have shown that SVZ-derived neurons and immature cells can be discriminated on the basis of their selective [Ca(2+)](i) rise upon KCl and histamine stimulation, respectively. Herein, we demonstrate that O4+ and proteolipid protein-positive (PLP+) oligodendrocytes do not respond to these stimuli, but display a robust [Ca(2+)](i) rise following thrombin stimulation, whereas other cell types are thrombin-insensitive. Thrombin-induced Ca(2+) increase in oligodendrocytes is mediated by protease-activated receptor-1 (PAR-1) activation and downstream signaling through G(q/11) and phospholipase C (PLC), resulting in Ca(2+) recruitment from intracellular compartments. This method allows the analysis of functional properties of oligodendrocytes in living SVZ cultures, which is of major interest for the development of effective grafting strategies in the demyelinated brain. Additionally, it opens new perspectives for the search of new pro-oligodendrogenic factors to be used prior grafting.

  3. Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-β*

    PubMed Central

    Jana, Malabendu; Mondal, Susanta; Gonzalez, Frank J.; Pahan, Kalipada

    2012-01-01

    An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-α (PPAR-α), we were unable to detect PPAR-α in either gemfibrozil-treated or untreated human oligodendrocytes, and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-α(−/−) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-β but not PPAR-γ. Consistently, antisense knockdown of PPAR-β, but not PPAR-γ, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-β(−/−) mice. Chromatin immunoprecipitation analysis showed that gemfibrozil induced the recruitment of PPAR-β to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-β to the PLP promoter in vivo in the spinal cord of experimental autoimmune encephalomyelitis mice and suppression of experimental autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-β and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases. PMID:22879602

  4. Accumulation of the cyclin-dependent kinase inhibitor p27/Kip1 and the timing of oligodendrocyte differentiation.

    PubMed Central

    Durand, B; Gao, F B; Raff, M

    1997-01-01

    Many types of vertebrate precursor cells divide a limited number of times before they stop and terminally differentiate. In no case is it known what causes them to stop dividing. We have been studying this problem in the proliferating precursor cells that give rise to postmitotic oligodendrocytes, the cells that make myelin in the central nervous system. We show here that two components of the cell cycle control system, cyclin D1 and the Cdc2 kinase, are present in the proliferating precursor cells but not in differentiated oligodendrocytes, suggesting that the control system is dismantled in the oligodendrocytes. More importantly, we show that the cyclin-dependent kinase (Cdk) inhibitor p27 progressively accumulates in the precursor cells as they proliferate and is present at high levels in oligodendrocytes. Our findings are consistent with the possibility that the accumulation of p27 is part of both the intrinsic counting mechanism that determines when precursor cell proliferation stops and differentiation begins and the effector mechanism that arrests the cell cycle when the counting mechanism indicates it is time. The recent findings of others that p27-deficient mice have an increased number of cells in all of the organs examined suggest that this function of p27 is not restricted to the oligodendrocyte cell lineage. PMID:9029151

  5. The balance between oligodendrocyte and astrocyte production in major white matter tracts is linearly related to serum total thyroxine.

    PubMed

    Sharlin, David S; Tighe, Daniel; Gilbert, Mary E; Zoeller, R Thomas

    2008-05-01

    Thyroid hormone (TH) may control the ratio of oligodendrocytes to astrocytes in white matter by acting on a common precursor of these two cell types. If so, then TH should produce an equal but opposite effect on the density of these two cells types across all TH levels. To test this, we induced graded TH insufficiency by treating pregnant rats with increasing doses of propylthiouracil. Propylthiouracil induced a dose-dependent decrease in serum T(4) in postnatal d 15 pups, a dose-dependent decrease in the density of MAG-positive oligodendrocytes, and an equal increase in the density of glial fibrillary acidic protein-positive astrocytes in both the corpus callosum and anterior commissure. Linear regression analyses demonstrated a strong correlation between glial densities and serum T(4); this correlation was positive for astrocytes and negative for oligodendrocytes. Surprisingly, oligodendrocyte density in the corpus callosum was more sensitive to changes in TH than in the anterior commissure, as indicated by the slope of the regressions. Furthermore, we measured an overall reduction in the cellular density that was independent of changes in myelin-associated glycoprotein and glial fibrillary acidic protein-positive cells. These data strongly support the interpretation that TH controls the balance of production of oligodendrocytes and astrocytes in major white matter tracts of the developing brain by acting on a common precursor of these cell types. Moreover, these findings indicate that major white matter tracts may differ in their sensitivity to TH insufficiency.

  6. Predictive analysis of optical ablation in several dermatological tumoral tissues

    NASA Astrophysics Data System (ADS)

    Fanjul-Vélez, F.; Blanco-Gutiérrez, A.; Salas-García, I.; Ortega-Quijano, N.; Arce-Diego, J. L.

    2013-06-01

    Optical techniques for treatment and characterization of biological tissues are revolutionizing several branches of medical praxis, for example in ophthalmology or dermatology. The non-invasive, non-contact and non-ionizing character of optical radiation makes it specially suitable for these applications. Optical radiation can be employed in medical ablation applications, either for tissue resection or surgery. Optical ablation may provide a controlled and clean cut on a biological tissue. This is particularly relevant in tumoral tissue resection, where a small amount of cancerous cells could make the tumor appear again. A very important aspect of tissue optical ablation is then the estimation of the affected volume. In this work we propose a complete predictive model of tissue ablation that provides an estimation of the resected volume. The model is based on a Monte Carlo approach for the optical propagation of radiation inside the tissue, and a blow-off model for tissue ablation. This model is applied to several types of dermatological tumoral tissues, specifically squamous cells, basocellular and infiltrative carcinomas. The parameters of the optical source are varied and the estimated resected volume is calculated. The results for the different tumor types are presented and compared. This model can be used for surgical planning, in order to assure the complete resection of the tumoral tissue.

  7. Pío del Río Hortega and the discovery of the oligodendrocytes

    PubMed Central

    Pérez-Cerdá, Fernando; Sánchez-Gómez, María Victoria; Matute, Carlos

    2015-01-01

    Pío del Río Hortega (1882–1945) discovered microglia and oligodendrocytes (OLGs), and after Ramón y Cajal, was the most prominent figure of the Spanish school of neurology. He began his scientific career with Nicolás Achúcarro from whom he learned the use of metallic impregnation techniques suitable to study non-neuronal cells. Later on, he joined Cajal’s laboratory. and Subsequently, he created his own group, where he continued to develop other innovative modifications of silver staining methods that revolutionized the study of glial cells a century ago. He was also interested in neuropathology and became a leading authority on Central Nervous System (CNS) tumors. In parallel to this clinical activity, del Río Hortega rendered the first systematic description of a major polymorphism present in a subtype of macroglial cells that he named as oligodendroglia and later OLGs. He established their ectodermal origin and suggested that they built the myelin sheath of CNS axons, just as Schwann cells did in the periphery. Notably, he also suggested the trophic role of OLGs for neuronal functionality, an idea that has been substantiated in the last few years. Del Río Hortega became internationally recognized and established an important neurohistological school with outstanding pupils from Spain and abroad, which nearly disappeared after his exile due to the Spanish civil war. Yet, the difficulty of metal impregnation methods and their variability in results, delayed for some decades the confirmation of his great insights into oligodendrocyte biology until the development of electron microscopy and immunohistochemistry. This review aims at summarizing the pioneer and essential contributions of del Río Hortega to the current knowledge of oligodendrocyte structure and function, and to provide a hint of the scientific personality of this extraordinary and insufficiently recognized man. PMID:26217196

  8. Antioxidant Protection of NADPH-Depleted Oligodendrocyte Precursor Cells Is Dependent on Supply of Reduced Glutathione

    PubMed Central

    Kilanczyk, Ewa; Saraswat Ohri, Sujata; Whittemore, Scott R.

    2016-01-01

    The pentose phosphate pathway is the main source of NADPH, which by reducing oxidized glutathione, contributes to antioxidant defenses. Although oxidative stress plays a major role in white matter injury, significance of NADPH for oligodendrocyte survival has not been yet investigated. It is reported here that the NADPH antimetabolite 6-amino-NADP (6AN) was cytotoxic to cultured adult rat spinal cord oligodendrocyte precursor cells (OPCs) as well as OPC-derived oligodendrocytes. The 6AN-induced necrosis was preceded by increased production of superoxide, NADPH depletion, and lower supply of reduced glutathione. Moreover, survival of NADPH-depleted OPCs was improved by the antioxidant drug trolox. Such cells were also protected by physiological concentrations of the neurosteroid dehydroepiandrosterone (10−8 M). The protection by dehydroepiandrosterone was associated with restoration of reduced glutathione, but not NADPH, and was sensitive to inhibition of glutathione synthesis. A similar protective mechanism was engaged by the cAMP activator forskolin or the G protein-coupled estrogen receptor (GPER/GPR30) ligand G1. Finally, treatment with the glutathione precursor N-acetyl cysteine reduced cytotoxicity of 6AN. Taken together, NADPH is critical for survival of OPCs by supporting their antioxidant defenses. Consequently, injury-associated inhibition of the pentose phosphate pathway may be detrimental for the myelination or remyelination potential of the white matter. Conversely, steroid hormones and cAMP activators may promote survival of NADPH-deprived OPCs by increasing a NADPH-independent supply of reduced glutathione. Therefore, maintenance of glutathione homeostasis appears as a critical effector mechanism for OPC protection against NADPH depletion and preservation of the regenerative potential of the injured white matter. PMID:27449129

  9. Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination

    PubMed Central

    Mei, Feng; Mayoral, Sonia R.; Nobuta, Hiroko; Wang, Fei; Desponts, Caroline; Lorrain, Daniel S.; Xiao, Lan; Green, Ari J.; Rowitch, David; Whistler, Jennifer

    2016-01-01

    Remyelinating therapies seek to promote restoration of function and normal cellular architecture following demyelination in diseases, such as multiple sclerosis (MS). Functional screening for small molecules or novel targets for remyelination is a major hurdle to the identification and development of rational therapeutics for MS. Recent findings and technical advances provide us with a unique opportunity to provide insight into the cell autonomous mechanisms for remyelination and address this unmet need. Upon screening a G-protein-coupled receptor small-molecule library, we report the identification of a cluster of κ-opioid receptor (KOR) agonists that significantly promotes oligodendrocyte differentiation and myelination. KOR agonists were validated in purified rat oligodendroglial cultures, and the (±)U-50488 compound proved to be most effective for differentiation. (±)U-50488 treatment significantly enhances differentiation and myelination in purified oligodendroglial cocultures and greatly accelerates the kinetics of remyelination in vivo after focal demyelination with lysolecithin. The effect of (±)U-50488 is attenuated by KOR antagonists and completely abolished in KOR-null oligodendroglia. Conditional deletion of KOR in murine oligodendrocyte precursor cells (OPCs) greatly inhibits remyelination after focal demyelination lacking any response to (±)U-50488 treatment. To determine whether agonism of KOR represents a feasible therapeutic approach, human induced pluripotent stem cell-derived OPCs were treated with (±)U-50488. Consistent with findings, differentiation of human OPCs into mature oligodendrocytes was significantly enhanced. Together, KOR is a therapeutic target to consider for future remyelination therapy. SIGNIFICANCE STATEMENT Remyelination represents a promising strategy to achieve functional recovery in demyelinating diseases, like MS. Thus, identification of potent compounds and targets that promote remyelination represents a critically

  10. Trapidil-mediated inhibition of CNS remyelination results from reduced numbers and impaired differentiation of oligodendrocytes.

    PubMed

    McKay, J S; Blakemore, W F; Franklin, R J

    1998-12-01

    In a previous study, we described the inhibitory effects of the growth factor-antagonist, trapidil, on spontaneously occurring oligodendrocyte remyelination in the rat spinal cord following lysolecithin-induced demyelination [30]. The objective of the present study was to further investigate the mechanisms of trapidil-mediated impairment of remyelination and thus obtain greater insight into the steps at which growth factors may be involved in remyelination. To this end, an ultrastructural analysis of the cellular composition of lesions from control and trapidil-treated animals was undertaken. Demyelination was created in the dorsal funiculus of 6-week-old female rats by the injection of 1.0 microliter of 1% lysolecithin. The animals received daily intraperitoneal injections of trapidil (80 mg/kg) or saline for 21 days, beginning on the day of lesion induction. Quantitative electron microscopic examination of lesions from both groups of animals showed that trapidil-treated lesions had reduced numbers of oligodendrocytes (P = 0.02) with a higher relative proportion of immature phenotypes, but increased numbers of microglia (P = 0.0009) and dystrophic axons (P0.02). In addition, the numbers of myelin lamellae around remyelinated axons were fewer in trapidil-treated animals. These results suggest that trapidil-mediated impairment of CNS remyelination is due to a blockage of growth factor-mediated proliferation and/or recruitment of remyelinating cells. Furthermore, the presence of oligodendrocytes with a more immature phenotype and the decreased thickness of the myelin sheaths of remyelination in the trapidil-treated animals indicate an impairment of growth factor-mediated differentiation.

  11. Human embryonic stem cell-derived oligodendrocyte progenitors remyelinate the brain and rescue behavioral deficits following radiation.

    PubMed

    Piao, Jinghua; Major, Tamara; Auyeung, Gordon; Policarpio, Edelweiss; Menon, Jayanthi; Droms, Leif; Gutin, Philip; Uryu, Kunihiro; Tchieu, Jason; Soulet, Denis; Tabar, Viviane

    2015-02-05

    Radiation therapy to the brain is a powerful tool in the management of many cancers, but it is associated with significant and irreversible long-term side effects, including cognitive decline and impairment of motor coordination. Depletion of oligodendrocyte progenitors and demyelination are major pathological features that are particularly pronounced in younger individuals and severely limit therapeutic options. Here we tested whether human ESC-derived oligodendrocytes can functionally remyelinate the irradiated brain using a rat model. We demonstrate the efficient derivation and prospective isolation of human oligodendrocyte progenitors, which, upon transplantation, migrate throughout the major white matter tracts resulting in both structural and functional repair. Behavioral testing showed complete recovery of cognitive function while additional recovery from motor deficits required concomitant transplantation into the cerebellum. The ability to repair radiation-induced damage to the brain could dramatically improve the outlook for cancer survivors and enable more effective use of radiation therapies, especially in children.

  12. Femtosecond laser ablation of enamel

    NASA Astrophysics Data System (ADS)

    Le, Quang-Tri; Bertrand, Caroline; Vilar, Rui

    2016-06-01

    The surface topographical, compositional, and structural modifications induced in human enamel by femtosecond laser ablation is studied. The laser treatments were performed using a Yb:KYW chirped-pulse-regenerative amplification laser system (560 fs and 1030 nm) and fluences up to 14 J/cm2. The ablation surfaces were studied by scanning electron microscopy, grazing incidence x-ray diffraction, and micro-Raman spectroscopy. Regardless of the fluence, the ablation surfaces were covered by a layer of resolidified material, indicating that ablation is accompanied by melting of hydroxyapatite. This layer presented pores and exploded gas bubbles, created by the release of gaseous decomposition products of hydroxyapatite (CO2 and H2O) within the liquid phase. In the specimen treated with 1-kHz repetition frequency and 14 J/cm2, thickness of the resolidified material is in the range of 300 to 900 nm. The micro-Raman analysis revealed that the resolidified material contains amorphous calcium phosphate, while grazing incidence x-ray diffraction analysis allowed detecting traces of a calcium phosphate other than hydroxyapatite, probably β-tricalcium phosphate Ca3), at the surface of this specimen. The present results show that the ablation of enamel involves melting of enamel's hydroxyapatite, but the thickness of the altered layer is very small and thermal damage of the remaining material is negligible.

  13. Laser ablation studies of concrete

    SciTech Connect

    Savina, M.; Xu, Z.; Wang, Y.; Reed, C.; Pellin, M.

    1999-10-20

    Laser ablation was studied as a means of removing radioactive contaminants from the surface and near-surface regions of concrete. The authors present the results of ablation tests on cement and concrete samples using a 1.6 kW pulsed Nd:YAG laser with fiber optic beam delivery. The laser-surface interaction was studied using cement and high density concrete as targets. Ablation efficiency and material removal rates were determined as functions of irradiance and pulse overlap. Doped samples were also ablated to determine the efficiency with which surface contaminants were removed and captured in the effluent. The results show that the cement phase of the material melts and vaporizes, but the aggregate portion (sand and rock) fragments. The effluent consists of both micron-size aerosol particles and chunks of fragmented aggregate material. Laser-induced optical emission spectroscopy was used to analyze the surface during ablation. Analysis of the effluent showed that contaminants such as cesium and strontium were strongly segregated into different regions of the particle size distribution of the aerosol.

  14. Fragmentation and ablation during entry

    SciTech Connect

    Canavan, G.H.

    1997-09-01

    This note discusses objects that both fragment and ablate during entry, using the results of previous reports to describe the velocity, pressure, and fragmentation of entering objects. It shows that the mechanisms used there to describe the breakup of non-ablating objects during deceleration remain valid for most ablating objects. It treats coupled fragmentation and ablation during entry, building on earlier models that separately discuss the entry of objects that are hard, whose high heat of ablation permits little erosion, and those who are strong whose strength prevents fragmentation, which are discussed in ``Radiation from Hard Objects,`` ``Deceleration and Radiation of Strong, Hard, Asteroids During Atmospheric Impact,`` and ``Meteor Signature Interpretation.`` This note provides a more detailed treatment of the further breakup and separation of fragments during descent. It replaces the constraint on mass per unit area used earlier to determine the altitude and magnitude of peak power radiation with a detailed analytic solution of deceleration. Model predictions are shown to be in agreement with the key features of numerical calculations of deceleration. The model equations are solved for the altitudes of maximum radiation, which agree with numerical integrations. The model is inverted analytically to infer object size and speed from measurements of peak power and altitude to provide a complete model for the approximate inversion of meteor data.

  15. Thermal ablation of lung tumors.

    PubMed

    McTaggart, Ryan A; Dupuy, Damian E

    2007-06-01

    Thermal ablation can be applied to treat any thoracic malignancy: primary lung cancers, recurrent primary lung cancers, metastatic disease, chest wall masses, and painful, bony metastases. Since the first reported use of thermal ablation for lung cancer in 2000 there has been an explosive use of the procedure, and by 2010 the number of procedures to treat thoracic malignancy is expected to exceed 150,000 per year. Presently, thermal ablation is best used for patients with early-stage lung cancers in patients who are not surgical candidates, patients with small and favorably located pulmonary metastases, and patients in whom palliation of tumor-related symptoms is the goal. Radiofrequency ablation, microwave ablation, and cryoablation are novel treatment modalities for lung cancer and can safely accomplish tumor destruction and even complete eradication of tumor in patients who are not candidates for surgical resection. In this article, we discuss technical considerations for each modality and the periprocedure and postprocedure management of patients with this disease.

  16. Effect of berberine on nitric oxide production during oxygen-glucose deprivation/reperfusion in OLN-93 oligodendrocytes.

    PubMed

    Nadjafi, Shabnam; Ebrahimi, Soltan-Ahmad; Rahbar-Roshandel, Nahid

    2014-11-01

    In this study, the effect of berberine, an isoquinoline alkaloid isolated from Coptidis rhizoma, on Nitric Oxide (NO) production, as a possible involved factor, during excitotoxic injury in oligodendroglial cells were evaluated. The overactivation of ionotropic glutamate receptors which is known as the excitotoxicity, is an important phenomenon because of the contribution in acute injury to the central nervous system, chronic neurodegenerative disorders, oligodendrocyte loss and demyelinating diseases as Multiple Sclerosis (MS). Intracellular Ca2+ overload, have a key role during excitotoxic injury and such increase in cytoplasmic Ca2+ triggers a series of events such as production of NO that end to cell death. Previous report showed the protective effects of berberine on ischemic-induced excitotoxic insult in oligodendrocytes. Hereby, we intended to know if the NO production could be associated with oxygen-glucose deprivation/reperfusion-induced excitotoxic damage in oligodendrocyte; moreover, the alteration of NO production could be considered as an involved mechanism for protective effect of berberine in such condition. Therefore, the effect of berberine (2 μM) on NO production during oxygen-glucose deprivation/24 h reperfusion in oligodendrocytes were examined. The OLN-93 cell line (a permanent immature rat oligodendrocyte) was used as a model of oligodendrocyte. Thirty minutes-oxygen-glucose deprivation/24 h reperfusion was used to induce excitotoxicity. NO production was evaluated by Griess method. Our results demonstrated that berberine (2 μM) significantly decreased NO production during 30 min oxygen-glucose deprivation/reperfusion. It seems that blockade of NO production by berberine may also participate in oligodendroglial cell protection against oxygen-glucose deprivation/reperfusion-induced insult.

  17. Transplanted miR-219-overexpressing oligodendrocyte precursor cells promoted remyelination and improved functional recovery in a chronic demyelinated model.

    PubMed

    Fan, Hong-Bin; Chen, Li-Xia; Qu, Xue-Bin; Ren, Chuan-Lu; Wu, Xiu-Xiang; Dong, Fu-Xing; Zhang, Bao-Le; Gao, Dian-Shuai; Yao, Rui-Qin

    2017-02-01

    Oligodendrocyte precursor cells (OPCs) have the ability to repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. Recent evidence suggests that miR-219 helps regulate the differentiation of OPCs into oligodendrocytes. We performed oligodendrocyte differentiation studies using miR-219-overexpressing mouse embryonic stem cells (miR219-mESCs). The self-renewal and multiple differentiation properties of miR219-mESCs were analyzed by the expression of the stage-specific cell markers Nanog, Oct4, nestin, musashi1, GFAP, Tuj1 and O4. MiR-219 accelerated the differentiation of mESC-derived neural precursor cells (NPCs) into OPCs. We further transplanted OPCs derived from miR219-mESCs (miR219-OPCs) into cuprizone-induced chronically demyelinated mice to observe remyelination, which resulted in well-contained oligodendrocyte grafts that migrated along the corpus callosum and matured to express myelin basic protein (MBP). Ultrastructural studies further confirmed the presence of new myelin sheaths. Improved cognitive function in these mice was confirmed by behavioral tests. Importantly, the transplanted miR219-OPCs induced the proliferation of endogenous NPCs. In conclusion, these data demonstrate that miR-219 rapidly transforms mESCs into oligodendrocyte lineage cells and that the transplantation of miR219-OPCs not only promotes remyelination and improves cognitive function but also enhances the proliferation of host endogenous NPCs following chronic demyelination. These results support the potential of a therapeutic role for miR-219 in demyelinating diseases.

  18. Transplanted miR-219-overexpressing oligodendrocyte precursor cells promoted remyelination and improved functional recovery in a chronic demyelinated model

    PubMed Central

    Fan, Hong-Bin; Chen, Li-Xia; Qu, Xue-Bin; Ren, Chuan-Lu; Wu, Xiu-Xiang; Dong, Fu-Xing; Zhang, Bao-Le; Gao, Dian-Shuai; Yao, Rui-Qin

    2017-01-01

    Oligodendrocyte precursor cells (OPCs) have the ability to repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. Recent evidence suggests that miR-219 helps regulate the differentiation of OPCs into oligodendrocytes. We performed oligodendrocyte differentiation studies using miR-219-overexpressing mouse embryonic stem cells (miR219-mESCs). The self-renewal and multiple differentiation properties of miR219-mESCs were analyzed by the expression of the stage-specific cell markers Nanog, Oct4, nestin, musashi1, GFAP, Tuj1 and O4. MiR-219 accelerated the differentiation of mESC-derived neural precursor cells (NPCs) into OPCs. We further transplanted OPCs derived from miR219-mESCs (miR219-OPCs) into cuprizone-induced chronically demyelinated mice to observe remyelination, which resulted in well-contained oligodendrocyte grafts that migrated along the corpus callosum and matured to express myelin basic protein (MBP). Ultrastructural studies further confirmed the presence of new myelin sheaths. Improved cognitive function in these mice was confirmed by behavioral tests. Importantly, the transplanted miR219-OPCs induced the proliferation of endogenous NPCs. In conclusion, these data demonstrate that miR-219 rapidly transforms mESCs into oligodendrocyte lineage cells and that the transplantation of miR219-OPCs not only promotes remyelination and improves cognitive function but also enhances the proliferation of host endogenous NPCs following chronic demyelination. These results support the potential of a therapeutic role for miR-219 in demyelinating diseases. PMID:28145507

  19. Pluripotent stem cell-derived radial glia-like cells as stable intermediate for efficient generation of human oligodendrocytes.

    PubMed

    Gorris, Raphaela; Fischer, Julia; Erwes, Kim Lina; Kesavan, Jaideep; Peterson, Daniel A; Alexander, Michael; Nöthen, Markus M; Peitz, Michael; Quandel, Tamara; Karus, Michael; Brüstle, Oliver

    2015-12-01

    Neural precursor cells (NPCs) derived from human pluripotent stem cells (hPSCs) represent an attractive tool for the in vitro generation of various neural cell types. However, the developmentally early NPCs emerging during hPSC differentiation typically show a strong propensity for neuronal differentiation, with more limited potential for generating astrocytes and, in particular, for generating oligodendrocytes. This phenomenon corresponds well to the consecutive and protracted generation of neurons and GLIA during normal human development. To obtain a more gliogenic NPC type, we combined growth factor-mediated expansion with pre-exposure to the differentiation-inducing agent retinoic acid and subsequent immunoisolation of CD133-positive cells. This protocol yields an adherent and self-renewing population of hindbrain/spinal cord radial glia (RG)-like neural precursor cells (RGL-NPCs) expressing typical neural stem cell markers such as nestin, ASCL1, SOX2, and PAX6 as well as RG markers BLBP, GLAST, vimentin, and GFAP. While RGL-NPCs maintain the ability for tripotential differentiation into neurons, astrocytes, and oligodendrocytes, they exhibit greatly enhanced propensity for oligodendrocyte generation. Under defined differentiation conditions promoting the expression of the major oligodendrocyte fate-determinants OLIG1/2, NKX6.2, NKX2.2, and SOX10, RGL-NPCs efficiently convert into NG2-positive oligodendroglial progenitor cells (OPCs) and are subsequently capable of in vivo myelination. Representing a stable intermediate between PSCs and OPCs, RGL-NPCs expedite the generation of PSC-derived oligodendrocytes with O4-, 4860-, and myelin basic protein (MBP)-positive cells that already appear within 7 weeks following growth factor withdrawal-induced differentiation. Thus, RGL-NPCs may serve as robust tool for time-efficient generation of human oligodendrocytes from embryonic and induced pluripotent stem cells.

  20. miR-32 and its target SLC45A3 regulate the lipid metabolism of oligodendrocytes and myelin

    PubMed Central

    Shin, Daesung; Howng, Shen Yi B.

    2012-01-01

    Oligodendrocytes generate large amounts of myelin by extension of their cell membranes. Though lipid is the major component of myelin, detailed lipid metabolism in the maintenance of myelin is not understood. We reported previously that miR-32 might be involved in myelin maintenance (Shin et al., 2009). Here we demonstrate a novel role for miR-32 in oligodendrocyte function and development through the regulation of SLC45A3 (solute carrier family 45, member 3) and other downstream targets such as CLDN-11. miR-32 is highly expressed in the myelin-enriched regions of the brain and mature oligodendrocytes, and it promotes myelin protein expression. We found that miR-32 directly regulates the expression of SLC45A3 by binding to the complementary sequence on the 3’UTR of cldn11 and slc45a3. As a myelin-enriched putative sugar transporter, SLC45A3 enhances intracellular glucose levels and the synthesis of long-chain fatty acids. Therefore, overexpression of SLC45A3 triggers neutral lipid accumulation. Interestingly, both overexpression and suppression of SLC45A3 reduces myelin protein expression in mature oligodendrocytes and alters oligodendrocyte morphology, indicating that tight regulation of SLC45A3 expression is necessary for the proper maintenance of myelin proteins and structure. Taken together, our data suggest that miR-32 and its downstream target SLC45A3 play important roles in myelin maintenance by modulating glucose and lipid metabolism and myelin protein expression in oligodendrocytes. PMID:22521588

  1. The opioid system and brain development: methadone effects on the oligodendrocyte lineage and the early stages of myelination

    PubMed Central

    Vestal-Laborde, Allison A.; Eschenroeder, Andrew C.; Bigbee, John W.; Robinson, Susan E.; Sato-Bigbee, Carmen

    2014-01-01

    Oligodendrocytes express opioid receptors throughout development but the role of the opioid system in myelination remains poorly understood. This is a significant problem as opioid use and abuse continue to increase in two particular populations: pregnant addicts where drug effects could target early myelination in the fetus and newborns; and adolescents and young adults where late myelination of “higher-order” regions takes place. Maintenance treatments for opioid addicts include the long-lasting opioids methadone and buprenorphine. Similar to our previous findings on buprenorphine effects, we now find that early myelination in the developing rat brain is also altered by perinatal exposure to therapeutic doses of methadone. Pups exposed to this drug exhibit elevated brain levels of the four major splicing variants of myelin basic proteins (MBPs), myelin proteolipid protein (PLP), and myelin-oligodendrocyte glycoprotein (MOG). Consistent with the enrichment and function of these proteins in mature myelin, analysis of the corpus callosum in these young animals also indicated elevated number of axons with already highly compacted myelin sheaths. Moreover, studies in cultured cells showed that methadone exerts direct effects at specific stages of the oligodendrocyte lineage, stimulating the proliferation of the progenitor cells while on the other hand accelerating the maturation of the more differentiated but still immature pre-oligodendrocytes. While the long-term effects of these observations remain unknown, accelerated or increased oligodendrocyte maturation and myelination could both disrupt the complex sequence of synchronized events leading to normal connectivity in the developing brain. Together with our previous observations on buprenorphine effects, the present findings further underscore a crucial function of the endogenous opioid system in the control of oligodendrocyte development and the timing of myelination. Interference with these regulatory

  2. Events at the transition between cell cycle exit and oligodendrocyte progenitor differentiation: the role of HDAC and YY1.

    PubMed

    He, Ye; Sandoval, Juan; Casaccia-Bonnefil, Patrizia

    2007-08-01

    The complexity of the adult brain is the result of an integrated series of developmental events that depends on appropriate timing of differentiation. The importance of transcriptional regulatory networks and epigenetic mechanisms of regulation of gene expression is becoming increasingly evident. Among these mechanisms, previous work has revealed the importance of histone deacetylation in oligodendrocyte differentiation. In this manuscript we define the region of interaction between transcription factor Yin-Yang 1 (YY1) and histone deacetylase 1, and characterize the functional consequences of YY1 overexpression on the differentiation of oligodendrocyte progenitors.

  3. A review of induced pluripotent stem cell, direct conversion by trans-differentiation, direct reprogramming and oligodendrocyte differentiation.

    PubMed

    Prasad, Ankshita; Manivannan, Janani; Loong, Daniel T B; Chua, Soo M; Gharibani, Payam M; All, Angelo H

    2016-03-01

    Rapid progress in the field of stem cell therapy and cellular reprogramming provides convincing evidence of its feasibility in treating a wide range of pathologies through autologous cell replacement therapy. This review article describes in detail on three widely used approaches of somatic cell reprogramming: induced pluripotent stem cells, direct conversion and direct reprogramming, in the context of demyelination in the CNS. The potential limitations of each reprogramming technique are reviewed along with their distinct molecular approach to reprogramming. This is followed by an analysis on the scopes and challenges of its translational applications in deriving oligodendrocyte progenitor cells and oligodendrocytes for cell replacement treatment of demyelinating conditions in the CNS.

  4. Theoretical Modeling for Hepatic Microwave Ablation

    PubMed Central

    Prakash, Punit

    2010-01-01

    Thermal tissue ablation is an interventional procedure increasingly being used for treatment of diverse medical conditions. Microwave ablation is emerging as an attractive modality for thermal therapy of large soft tissue targets in short periods of time, making it particularly suitable for ablation of hepatic and other tumors. Theoretical models of the ablation process are a powerful tool for predicting the temperature profile in tissue and resultant tissue damage created by ablation devices. These models play an important role in the design and optimization of devices for microwave tissue ablation. Furthermore, they are a useful tool for exploring and planning treatment delivery strategies. This review describes the status of theoretical models developed for microwave tissue ablation. It also reviews current challenges, research trends and progress towards development of accurate models for high temperature microwave tissue ablation. PMID:20309393

  5. Image-guided ablation of adrenal lesions.

    PubMed

    Yamakado, Koichiro

    2014-06-01

    Although laparoscopic adrenalectomy has remained the standard of care for the treatment for adrenal tumors, percutaneous image-guided ablation therapy, such as chemical ablation, radiofrequency ablation, cryoablation, and microwave ablation, has been shown to be clinically useful in many nonsurgical candidates. Ablation therapy has been used to treat both functioning adenomas and malignant tumors, including primary adrenal carcinoma and metastasis. For patients with functioning adenomas, biochemical and symptomatic improvement is achieved in 96 to 100% after ablation; for patients with malignant adrenal neoplasms, however, the survival benefit from ablation therapy remains unclear, though good initial results have been reported. This article outlines the current role of ablation therapy for adrenal lesions, as well as identifying some of the technical considerations for this procedure.

  6. Microwave ablation of hepatocellular carcinoma

    PubMed Central

    Poggi, Guido; Tosoratti, Nevio; Montagna, Benedetta; Picchi, Chiara

    2015-01-01

    Although surgical resection is still the optimal treatment option for early-stage hepatocellular carcinoma (HCC) in patients with well compensated cirrhosis, thermal ablation techniques provide a valid non-surgical treatment alternative, thanks to their minimal invasiveness, excellent tolerability and safety profile, proven efficacy in local disease control, virtually unlimited repeatability and cost-effectiveness. Different energy sources are currently employed in clinics as physical agents for percutaneous or intra-surgical thermal ablation of HCC nodules. Among them, radiofrequency (RF) currents are the most used, while microwave ablations (MWA) are becoming increasingly popular. Starting from the 90s’, RF ablation (RFA) rapidly became the standard of care in ablation, especially in the treatment of small HCC nodules; however, RFA exhibits substantial performance limitations in the treatment of large lesions and/or tumors located near major heat sinks. MWA, first introduced in the Far Eastern clinical practice in the 80s’, showing promising results but also severe limitations in the controllability of the emitted field and in the high amount of power employed for the ablation of large tumors, resulting in a poor coagulative performance and a relatively high complication rate, nowadays shows better results both in terms of treatment controllability and of overall coagulative performance, thanks to the improvement of technology. In this review we provide an extensive and detailed overview of the key physical and technical aspects of MWA and of the currently available systems, and we want to discuss the most relevant published data on MWA treatments of HCC nodules in regard to clinical results and to the type and rate of complications, both in absolute terms and in comparison with RFA. PMID:26557950

  7. Surgical Ablation of Atrial Fibrillation.

    PubMed

    Ramlawi, Basel; Abu Saleh, Walid K

    2015-01-01

    The Cox-maze procedure for the restoration of normal sinus rhythm, initially developed by Dr. James Cox, underwent several iterations over the years. The main concept consists of creating a series of transmural lesions in the right and left atria that disrupt re-entrant circuits responsible for propagating the abnormal atrial fibrillation rhythm. The left atrial appendage is excluded as a component of the Maze procedure. For the first three iterations of the Cox- maze procedure, these lesions were performed using a surgical cut-and-sew approach that ensured transmurality. The Cox-Maze IV is the most currently accepted iteration. It achieves the same lesion set of the Cox- maze III but uses alternative energy sources to create the transmural lesions, potentially in a minimally invasive approach on the beating heart. High-frequency ultrasound, microwave, and laser energy have all been used with varying success in the past. Today, bipolar radiofrequency heat or cryotherapy cooling are the most accepted sources for creating linear lesions with consistent safety and transmurality. The robust and reliable nature of these energy delivery methods has yielded a success rate reaching 90% freedom from atrial fibrillation at 12 months. Such approaches offer a significant long-term advantage over catheter-based ablation, especially in patients having longstanding, persistent atrial fibrillation with characteristics such as dilated left atrial dimensions, poor ejection fraction, and failed catheter ablation. Based on these improved results, there currently is significant interest in developing a hybrid ablation strategy that incorporates the superior transmural robust lesions of surgical ablation, the reliable stroke prevention potential of epicardial left atrial appendage exclusion, and sophisticated mapping and confirmatory catheter-based ablation technology. Such a minimally invasive hybrid strategy for ablation may lead to the development of multidisciplinary "Afib teams" to

  8. Induction of caspase-dependent apoptosis in cultured rat oligodendrocytes by murine coronavirus is mediated during cell entry and does not require virus replication.

    PubMed

    Liu, Yin; Cai, Yingyun; Zhang, Xuming

    2003-11-01

    Murine coronavirus mouse hepatitis virus (MHV) causes demyelination of the central nervous system (CNS) in rats and mice. Apoptotic oligodendrocytes have been detected in the vicinity of the CNS demyelinating lesions in these animals. However, whether MHV can directly induce oligodendrocyte apoptosis has not been documented. Here, we established a rat oligodendrocyte culture that is morphologically and phenotypically indistinguishable from the primary rat oligodendrocytes. Using this culture, we showed that mature rat oligodendrocytes were permissive to MHV infection but did not support productive virus replication. Significantly, oligodendrocytes infected with both live and ultraviolet light-inactivated viruses underwent apoptosis to a similar extent, which was readily detectable at 24 h postinfection as revealed by apoptotic bodies and DNA fragmentation, indicating that MHV-induced apoptosis is mediated during the early stages of the virus life cycle and does not require virus replication. Prior treatment of cells with the lysosomotropic agents NH(4)Cl and chloroquine as well as the vacuolar proton pump-ATPase inhibitor bafilomycin A1, all of which block the acidification of the endosome, prevented oligodendrocytes from succumbing to apoptosis induced by MHV mutant OBLV60, which enters cells via endocytosis, indicating that fusion between the viral envelope and cell membranes triggers the apoptotic cascade. Treatment with the pan-caspase inhibitor Z-VAD-fmk blocked MHV-induced apoptosis, suggesting an involvement of the caspase-dependent pathway. Our results, thus, for the first time provide unequivocal evidence that infection of oligodendrocytes with MHV directly results in apoptosis. This finding provides an explanation for the destruction of oligodendrocytes and the damage of myelin sheath in MHV-infected CNS and suggests that oligodendrocyte apoptosis may be one of the underlying mechanisms for the pathogenesis of MHV-induced demyelinating diseases in animals.

  9. c-Myc-dependent transcriptional regulation of cell cycle and nucleosomal histones during oligodendrocyte differentiation

    PubMed Central

    Magri, Laura; Gacias, Mar; Wu, Muzhou; Swiss, Victoria A; Janssen, William G; Casaccia, Patrizia

    2014-01-01

    Oligodendrocyte progenitor cells (OPCs) have the ability to divide or to arrest growth and differentiate into myelinating oligodendrocytes in the developing brain. Due to their high number and the persistence of their proliferative capacity in the adult brain, OPCs are being studied as potential targets for myelin repair and also as potential source of brain tumors. This study addresses the molecular mechanisms regulating the transcriptional changes occurring at the critical transition between proliferation and cell cycle exit in cultured OPCs. Using bioinformatic analysis of existing datasets, we identified c-Myc as a key transcriptional regulator of this transition and confirmed direct binding of this transcription factor to identified target genes using chromatin immunoprecipitation. The expression of c-Myc was elevated in proliferating OPCs, where it also bound to the promoter of genes involved in cell cycle regulation (i.e. Cdc2) or chromosome organization (i.e. H2afz). Silencing of c-Myc was associated with decreased histone acetylation at target gene promoters and consequent decrease of gene transcripts. c-Myc silencing induced also a global increase of repressive histone methylation and premature nuclear peripheral chromatin compaction and promoted the progression of OPCs towards differentiation. We conclude that c-Myc is an important modulator of the transition between proliferation and differentiation of OPCs, although its decrease is not sufficient to induce progression into a myelinating phenotype. PMID:24502923

  10. Sonic hedgehog and neurotrophin-3 increase oligodendrocyte numbers and myelination after spinal cord injury

    PubMed Central

    Goodman, Ashley G.; Kukushliev, Todor V.; Hassani, Donna M.; Cummings, Brian J.; Anderson, Aileen J.; Shea, Lonnie D.

    2014-01-01

    Spinal cord injury (SCI) results in loss of sensory and motor function below the level of injury and has limited available therapies. Multiple channel bridges have been investigated as a means to create a permissive environment for regeneration, with channels supporting axonal growth through the injury. Bridges support robust axon growth with myelination of the axons, and herein we investigated the cell types that are myelinating the axons and whether trophic factors can enhance myelination. Lentivirus encoding for neurotrophin-3 (NT3), sonic hedgehog (SHH) and the combination of these factors was delivered from bridges implanted into a lateral hemisection defect at T9/T10 in mice, and the response of endogenous progenitor cells within the spinal cord was investigated. Relative to control, the localized sustained expression of these factors significantly increased growth of regenerating axons into the bridge and enhanced axon myelination 8 weeks after injury. SHH decreased Sox2+ cells and increased Olig2+ cells, whereas NT3 alone or in combination with SHH enhanced GFAP+ and Olig2+ cells relative to control. For delivery of lentivirus encoding for either factor, we identified cells at various stages of differentiation along the oligodendrocyte lineage (e.g., O4+, GalC+). Expression of NT3 enhanced myelination primarily by infiltrating Schwann cells, whereas SHH over-expression substantially increased myelination by oligodendrocytes. Gene delivery represents a promising tool to direct activation and differentiation of endogenous progenitor cells for applications in regenerative medicine. PMID:24873988

  11. Role of Proteolipid Protein in HSV-1 Entry in Oligodendrocytic Cells

    PubMed Central

    Bello-Morales, Raquel; Crespillo, Antonio Jesús; Praena, Beatriz; Tabarés, Enrique; Revilla, Yolanda; García, Elena; Fraile-Ramos, Alberto; Baron, Wia; Krummenacher, Claude; López-Guerrero, José Antonio

    2016-01-01

    Herpes simplex virus type 1 (HSV-1) has the ability to enter many different hosts and cell types by several strategies. This highly prevalent alphaherpesvirus can enter target cells using different receptors and different pathways: fusion at a neutral pH, low-pH-dependent and low-pH-independent endocytosis. Several cell receptors for viral entry have been described, but several observations suggest that more receptors for HSV-1 might exist. In this work, we propose a novel role for the proteolipid protein (PLP) in HSV-1 entry into the human oligodendrocytic cell line HOG. Cells transfected with PLP-EGFP showed an increase in susceptibility to HSV-1. Furthermore, the infection of HOG and HOG-PLP transfected cells with the R120vGF virus–unable to replicate in ICP4-defficient cells- showed an increase in viral signal in HOG-PLP, suggesting a PLP involvement in viral entry. In addition, a mouse monoclonal antibody against PLP drastically inhibited HSV-1 entry into HOG cells. PLP and virions colocalized in confocal immunofluorescence images, and in electron microscopy images, which suggest that PLP acts at the site of entry into HOG cells. Taken together these results suggest that PLP may be involved in HSV-1 entry in human oligodendrocytic cells. PMID:26807581

  12. A Novel Approach for Amplification and Purification of Mouse Oligodendrocyte Progenitor Cells

    PubMed Central

    Yang, Junlin; Cheng, Xuejun; Shen, Jiaxi; Xie, Binghua; Zhao, Xiaofeng; Zhang, Zunyi; Cao, Qilin; Shen, Ying; Qiu, Mengsheng

    2016-01-01

    Although transgenic and knockout mice are widely used to study the specification and differentiation of oligodendrocyte precursor cells (OPCs), mouse primary OPCs are difficult to be purified and maintained, and many in vitro studies have to resort to rat OPCs as substitutes. In this study, we reported that mouse O4 negative early-stage OPCs can be obtained by culturing cortical tissue blocks, and the simultaneous treatment of OPCs with Platelet Derived Growth Factor-AA (PDGFaa), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) is the key for the propagation of mouse OPCs in culture. EGF was found to be a potent mitogen for OPCs and cooperate with PDGFaa to extend cell division and inhibit their differentiation. EGF also collaborates with PDGFaa and bFGF to convert bipolar or tripolar OPCs to more vital fibroblast-like OPCs without compromising their oligodendrocyte differentiation potential. In addition, EGF promoted the survival and proliferation of glial progenitor cells (GPCs) derived from primary OPC cultures, and a mixture of GPCs and OPCs can be obtained and propagated in the presence of EGF, bFGF, and PDGFaa. Once EGF is withdrawn, GPC population decreased sharply and fibroblast-like OPCs changed into typical OPCs morphology, then homogeneous OPCs were obtained subsequently. PMID:27597818

  13. Role of Proteolipid Protein in HSV-1 Entry in Oligodendrocytic Cells.

    PubMed

    Bello-Morales, Raquel; Crespillo, Antonio Jesús; Praena, Beatriz; Tabarés, Enrique; Revilla, Yolanda; García, Elena; Fraile-Ramos, Alberto; Baron, Wia; Krummenacher, Claude; López-Guerrero, José Antonio

    2016-01-01

    Herpes simplex virus type 1 (HSV-1) has the ability to enter many different hosts and cell types by several strategies. This highly prevalent alphaherpesvirus can enter target cells using different receptors and different pathways: fusion at a neutral pH, low-pH-dependent and low-pH-independent endocytosis. Several cell receptors for viral entry have been described, but several observations suggest that more receptors for HSV-1 might exist. In this work, we propose a novel role for the proteolipid protein (PLP) in HSV-1 entry into the human oligodendrocytic cell line HOG. Cells transfected with PLP-EGFP showed an increase in susceptibility to HSV-1. Furthermore, the infection of HOG and HOG-PLP transfected cells with the R120vGF virus--unable to replicate in ICP4-defficient cells--showed an increase in viral signal in HOG-PLP, suggesting a PLP involvement in viral entry. In addition, a mouse monoclonal antibody against PLP drastically inhibited HSV-1 entry into HOG cells. PLP and virions colocalized in confocal immunofluorescence images, and in electron microscopy images, which suggest that PLP acts at the site of entry into HOG cells. Taken together these results suggest that PLP may be involved in HSV-1 entry in human oligodendrocytic cells.

  14. RNA-sequencing reveals oligodendrocyte and neuronal transcripts in microglia relevant to central nervous system disease

    PubMed Central

    Walker, Jason; Wylie, Todd; Magrini, Vincent; Apicelli, Anthony J.; Griffith, Malachi; Griffith, Obi L.; Kohsaka, Shinichi; Wu, Gregory F.; Brody, David L.; Mardis, Elaine R.; Gutmann, David H.

    2014-01-01

    Expression profiling of distinct central nervous system (CNS) cell populations has been employed to facilitate disease classification and to provide insights into the molecular basis of brain pathology. One important cell type implicated in a wide variety of CNS disease states is the resident brain macrophage (microglia). In these studies, microglia are often isolated from dissociated brain tissue by flow sorting procedures (FACS) or from postnatal glial cultures by mechanic isolation. Given the highly dynamic and state-dependent functions of these cells, the use of FACS or short-term culture methods may not accurately capture the biology of brain microglia. In the current study, we performed RNA-sequencing using Cx3cr1+/GFP labeled microglia isolated from the brainstem of 6-week old mice to compare the transcriptomes of FACS-sorted versus laser-captured (LCM) microglia. While both isolation techniques resulted in a large number of shared (common) transcripts, we identified transcripts unique to FACS-isolated and LCM-captured microglia. In particular, ~50% of these LCM-isolated microglial transcripts represented genes typically associated with neurons and glia. While these transcripts clearly localized to microglia using complementary methods, they were not translated into protein. Following the induction of murine experimental autoimmune encephalomyelitis (EAE), increased oligodendrocyte and neuronal transcripts were detected in microglia, while only the myelin basic protein oligodendrocyte transcript was increased in microglia after traumatic brain injury (TBI). Collectively, these findings have implications for the design and interpretation of microglia transcriptome-based investigations. PMID:25258010

  15. Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress.

    PubMed

    Mecha, M; Torrao, A S; Mestre, L; Carrillo-Salinas, F J; Mechoulam, R; Guaza, C

    2012-06-28

    Cannabidiol (CBD) is the most abundant cannabinoid in Cannabis sativa that has no psychoactive properties. CBD has been approved to treat inflammation, pain and spasticity associated with multiple sclerosis (MS), of which demyelination and oligodendrocyte loss are hallmarks. Thus, we investigated the protective effects of CBD against the damage to oligodendrocyte progenitor cells (OPCs) mediated by the immune system. Doses of 1 μM CBD protect OPCs from oxidative stress by decreasing the production of reactive oxygen species. CBD also protects OPCs from apoptosis induced by LPS/IFNγ through the decrease of caspase 3 induction via mechanisms that do not involve CB1, CB2, TRPV1 or PPARγ receptors. Tunicamycin-induced OPC death was attenuated by CBD, suggesting a role of endoplasmic reticulum (ER) stress in the mode of action of CBD. This protection against ER stress-induced apoptosis was associated with reduced phosphorylation of eiF2α, one of the initiators of the ER stress pathway. Indeed, CBD diminished the phosphorylation of PKR and eiF2α induced by LPS/IFNγ. The pro-survival effects of CBD in OPCs were accompanied by decreases in the expression of ER apoptotic effectors (CHOP, Bax and caspase 12), and increased expression of the anti-apoptotic Bcl-2. These findings suggest that attenuation of the ER stress pathway is involved in the 'oligoprotective' effects of CBD during inflammation.

  16. Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress

    PubMed Central

    Mecha, M; Torrao, A S; Mestre, L; Carrillo-Salinas, F J; Mechoulam, R; Guaza, C

    2012-01-01

    Cannabidiol (CBD) is the most abundant cannabinoid in Cannabis sativa that has no psychoactive properties. CBD has been approved to treat inflammation, pain and spasticity associated with multiple sclerosis (MS), of which demyelination and oligodendrocyte loss are hallmarks. Thus, we investigated the protective effects of CBD against the damage to oligodendrocyte progenitor cells (OPCs) mediated by the immune system. Doses of 1 μM CBD protect OPCs from oxidative stress by decreasing the production of reactive oxygen species. CBD also protects OPCs from apoptosis induced by LPS/IFNγ through the decrease of caspase 3 induction via mechanisms that do not involve CB1, CB2, TRPV1 or PPARγ receptors. Tunicamycin-induced OPC death was attenuated by CBD, suggesting a role of endoplasmic reticulum (ER) stress in the mode of action of CBD. This protection against ER stress-induced apoptosis was associated with reduced phosphorylation of eiF2α, one of the initiators of the ER stress pathway. Indeed, CBD diminished the phosphorylation of PKR and eiF2α induced by LPS/IFNγ. The pro-survival effects of CBD in OPCs were accompanied by decreases in the expression of ER apoptotic effectors (CHOP, Bax and caspase 12), and increased expression of the anti-apoptotic Bcl-2. These findings suggest that attenuation of the ER stress pathway is involved in the ‘oligoprotective' effects of CBD during inflammation. PMID:22739983

  17. Interneurons and oligodendrocyte progenitors form a structured synaptic network in the developing neocortex.

    PubMed

    Orduz, David; Maldonado, Paloma P; Balia, Maddalena; Vélez-Fort, Mateo; de Sars, Vincent; Yanagawa, Yuchio; Emiliani, Valentina; Angulo, Maria Cecilia

    2015-04-22

    NG2 cells, oligodendrocyte progenitors, receive a major synaptic input from interneurons in the developing neocortex. It is presumed that these precursors integrate cortical networks where they act as sensors of neuronal activity. We show that NG2 cells of the developing somatosensory cortex form a transient and structured synaptic network with interneurons that follows its own rules of connectivity. Fast-spiking interneurons, highly connected to NG2 cells, target proximal subcellular domains containing GABAA receptors with γ2 subunits. Conversely, non-fast-spiking interneurons, poorly connected with these progenitors, target distal sites lacking this subunit. In the network, interneuron-NG2 cell connectivity maps exhibit a local spatial arrangement reflecting innervation only by the nearest interneurons. This microcircuit architecture shows a connectivity peak at PN10, coinciding with a switch to massive oligodendrocyte differentiation. Hence, GABAergic innervation of NG2 cells is temporally and spatially regulated from the subcellular to the network level in coordination with the onset of oligodendrogenesis.

  18. Myelinating satellite oligodendrocytes are integrated in a glial syncytium constraining neuronal high-frequency activity

    PubMed Central

    Battefeld, Arne; Klooster, Jan; Kole, Maarten H. P.

    2016-01-01

    Satellite oligodendrocytes (s-OLs) are closely apposed to the soma of neocortical layer 5 pyramidal neurons but their properties and functional roles remain unresolved. Here we show that s-OLs form compact myelin and action potentials of the host neuron evoke precisely timed Ba2+-sensitive K+ inward rectifying (Kir) currents in the s-OL. Unexpectedly, the glial K+ inward current does not require oligodendrocytic Kir4.1. Action potential-evoked Kir currents are in part mediated by gap–junction coupling with neighbouring OLs and astrocytes that form a syncytium around the pyramidal cell body. Computational modelling predicts that glial Kir constrains the perisomatic [K+]o increase most importantly during high-frequency action potentials. Consistent with these predictions neurons with s-OLs showed a reduced probability for action potential burst firing during [K+]o elevations. These data suggest that s-OLs are integrated into a glial syncytium for the millisecond rapid K+ uptake limiting activity-dependent [K+]o increase in the perisomatic neuron domain. PMID:27161034

  19. Preparation of Rat Oligodendrocyte Progenitor Cultures and Quantification of Oligodendrogenesis Using Dual-infrared Fluorescence Scanning

    PubMed Central

    Calabresi, Peter A.; Baxi, Emily G.

    2016-01-01

    Efficient oligodendrogenesis is the therapeutic goal of a number of areas of research including spinal cord injury, neonatal hypoxia, and demyelinating diseases such as multiple sclerosis and transverse myelitis. Myelination is required to not only facilitate rapid impulse propagation within the central nervous system, but also to provide trophic support to underlying axons. Oligodendrocyte progenitor cells (OPCs) can be studied in vitro to help identify factors that may promote or inhibit oligodendrocyte differentiation. To date, many of the methods available to evaluate this process have either required large numbers of cells, thus limiting the number of conditions that can be investigated at any one time, or labor-intensive methods of quantification. Herein, we describe a protocol for the isolation of large numbers of highly pure OPCs together with a fast and reliable method to determine oligodendrogenesis from multiple conditions simultaneously. OPCs are isolated from P5-P7 neonatal rat cortices and grown in vitro for three days prior to differentiation. Four days after differentiation, oligodendrogenesis is evaluated using a dual-infrared fluorescence-scanning assay to determine expression of the myelin protein. PMID:26967760

  20. Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination.

    PubMed

    Olmos-Serrano, Jose Luis; Kang, Hyo Jung; Tyler, William A; Silbereis, John C; Cheng, Feng; Zhu, Ying; Pletikos, Mihovil; Jankovic-Rapan, Lucija; Cramer, Nathan P; Galdzicki, Zygmunt; Goodliffe, Joseph; Peters, Alan; Sethares, Claire; Delalle, Ivana; Golden, Jeffrey A; Haydar, Tarik F; Sestan, Nenad

    2016-03-16

    Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. To gain insight into the underlying molecular and cellular pathogenesis, we conducted a multi-region transcriptome analysis of DS and euploid control brains spanning from mid-fetal development to adulthood. We found genome-wide alterations in the expression of a large number of genes, many of which exhibited temporal and spatial specificity and were associated with distinct biological processes. In particular, we uncovered co-dysregulation of genes associated with oligodendrocyte differentiation and myelination that were validated via cross-species comparison to Ts65Dn trisomy mice. Furthermore, we show that hypomyelination present in Ts65Dn mice is in part due to cell-autonomous effects of trisomy on oligodendrocyte differentiation and results in slower neocortical action potential transmission. Together, these results identify defects in white matter development and function in DS, and they provide a transcriptional framework for further investigating DS neuropathogenesis.

  1. Interneurons and oligodendrocyte progenitors form a structured synaptic network in the developing neocortex

    PubMed Central

    Orduz, David; Maldonado, Paloma P; Balia, Maddalena; Vélez-Fort, Mateo; de Sars, Vincent; Yanagawa, Yuchio; Emiliani, Valentina; Angulo, Maria Cecilia

    2015-01-01

    NG2 cells, oligodendrocyte progenitors, receive a major synaptic input from interneurons in the developing neocortex. It is presumed that these precursors integrate cortical networks where they act as sensors of neuronal activity. We show that NG2 cells of the developing somatosensory cortex form a transient and structured synaptic network with interneurons that follows its own rules of connectivity. Fast-spiking interneurons, highly connected to NG2 cells, target proximal subcellular domains containing GABAA receptors with γ2 subunits. Conversely, non-fast-spiking interneurons, poorly connected with these progenitors, target distal sites lacking this subunit. In the network, interneuron-NG2 cell connectivity maps exhibit a local spatial arrangement reflecting innervation only by the nearest interneurons. This microcircuit architecture shows a connectivity peak at PN10, coinciding with a switch to massive oligodendrocyte differentiation. Hence, GABAergic innervation of NG2 cells is temporally and spatially regulated from the subcellular to the network level in coordination with the onset of oligodendrogenesis. DOI: http://dx.doi.org/10.7554/eLife.06953.001 PMID:25902404

  2. Laser ablation based fuel ignition

    DOEpatents

    Early, James W.; Lester, Charles S.

    1998-01-01

    There is provided a method of fuel/oxidizer ignition comprising: (a) application of laser light to a material surface which is absorptive to the laser radiation; (b) heating of the material surface with the laser light to produce a high temperature ablation plume which emanates from the heated surface as an intensely hot cloud of vaporized surface material; and (c) contacting the fuel/oxidizer mixture with the hot ablation cloud at or near the surface of the material in order to heat the fuel to a temperature sufficient to initiate fuel ignition.

  3. Laser ablation based fuel ignition

    DOEpatents

    Early, J.W.; Lester, C.S.

    1998-06-23

    There is provided a method of fuel/oxidizer ignition comprising: (a) application of laser light to a material surface which is absorptive to the laser radiation; (b) heating of the material surface with the laser light to produce a high temperature ablation plume which emanates from the heated surface as an intensely hot cloud of vaporized surface material; and (c) contacting the fuel/oxidizer mixture with the hot ablation cloud at or near the surface of the material in order to heat the fuel to a temperature sufficient to initiate fuel ignition. 3 figs.

  4. Transhemangioma Ablation of Hepatocellular Carcinoma

    SciTech Connect

    Pua, Uei

    2012-12-15

    Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC.

  5. Fractional ablative laser skin resurfacing: a review.

    PubMed

    Tajirian, Ani L; Tarijian, Ani L; Goldberg, David J

    2011-12-01

    Ablative laser technology has been in use for many years now. The large side effect profile however has limited its use. Fractional ablative technology is a newer development which combines a lesser side effect profile along with similar efficacy. In this paper we review fractional ablative laser skin resurfacing.

  6. The effect of elastic modulus on ablation catheter contact area

    NASA Astrophysics Data System (ADS)

    Camp, Jon J.; Linte, Cristian A.; Rettmann, Maryam E.; Sun, Deyu; Packer, Douglas L.; Robb, Richard A.; Holmes, David R.

    2015-03-01

    Cardiac ablation consists of navigating a catheter into the heart and delivering RF energy to electrically isolate tissue regions that generate or propagate arrhythmia. Besides the challenges of accurate and precise targeting of the arrhythmic sites within the beating heart, limited information is currently available to the cardiologist regarding intricate electrodetissue contact, which directly impacts the quality of produced lesions. Recent advances in ablation catheter design provide intra-procedural estimates of tissue-catheter contact force, but the most direct indicator of lesion quality for any particular energy level and duration is the tissue-catheter contact area, and that is a function of not only force, but catheter pose and material elasticity as well. In this experiment, we have employed real-time ultrasound (US) imaging to determine the complete interaction between the ablation electrode and tissue to accurately estimate contact, which will help to better understand the effect of catheter pose and position relative to the tissue. By simultaneously recording tracked position, force reading and US image of the ablation catheter, the differing material properties of polyvinyl alcohol cryogel[1] phantoms are shown to produce varying amounts of tissue depression and contact area (implying varying lesion quality) for equivalent force readings. We have shown that the elastic modulus significantly affects the surface-contact area between the catheter and tissue at any level of contact force. Thus we provide evidence that a prescribed level of catheter force may not always provide sufficient contact area to produce an effective ablation lesion in the prescribed ablation time.

  7. Modern Advances in Ablative TPS

    NASA Technical Reports Server (NTRS)

    Venkatapathy, Ethiraj

    2013-01-01

    Topics covered include: Physics of Hypersonic Flow and TPS Considerations. Destinations, Missions and Requirements. State of the Art Thermal Protection Systems Capabilities. Modern Advances in Ablative TPS. Entry Systems Concepts. Flexible TPS for Hypersonic Inflatable Aerodynamic Decelerators. Conformal TPS for Rigid Aeroshell. 3-D Woven TPS for Extreme Entry Environment. Multi-functional Carbon Fabric for Mechanically Deployable.

  8. The Influence of Platelet-Derived Growth Factor and Fibroblast Growth Factor 2 on Oligodendrocyte Development and Remyelination

    DTIC Science & Technology

    2004-01-01

    AE, Bansal R (1993) The oligodendrocyte and its many cellular processes. Trends Cell Biol 3:191-197. Pluchino S, Quattrini A, Brambilla E, Gritti A...Rosenberg D, Cheung SW, Mobley WC, Fisher S, Genain CP (2000) Human nerve growth factor protects common 141 marmosets against autoimmune

  9. The balance between oligodendrocyte and astrocyte production in major white matter tracts is linearly related to serum total thyroxine

    EPA Science Inventory

    Thyroid hormone (TH) may control the ratio of oligodendrocytes to astrocytes in white matter by acting on a common precursor of these two cell types. If so, then TH should produce an equal but opposite effect on the density of these two cells types across all TH levels. To test t...

  10. Production and Use of Lentivirus to Selectively Transduce Primary Oligodendrocyte Precursor Cells for In Vitro Myelination Assays

    PubMed Central

    Peckham, Haley M.; Ferner, Anita H.; Giuffrida, Lauren; Murray, Simon S.; Xiao, Junhua

    2015-01-01

    Myelination is a complex process that involves both neurons and the myelin forming glial cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). We use an in vitro myelination assay, an established model for studying CNS myelination in vitro. To do this, oligodendrocyte precursor cells (OPCs) are added to the purified primary rodent dorsal root ganglion (DRG) neurons to form myelinating co-cultures. In order to specifically interrogate the roles that particular proteins expressed by oligodendrocytes exert upon myelination we have developed protocols that selectively transduce OPCs using the lentivirus overexpressing wild type, constitutively active or dominant negative proteins before being seeded onto the DRG neurons. This allows us to specifically interrogate the roles of these oligodendroglial proteins in regulating myelination. The protocols can also be applied in the study of other cell types, thus providing an approach that allows selective manipulation of proteins expressed by a desired cell type, such as oligodendrocytes for the targeted study of signaling and compensation mechanisms. In conclusion, combining the in vitro myelination assay with lentiviral infected OPCs provides a strategic tool for the analysis of molecular mechanisms involved in myelination. PMID:25650722

  11. Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Anti-Retrovirals in HIV-Associated Neurocognitive Disorders

    PubMed Central

    Jensen, Brigid K.; Monnerie, Hubert; Mannell, Maggie V.; Gannon, Patrick J.; Espinoza, Cagla Akay; Erickson, Michelle A.; Bruce-Keller, Annadora J.; Gelman, Benjamin B.; Briand, Lisa A.; Pierce, R. Christopher; Jordan-Sciutto, Kelly L.; Grinspan, Judith B.

    2015-01-01

    Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals suffer from HIV-Associated Neurocognitive Disorders (HAND). Studies of antiretroviral treated patients have revealed persistent white matter pathologies including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction as the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors Ritonavir or Lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed following drug removal. Conversely, nucleoside reverse transcriptase inhibitor Zidovudine had no effect. Furthermore, in vivo Ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity, and have implications for myelination in juvenile HIV patients, and myelin maintenance in adults on lifelong therapy. PMID:26469251

  12. Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex.

    PubMed

    García-Díaz, Beatriz; Riquelme, Raquel; Varela-Nieto, Isabel; Jiménez, Antonio Jesús; de Diego, Isabel; Gómez-Conde, Ana Isabel; Matas-Rico, Elisa; Aguirre, José Ángel; Chun, Jerold; Pedraza, Carmen; Santín, Luis Javier; Fernández, Oscar; Rodríguez de Fonseca, Fernando; Estivill-Torrús, Guillermo

    2015-11-01

    Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA(1-6)). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases.

  13. Expression of GPR17, a regulator of oligodendrocyte differentiation and maturation, in Nasu-Hakola disease brains

    PubMed Central

    Satoh, Jun-ichi; Kino, Yoshihiro; Yanaizu, Motoaki; Tosaki, Youhei; Sakai, Kenji; Ishida, Tusyoshi; Saito, Yuko

    2017-01-01

    Summary The G protein-coupled receptor 17 (GPR17), a Gi-coupled GPCR, acts as an intrinsic timer of oligodendrocyte differentiation and myelination. The expression of GPR17 is upregulated during differentiation of oligodendrocyte precursor cells (OPCs) into premyelinating oligodendrocytes (preoligodendrocytes), whereas it is markedly downregulated during terminal maturation of myelinating oligodendrocytes. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2. Pathologically, the brains of NHD patients exhibit extensive demyelination designated leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and activation of microglia predominantly in the white matter of frontal and temporal lobes. Although GPR17 is a key regulator of oligodendrogenesis, a pathological role of GPR17 in NHD brains with relevance to development of leukoencephalopathy remains unknown. We studied the expression of GPR17 in five NHD brains and eight control brains by immunohistochemistry. We identified GPR17-immunoreactive preoligodendrocytes with a multipolar ramified morphology distributed in the white matter and the grey matter of all cases examined. However, we did not find statistically significant differences in the number of GPR17-expressing cells between NHD and control brains both in the white matter and the grey matter due to great variability from case to case. These observations do not support the view that GPR17-positive preoligodendrocytes play a central role in the development of leukoencephalopathy in NHD brains. PMID:28357182

  14. Esophageal papilloma: Flexible endoscopic ablation by radiofrequency

    PubMed Central

    del Genio, Gianmattia; del Genio, Federica; Schettino, Pietro; Limongelli, Paolo; Tolone, Salvatore; Brusciano, Luigi; Avellino, Manuela; Vitiello, Chiara; Docimo, Giovanni; Pezzullo, Angelo; Docimo, Ludovico

    2015-01-01

    Squamous papilloma of the esophagus is a rare benign lesion of the esophagus. Radiofrequency ablation is an established endoscopic technique for the eradication of Barrett esophagus. No cases of endoscopic ablation of esophageal papilloma by radiofrequency ablation (RFA) have been reported. We report a case of esophageal papilloma successfully treated with a single session of radiofrequency ablation. Endoscopic ablation of the lesion was achieved by radiofrequency using a new catheter inserted through the working channel of endoscope. The esophageal ablated tissue was removed by a specifically designed cup. Complete ablation was confirmed at 3 mo by endoscopy with biopsies. This case supports feasibility and safety of as a new potential indication for BarrxTM RFA in patients with esophageal papilloma. PMID:25789102

  15. Percutaneous ablation of benign bone tumors.

    PubMed

    Welch, Brian T; Welch, Timothy J

    2011-09-01

    Percutaneous image-guided ablation has become a standard of practice and one of the primary modalities for treatment of benign bone tumors. Ablation is most commonly used to treat osteoid osteomas but may also be used in the treatment of chondroblastomas, osteoblastomas, and giant cell tumors. Percutaneous image-guided ablation of benign bone tumors carries a high success rate (>90% in case series) and results in decreased morbidity, mortality, and expense compared with traditional surgical methods. The ablation technique most often applied to benign bone lesions is radiofrequency ablation. Because the ablation technique has been extensively applied to osteoid osteomas and because of the uncommon nature of other benign bone tumors, we will primarily focus this discussion on the percutaneous ablation of osteoid osteomas.

  16. An in vitro study on the involvement of LINGO-1 and Rho GTPases in Nogo-A regulated differentiation of oligodendrocyte precursor cells.

    PubMed

    Zhao, Xiang-Hui; Jin, Wei-Lin; Ju, Gong

    2007-10-01

    Nogo-A has been considered as one of the most important myelin-associated axonal regeneration inhibitors in the central nervous system. Recent studies have demonstrated various additional physiological roles of Nogo family members. To understand the possible effect of Nogo-A on the differentiation of oligodendrocytes, antibodies against distinct extracellular domains of Nogo-A were applied in cell cultures. Oligodendrocyte precursor cells from P2 rat cortex were grown in the presence of monoclonal antibody against the N-terminal inhibitory domain of Nogo-A or the C-terminal 66 amino acid loop of Nogo-A for 3 days, and the antibody treatment resulted in stunted process extension and inhibited differentiation of oligodendrocytes. Concomitant with morphology changes, Rho GTPases activity was greatly increased upon the antibody treatment and the expression level of LINGO-1, which was recently shown to be a negative regulator for the oligodendrocyte maturation, was upregulated in the process of antibody treatment. These results indicate that endogenous Nogo-A expressed in oligodendrocyte may act though Rho GTPase and LINGO-1 to influence the morphological differentiation of oligodendrocytes and will help us to understand the physiology role of Nogo-A in oligodendrocyte biology.

  17. Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia

    PubMed Central

    Georgieva, Lyudmila; Moskvina, Valentina; Peirce, Tim; Norton, Nadine; Bray, Nicholas J.; Jones, Lesley; Holmans, Peter; MacGregor, Stuart; Zammit, Stanley; Wilkinson, Jennifer; Williams, Hywel; Nikolov, Ivan; Williams, Nigel; Ivanov, Dobril; Davis, Kenneth L.; Haroutunian, Vahram; Buxbaum, Joseph D.; Craddock, Nick; Kirov, George; Owen, Michael J.; O’Donovan, Michael C.

    2006-01-01

    Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = ≈1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10−7) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other’s expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function. PMID:16891421

  18. TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination.

    PubMed

    Wong, Agnes W; Giuffrida, Lauren; Wood, Rhiannon; Peckham, Haley; Gonsalvez, David; Murray, Simon S; Hughes, Richard A; Xiao, Junhua

    2014-11-01

    Brain-derived neurotrophic factor (BDNF) plays critical roles in the development and maintenance of the central (CNS) and peripheral nervous systems (PNS). BDNF exerts its biological effects via tropomyosin-related kinase B (TrkB) and the p75 neurotrophin receptor (p75NTR). We have recently identified that BDNF promotes CNS myelination via oligodendroglial TrkB receptors. In order to selectively target TrkB to promote CNS myelination, we have used a putative TrkB agonist, a small multicyclic peptide (tricyclic dimeric peptide 6, TDP6) previously described by us that structurally mimics a region of BDNF that binds TrkB. We confirmed that TDP6 acts as a TrkB agonist as it provoked autophosphorylation of TrkB and its downstream signalling effector extracellular related-kinase 1 and 2 (Erk1/2) in primary oligodendrocytes. Using an in vitro myelination assay, we show that TDP6 significantly promotes myelination by oligodendrocytes in vitro, as evidenced by enhanced myelin protein expression and an increased number of myelinated axonal segments. In contrast, a second, structurally distinct BDNF mimetic (cyclo-dPAKKR) that targets p75NTR had no effect upon oligodendrocyte myelination in vitro, despite the fact that cyclo-dPAKKR is a very effective promoter of peripheral (Schwann cell) myelination. The selectivity of TDP6 was further verified by using TrkB-deficient oligodendrocytes, in which TDP6 failed to promote myelination, indicating that the pro-myelinating effect of TDP6 is oligodendroglial TrkB-dependent. Together, our results demonstrate that TDP6 is a novel BDNF mimetic that promotes oligodendrocyte myelination in vitro via targeting TrkB.

  19. The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination.

    PubMed

    Vestal-Laborde, Allison A; Eschenroeder, Andrew C; Bigbee, John W; Robinson, Susan E; Sato-Bigbee, Carmen

    2014-01-01

    Oligodendrocytes express opioid receptors throughout development, but the role of the opioid system in myelination remains poorly understood. This is a significant problem as opioid use and abuse continue to increase in two particular populations: pregnant addicts (in whom drug effects could target early myelination in the fetus and newborn) and adolescents and young adults (in whom late myelination of 'higher-order' regions takes place). Maintenance treatments for opioid addicts include the long-lasting opioids methadone and buprenorphine. Similar to our previous findings on the effects of buprenorphine, we have now found that early myelination in the developing rat brain is also altered by perinatal exposure to therapeutic doses of methadone. Pups exposed to this drug exhibited elevated brain levels of the 4 major splicing variants of myelin basic protein, myelin proteolipid protein, and myelin-oligodendrocyte glycoprotein. Consistent with the enrichment and function of these proteins in mature myelin, analysis of the corpus callosum in these young animals also indicated an elevated number of axons with already highly compacted myelin sheaths. Moreover, studies in cultured cells showed that methadone exerts direct effects at specific stages of the oligodendrocyte lineage, stimulating the proliferation of progenitor cells while on the other hand accelerating the maturation of the more differentiated but still immature preoligodendrocytes. While the long-term effects of these observations remain unknown, accelerated or increased oligodendrocyte maturation and myelination could both disrupt the complex sequence of synchronized events leading to normal connectivity in the developing brain. Together with our previous observations on the effects of buprenorphine, the present findings further underscore a crucial function of the endogenous opioid system in the control of oligodendrocyte development and the timing of myelination. Interference with these regulatory

  20. Survival after Radiofrequency Ablation in 122 Patients with Inoperable Colorectal Lung Metastases

    SciTech Connect

    Gillams, Alice; Khan, Zahid; Osborn, Peter; Lees, William

    2013-06-15

    Purpose. To analyze the factors associated with favorable survival in patients with inoperable colorectal lung metastases treated with percutaneous image-guided radiofrequency ablation. Methods. Between 2002 and 2011, a total of 398 metastases were ablated in 122 patients (87 male, median age 68 years, range 29-90 years) at 256 procedures. Percutaneous CT-guided cool-tip radiofrequency ablation was performed under sedation/general anesthesia. Maximum tumor size, number of tumors ablated, number of procedures, concurrent/prior liver ablation, previous liver or lung resection, systemic chemotherapy, disease-free interval from primary resection to lung metastasis, and survival from first ablation were recorded prospectively. Kaplan-Meier analysis was performed, and factors were compared by log rank test. Results. The initial number of metastases ablated was 2.3 (range 1-8); the total number was 3.3 (range 1-15). The maximum tumor diameter was 1.7 (range 0.5-4) cm, and the number of procedures was 2 (range 1-10). The major complication rate was 3.9 %. Overall median and 3-year survival rate were 41 months and 57 %. Survival was better in patients with smaller tumors-a median of 51 months, with 3-year survival of 64 % for tumors 2 cm or smaller versus 31 months and 44 % for tumors 2.1-4 cm (p = 0.08). The number of metastases ablated and whether the tumors were unilateral or bilateral did not affect survival. The presence of treated liver metastases, systemic chemotherapy, or prior lung resection did not affect survival. Conclusion. Three-year survival of 57 % in patients with inoperable colorectal lung metastases is better than would be expected with chemotherapy alone. Patients with inoperable but small-volume colorectal lung metastases should be referred for ablation.

  1. Healing responses following cryothermic and hyperthermic tissue ablation

    NASA Astrophysics Data System (ADS)

    Godwin, Braden L.; Coad, James E.

    2009-02-01

    Minimally invasive, thermally ablative, interventional technologies have been changing the practice of medicine since before the turn of the 20th century. More recently, cryothermic and hyperthermic therapies have expanded in terms of their spectrum of thermal generators, modes for controlling and monitoring the treatment zone and both benign and malignant medical applications. The final tissue, and hence clinical outcome, of a thermal ablation is determined by the summation of direct primary (thermal) and secondary (apoptosis, ischemia, free radical, inflammation, wound healing, etc.) injury followed by possible cellular regeneration and scar formation. The initial thermal lesion can be broadly divided into two major zones of cellular death: 1) the complete ablation zone closer to the thermal source and 2) the peripheral transition zone with a decreasing gradient of cell death. While not applicable to cryotherapy, hyperthermic complete ablation zones are subdivided into two zones: 1) thermal or heat fixation and 2) coagulative necrosis. It is important to clearly differentiate these tissue zones because of their substantially different healing responses. Therefore, the development of clinically successful thermal therapies requires an understanding of tissue healing responses. The healing responses can be affected by a number of additional factors such as the tissue's anatomy, organ specific healing differences, blood supply, protein vs. lipid content, and other factors. Thus, effective biomedical instrument development requires both an understanding of thermal cell injury/death and the body's subsequent healing responses. This paper provides a general overview of the healing pathways that follow thermal tissue treatment.

  2. Central Nervous System Regenerative Failure: Role of Oligodendrocytes, Astrocytes, and Microglia

    PubMed Central

    Silver, Jerry; Schwab, Martin E.; Popovich, Phillip G.

    2015-01-01

    Animal studies are now showing the exciting potential to achieve significant functional recovery following central nervous system (CNS) injury by manipulating both the inefficient intracellular growth machinery in neurons, as well as the extracellular barriers, which further limit their regenerative potential. In this review, we have focused on the three major glial cell types: oligodendrocytes, astrocytes, and microglia/macrophages, in addition to some of their precursors, which form major extrinsic barriers to regrowth in the injured CNS. Although axotomized neurons in the CNS have, at best, a limited capacity to regenerate or sprout, there is accumulating evidence that even in the adult and, especially after boosting their growth motor, neurons possess the capacity for considerable circuit reorganization and even lengthy regeneration when these glial obstacles to neuronal regrowth are modified, eliminated, or overcome. PMID:25475091

  3. Migration of oligodendrocyte progenitor cells is controlled by transforming growth factor β family proteins during corticogenesis.

    PubMed

    Choe, Youngshik; Huynh, Trung; Pleasure, Samuel J

    2014-11-05

    During embryonic development oligodendrocyte precursor cells (OPCs) are generated first in the ventral forebrain and migrate dorsally to occupy the cortex. The molecular cues that guide this migratory route are currently completely unknown. Here, we show that bone morphogenetic protein-4 (Bmp4), Bmp7, and Tgfβ1 produced by the meninges and pericytes repelled ventral OPCs into the cortex at mouse embryonic stages. Ectopic activation of Bmp or Tgfβ1 signaling before the entrance of OPCs into the cortex hindered OPC migration into the cortical areas. OPCs without Smad4 signaling molecules also failed to migrate into the cortex efficiently and formed heterotopia in ventral areas. OPC migration into the cortex was also dramatically reduced by conditional inhibition of Tgfβ1 or Bmp expression from mesenchymal cells. The data suggest that mesenchymal Tgfβ family proteins promote migration of ventral OPCs into the cortex during corticogenesis.

  4. Structure of the human myelin/oligodendrocyte glycoprotein gene and multiple alternative spliced isoforms

    SciTech Connect

    Pham-Dinh, D.; Gaspera, D.B.; Dautigny, A.

    1995-09-20

    Myelin/oligodendrocyte glycoprotein (MOG), a special component of the central nervous system localization on the outermost lamellae of mature myelin, is a member of the immunoglobulin superfamily. We report here the organization of the human MOG gene, which spans approximately 17 kb, and the characterization of six MOG mRNA splicing variants. The intron/exon structure of the human MOG gene confirmed the splicing pattern, supporting the hypothesis that mRNA isoforms could arise by alternative splicing of a single gene. In addition to the eight exons coding for the major MOG isoform, the human MOG gene also contains 3` region, a previously unknown alternatively spliced coding exon, VIA. Alternative utilization of two acceptor splicing sites for exon VIII could produce two different C-termini. The nucleotide sequences presented here may be a useful tool to study further possible involvement if the MOG gene in hereditary neurological disorders. 23 refs., 5 figs.

  5. Ionic transporter activity in astrocytes, microglia, and oligodendrocytes during brain ischemia

    PubMed Central

    Annunziato, Lucio; Boscia, Francesca; Pignataro, Giuseppe

    2013-01-01

    Glial cells constitute a large percentage of cells in the nervous system. During recent years, a large number of studies have critically attributed to glia a new role which no longer reflects the long-held view that glia constitute solely a silent and passive supportive scaffolding for brain cells. Indeed, it has been hypothesized that glia, partnering neurons, have a much more actively participating role in brain function. Alteration of intraglial ionic homeostasis in response to ischemic injury has a crucial role in inducing and maintaining glial responses in the ischemic brain. Therefore, glial transporters as potential candidates in stroke intervention are becoming promising targets to enhance an effective and additional therapy for brain ischemia. In this review, we will describe in detail the role played by ionic transporters in influencing astrocyte, microglia, and oligodendrocyte activity and the implications that these transporters have in the progression of ischemic lesion. PMID:23549380

  6. Electric Signals Regulate the Directional Migration of Oligodendrocyte Progenitor Cells (OPCs) via β1 Integrin.

    PubMed

    Zhu, Bangfu; Nicholls, Matthew; Gu, Yu; Zhang, Gaofeng; Zhao, Chao; Franklin, Robin J M; Song, Bing

    2016-11-22

    The guided migration of neural cells is essential for repair in the central nervous system (CNS). Oligodendrocyte progenitor cells (OPCs) will normally migrate towards an injury site to re-sheath demyelinated axons; however the mechanisms underlying this process are not well understood. Endogenous electric fields (EFs) are known to influence cell migration in vivo, and have been utilised in this study to direct the migration of OPCs isolated from neonatal Sprague-Dawley rats. The OPCs were exposed to physiological levels of electrical stimulation, and displayed a marked electrotactic response that was dependent on β1 integrin, one of the key subunits of integrin receptors. We also observed that F-actin, an important component of the cytoskeleton, was re-distributed towards the leading edge of the migrating cells, and that this asymmetric rearrangement was associated with β1 integrin function.

  7. Electric Signals Regulate the Directional Migration of Oligodendrocyte Progenitor Cells (OPCs) via β1 Integrin

    PubMed Central

    Zhu, Bangfu; Nicholls, Matthew; Gu, Yu; Zhang, Gaofeng; Zhao, Chao; Franklin, Robin J. M.; Song, Bing

    2016-01-01

    The guided migration of neural cells is essential for repair in the central nervous system (CNS). Oligodendrocyte progenitor cells (OPCs) will normally migrate towards an injury site to re-sheath demyelinated axons; however the mechanisms underlying this process are not well understood. Endogenous electric fields (EFs) are known to influence cell migration in vivo, and have been utilised in this study to direct the migration of OPCs isolated from neonatal Sprague-Dawley rats. The OPCs were exposed to physiological levels of electrical stimulation, and displayed a marked electrotactic response that was dependent on β1 integrin, one of the key subunits of integrin receptors. We also observed that F-actin, an important component of the cytoskeleton, was re-distributed towards the leading edge of the migrating cells, and that this asymmetric rearrangement was associated with β1 integrin function. PMID:27879672

  8. Beta4 tubulin identifies a primitive cell source for oligodendrocytes in the mammalian brain.

    PubMed

    Wu, Chuanshen; Chang, Ansi; Smith, Maria C; Won, Roy; Yin, Xinghua; Staugaitis, Susan M; Agamanolis, Dimitri; Kidd, Grahame J; Miller, Robert H; Trapp, Bruce D

    2009-06-17

    We have identified a novel population of cells in the subventricular zone (SVZ) of the mammalian brain that expresses beta4 tubulin (betaT4) and has properties of primitive neuroectodermal cells. betaT4 cells are scattered throughout the SVZ of the lateral ventricles in adult human brain and are significantly increased in the SVZs bordering demyelinated white matter in multiple sclerosis brains. In human fetal brain, betaT4 cell densities peak during the latter stages of gliogenesis, which occurs in the SVZ of the lateral ventricles. betaT4 cells represent <2% of the cells present in neurospheres generated from postnatal rat brain but >95% of cells in neurospheres treated with the anti-mitotic agent Ara C. betaT4 cells produce oligodendrocytes, neurons, and astrocytes in vitro. We compared the myelinating potential of betaT4-positive cells with A2B5-positive oligodendrocyte progenitor cells after transplantation (25,000 cells) into postnatal day 3 (P3) myelin-deficient rat brains. At P20, the progeny of betaT4 cells myelinated up to 4 mm of the external capsule, which significantly exceeded that of transplanted A2B5-positive progenitor cells. Such extensive and rapid mature CNS cell generation by a relatively small number of transplanted cells provides in vivo support for the therapeutic potential of betaT4 cells. We propose that betaT4 cells are an endogenous cell source that can be recruited to promote neural repair in the adult telencephalon.

  9. Differential effects of antipsychotics on the development of rat oligodendrocyte precursor cells exposed to cuprizone.

    PubMed

    Xu, Haiyun; Yang, Hong-Ju; Li, Xin-Min

    2014-03-01

    Cuprizone (CPZ) is a copper-chelating agent and has been shown to induce white matter damage in mice and rats. The compromised white matter and oligodendrocytes (OLs) respond to some antipsychotics in vivo. However, little is known about the effects of antipsychotics on cultured OLs in the presence of CPZ. The aim of this study was to examine effects of some antipsychotics on developing OLs in the presence of CPZ. Oligodendrocyte progenitor cells (OPCs) were prepared from rat embryos; OLs at different developing stages were labeled with specific antibodies; levels of CNP and MBP proteins in mature OLs were assessed by Western-blot analysis; malondialdehyde (MDA) levels and activity of catalase were evaluated as well for an assessment of oxidative stress and antioxidative status. In immunofluorescent staining, CPZ was shown to inhibit the differentiation of cultured OPCs into O4-positive cells, reduce the maturation of O4-positive cells into CNP- and MBP-positive cells, and decrease levels of CNP and MBP in mature OLs. These inhibitory effects of CPZ were ameliorated by clozapine and quetiapine (QUE), but not by haloperidol and olanzapine. Further experiments were performed to explore the mechanism of the protective effects of QUE. QUE attenuated the decreases in CNP and MBP in CPZ-treated OLs, and blocked the CPZ-induced increase in MDA and decrease in catalase activity in cultured OLs. These results are relevant to the pathophysiology and treatment of schizophrenia considering the aberrant white matter development and evidence suggesting the derangement of the oxidant and antioxidant defense system in some of the patients with schizophrenia.

  10. Characterization of tracked radiofrequency ablation in phantom

    SciTech Connect

    Chen, Chun-Cheng R.; Miga, Michael I.; Galloway, Robert L.

    2007-10-15

    In radiofrequency ablation (RFA), successful therapy requires accurate, image-guided placement of the ablation device in a location selected by a predictive treatment plan. Current planning methods rely on geometric models of ablations that are not sensitive to underlying physical processes in RFA. Implementing plans based on computational models of RFA with image-guided techniques, however, has not been well characterized. To study the use of computational models of RFA in planning needle placement, this work compared ablations performed with an optically tracked RFA device with corresponding models of the ablations. The calibration of the tracked device allowed the positions of distal features of the device, particularly the tips of the needle electrodes, to be determined to within 1.4{+-}0.6 mm of uncertainty. Ablations were then performed using the tracked device in a phantom system based on an agarose-albumin mixture. Images of the sliced phantom obtained from the ablation experiments were then compared with the predictions of a bioheat transfer model of RFA, which used the positional data of the tracked device obtained during ablation. The model was demonstrated to predict 90% of imaged pixels classified as being ablated. The discrepancies between model predictions and observations were analyzed and attributed to needle tracking inaccuracy as well as to uncertainties in model parameters. The results suggest the feasibility of using finite element modeling to plan ablations with predictable outcomes when implemented using tracked RFA.

  11. Comparative study on laser tissue ablation between PV and HPS lasers

    NASA Astrophysics Data System (ADS)

    Kang, Hyun Wook; Jebens, David; Mitchell, Gerald; Koullick, Ed

    2008-02-01

    Laser therapy for obstructive benign prostatic hyperplasia (BPH) has gained broad adoption due to effective tissue removal, immediate hemostasis, and minor complications. The aim of this study is to quantitatively compare ablation characteristics of PV (Photoselective Vaporization) and the newly introduced HPS (High Performance System) 532 nm lasers. Bovine prostatic tissues were ablated in vitro, using a custom-made scanning system. Laser-induced volume produced by two lasers was quantified as a function of applied power, fiber working distance (WD), and treatment speed. Given the same power of 80 W and speed of 4 mm/s, HPS created up to 50 % higher tissue ablation volume than PV did. PV induced a rapid decrease of ablation volume when WD increased from 0.5 mm to 3 mm while HPS yielded almost constant tissue removal up to 3 mm for both 80 W and 120 W. As the treatment speed increased, both lasers reached saturation in tissue ablation volume. Lastly, both PV and HPS lasers exhibited approximately 1 mm thick heat affected zone (HAZ) in this study although HPS created twice deeper ablation channels with a depth of up to 4 mm. Due to a smaller beam size and a higher output power, HPS maximized tissue ablation rate with minimal thermal effects to the adjacent tissue. Furthermore, more collimated beam characteristics provides more spatial flexibility and may even help to decrease the rate of fiber degradation associated with thermal damage from debris reattachment to the tip.

  12. Artificial meteor ablation studies: Olivine

    NASA Technical Reports Server (NTRS)

    Blanchard, M. B.; Cunningham, G. G.

    1973-01-01

    Artificial meteor ablation was performed on a Mg-rich olivine sample using an arc-heated plasma of ionized air. Experimental conditions simulated a meteor traveling about 12 km/sec at an altitude of 70 km. The mineral content of the original olivine sample was 98% olivine (including traces of olivine alteration products) and 2% chromite. Forsterite content of the original olivine was Fo-89. After ablation, the forsterite content had increased to Fo-94 in the recrystallized olivine. In addition, lamella-like intergrowths of magnetite were prevalent constituents. Wherever magnetite occurred, there was an increase in Mg and a corresponding decrease in Fe for the recrystallized olivine. The Allende fusion crust consisted of a recrystallized olivine, which was more Mg-rich and Fe-deficient than the original meteorite's olivine, and abundant magnetite grains. Although troilite and pentlandite were the common opaque mineral constituents in this meteorite, magnetite was the principal opaque mineral found in the fusion crust.

  13. Laser Ablation for Medical Applications

    NASA Astrophysics Data System (ADS)

    Hayashi, Ken-Ichi

    Medical applications of laser are measurement, laser surgery, in-situ monitoring, and processing of medical devices. In this paper, author briefly reviews the trends of medical applications, describes some new applications, and then discuss about the future trends and problems of medical applications. At present, the domestic market of laser equipment for medical applications is nearly 1/10 of that for industrial applications, which has registered significant growth continuously. Laser surgery as a minimum invasive surgery under arthroscope is expected to decrease the pain of patients. Precise processing such as cutting and welding is suitable for manufacturing medical devices. Pulsed laser deposition has been successfully applied to the thin film coating. The corneal refractive surgery by ArF excimer laser has been widely accepted for its highly safe operation. Laser ablation for retinal implant in the visual prosthesis is one of the promising applications of laser ablation in medicine. New applications with femtosecond laser are expected in the near future.

  14. Percutaneous ablation of pancreatic cancer

    PubMed Central

    D’Onofrio, Mirko; Ciaravino, Valentina; De Robertis, Riccardo; Barbi, Emilio; Salvia, Roberto; Girelli, Roberto; Paiella, Salvatore; Gasparini, Camilla; Cardobi, Nicolò; Bassi, Claudio

    2016-01-01

    Pancreatic ductal adenocarcinoma is a highly aggressive tumor with an overall 5-year survival rate of less than 5%. Prognosis and treatment depend on whether the tumor is resectable or not, which mostly depends on how quickly the diagnosis is made. Chemotherapy and radiotherapy can be both used in cases of non-resectable pancreatic cancer. In cases of pancreatic neoplasm that is locally advanced, non-resectable, but non-metastatic, it is possible to apply percutaneous treatments that are able to induce tumor cytoreduction. The aim of this article will be to describe the multiple currently available treatment techniques (radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation), their results, and their possible complications, with the aid of a literature review. PMID:27956791

  15. Laser Ablation Molecular Isotopic Spectrometry

    NASA Astrophysics Data System (ADS)

    Russo, Richard E.; Bol'shakov, Alexander A.; Mao, Xianglei; McKay, Christopher P.; Perry, Dale L.; Sorkhabi, Osman

    2011-02-01

    A new method of performing optical isotopic analysis of condensed samples in ambient air and at ambient pressure has been developed: Laser Ablation Molecular Isotopic Spectrometry (LAMIS). The technique uses radiative transitions from molecular species either directly vaporized from a sample or formed by associative mechanisms of atoms or ions in a laser ablation plume. This method is an advanced modification of a known atomic emission technique called laser-induced breakdown spectroscopy (LIBS). The new method — LAMIS — can determine not only chemical composition but also isotopic ratios of elements in the sample. Isotopic measurements are enabled by significantly larger isotopic shifts found in molecular spectra relative to atomic spectra. Analysis can be performed from a distance and in real time. No sample preparation or pre-treatment is required. Detection of the isotopes of hydrogen, boron, carbon, and oxygen are discussed to illustrate the technique.

  16. Percutaneous ablation of pancreatic cancer.

    PubMed

    D'Onofrio, Mirko; Ciaravino, Valentina; De Robertis, Riccardo; Barbi, Emilio; Salvia, Roberto; Girelli, Roberto; Paiella, Salvatore; Gasparini, Camilla; Cardobi, Nicolò; Bassi, Claudio

    2016-11-28

    Pancreatic ductal adenocarcinoma is a highly aggressive tumor with an overall 5-year survival rate of less than 5%. Prognosis and treatment depend on whether the tumor is resectable or not, which mostly depends on how quickly the diagnosis is made. Chemotherapy and radiotherapy can be both used in cases of non-resectable pancreatic cancer. In cases of pancreatic neoplasm that is locally advanced, non-resectable, but non-metastatic, it is possible to apply percutaneous treatments that are able to induce tumor cytoreduction. The aim of this article will be to describe the multiple currently available treatment techniques (radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation), their results, and their possible complications, with the aid of a literature review.

  17. Microwave Ablation Compared to Radiofrequency Ablation for Hepatic Lesions: A Meta-Analysis.

    PubMed

    Huo, Ya Ruth; Eslick, Guy D

    2015-08-01

    To evaluate the efficacy and safety of microwave (MW) ablation compared with radiofrequency (RF) ablation for hepatic lesions by using meta-analytic techniques. Overall, 16 studies involving 2,062 patients were included. MW ablation was found to have significantly better 6-year overall survival than RF ablation (odds ratio, 1.64, 95% confidence interval, 1.15-2.35), but this was based on a few articles (n = 3 of 16). MW ablation and RF ablation had similar 1-5-year overall survival, disease-free survival, local recurrence rate, and adverse events. Based on similar safety and efficacy outcomes, either MW ablation or RF ablation may be used for effective local hepatic therapy.

  18. Tumor Thermal Ablation Enhancement by Micromaterials.

    PubMed

    Zhao, Fan; Su, Hongying; Han, Xiangjun; Bao, Han; Qi, Ji

    2016-01-07

    Thermal ablation is a minimally invasive therapeutic technique that has shown remarkable potential in treating un resectable tumors. However, clinical applications have stalled, due to safety ambiguities, slow heat induction, lengthy ablation times, and post-therapeutic monitoring issues. To further improve treatment efficacy, an assortment of micro materials (eg, nano particulates of gold, silica, or iron oxide and single-walled carbon nanotubes) are under study as thermal ablative adjuncts.In recent years, the micro material domain has become especially interesting.In vivo and in vitro animal studies have validated the use of microspheres as embolic agents in liver tumors, in advance of radiofrequency ablation. Microcapsules and micro bubbles serving as ultrasound contrast and ablation sensibilizers are strong prospects for clinical applications. This review was conducted to explore benefits of the three aforementioned micro scale technologies, in conjunction with tumor thermal ablation.

  19. Percutaneous thermal ablation of primary lung cancer.

    PubMed

    de Baere, T; Tselikas, L; Catena, V; Buy, X; Deschamps, F; Palussière, J

    2016-10-01

    Percutaneous ablation of small-size non-small-cell lung cancer (NSCLC) has demonstrated feasibility and safety in nonsurgical candidates. Radiofrequency ablation (RFA), the most commonly used technique, has an 80-90% reported rate of complete ablation, with the best results obtained in tumors less than 2-3cm in diameter. The highest one-, three-, and five-year overall survival rates reported in NSCLC following RFA are 97.7%, 72.9%, and 55.7% respectively. Tumor size, tumor stage, and underlying comorbidities are the main predictors of survival. Other ablation techniques such as microwave or cryoablation may help overcome the limitations of RFA in the future, particularly for large tumors or those close to large vessels. Stereotactic ablative radiotherapy (SABR) has its own complications and carries the risk of fiducial placement requiring multiple lung punctures. SABR has also demonstrated significant efficacy in treating small-size lung tumors and should be compared to percutaneous ablation.

  20. Image-guided ablation for hepatocellular carcinoma.

    PubMed

    Lencioni, Riccardo; Crocetti, Laura

    2013-01-01

    Image-guided ablation is accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma (HCC) when surgical options-including resection and transplantation-are precluded. The term image-guided tumor ablation is defined as the direct application of chemical substances or sources of energy to a focal tumor in an attempt to achieve eradication or substantial tumor destruction. Over the past 25 years, several methods for local tumor destruction have been developed and clinically tested. Radiofrequency ablation (RFA) has shown superior anticancer effect and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials, and is currently established as the standard ablative modality. Nevertheless, novel thermal and nonthermal techniques for tumor ablation-including microwave ablation and irreversible electroporation-seem to have potential to improve the efficacy of RFA and are currently undergoing clinical investigation.

  1. 17β-Estradiol inhibits apoptotic cell death of oligodendrocytes by inhibiting RhoA-JNK3 activation after spinal cord injury.

    PubMed

    Lee, Jee Y; Choi, Soo Y; Oh, Tae H; Yune, Tae Y

    2012-08-01

    A delayed oligodendrocyte cell death after spinal cord injury (SCI) contributes to chronic demyelination of spared axons, leading to a permanent neurological deficit. Therefore, therapeutic approaches to prevent oligodendrocyte cell death after SCI should be considered. Estrogens are well known to have a broad neuroprotective effect, but the protective effect of estrogens on oligodendrocytes after injury is largely unknown. Here, we demonstrated that 17β-estradiol attenuates apoptosis of oligodendrocytes by inhibiting RhoA and c-Jun-N-terminal kinase activation after SCI. Estrogen receptor (ER)-α and -β were expressed in oligodendrocytes of the spinal cord, and 17β-estradiol treatment significantly inhibited oligodendrocyte cell death at 7 d after injury as compared with vehicle (cyclodextrin) control. 17β-Estradiol also attenuated caspase-3 and -9 activation at 7 d and reduced the loss of axons from progressive degeneration. In addition, 17β-estradiol inhibited RhoA and JNK3 activation, which were activated and peaked at 3 and/or 5 d after injury. Furthermore, administration of Rho inhibitor, PEP-1-C3 exoenzyme, inhibited RhoA and JNK3 activation, and decreased phosphorylated c-Jun level at 5 d after injury. Additionally, the attenuation of RhoA and JNK3 activation as well as oligodendrocyte cell death by 17β-estradiol was reversed by ER antagonist, ICI182780. Our results thus indicate that 17β-estradiol treatment improves functional recovery after SCI in part by reducing oligodendrocyte cell death via inhibition of RhoA and JNK3 activation, which were ER dependent. Furthermore, improvement of hindlimb motor function by posttreatment of 17β-estradiol suggests its potential as a therapeutic agent for SCI patients.

  2. Global Endometrial Ablation in the Presence of Essure® Microinserts

    PubMed Central

    Aldape, Diana; Chudnoff, Scott G; Levie, Mark D

    2013-01-01

    Abnormal uterine bleeding (AUB) affects 30% of women at some time during their reproductive years and is one of the most common reasons a woman sees a gynecologist. Many women are turning to endometrial ablation to manage their AUB. This article reviews the data relating to the available endometrial ablation techniques performed with hysteroscopic sterilization, and focuses on data from patients who had Essure® (Conceptus, San Carlos, CA) coils placed prior to performance of endometrial ablation. Reviewed specifically are data regarding safety and efficacy of these two procedures when combined. Data submitted to the US Food and Drug Administration for the three devices currently approved are reviewed, as well as all published case series. Articles included were selected based on a PubMed search for endometrial ablation (also using the brand names of the different techniques currently available), hysteroscopic sterilization, and Essure. PMID:24358407

  3. Plasma-mediated ablation of biofilm contamination

    NASA Astrophysics Data System (ADS)

    Guo, Zhixiong; Wang, Xiaoliang; Huang, Huan

    2010-12-01

    Ultra-short pulsed laser removal of thin biofilm contamination on different substrates has been conducted via the use of plasma-mediated ablation. The biofilms were formed using sheep whole blood. The ablation was generated using a 1.2 ps ultra-short pulsed laser with wavelength centered at 1552 nm. The blood contamination was transformed into plasma and collected with a vacuum system. The single line ablation features have been measured. The ablation thresholds of blood contamination and bare substrates were determined. It is found that the ablation threshold of the blood contamination is lower than those of the beneath substrates including the glass slide, PDMS, and human dermal tissues. The ablation effects of different laser parameters (pulse overlap rate and pulse energy) were studied and ablation efficiency was measured. Proper ablation parameters were found to efficiently remove contamination with maximum efficiency and without damage to the substrate surface for the current laser system. Complete removal of blood contaminant from the glass substrate surface and freeze-dried dermis tissue surface was demonstrated by the USP laser ablation with repeated area scanning. No obvious thermal damage was found in the decontaminated glass and tissue samples.

  4. Percutaneous ablation of hepatocellular carcinoma: current status.

    PubMed

    McWilliams, Justin P; Yamamoto, Shota; Raman, Steven S; Loh, Christopher T; Lee, Edward W; Liu, David M; Kee, Stephen T

    2010-08-01

    Hepatocellular carcinoma (HCC) is an increasingly common disease with dismal long-term survival. Percutaneous ablation has gained popularity as a minimally invasive, potentially curative therapy for HCC in nonoperative candidates. The seminal technique of percutaneous ethanol injection has been largely supplanted by newer modalities, including radiofrequency ablation, microwave ablation, cryoablation, and high-intensity focused ultrasound ablation. A review of these modalities, including technical success, survival rates, and complications, will be presented, as well as considerations for treatment planning and follow-up.

  5. Ablation of liver metastases: current status.

    PubMed

    Flanders, Vincent L; Gervais, Debra A

    2010-08-01

    Local ablative therapy for the treatment of metastatic disease to the liver has been evaluated most extensively in colorectal cancer with 5-year survival rates up to 55% after RF ablation. Recent findings suggest selected patients with other malignant processes may benefit as well, but conclusive evidence is limited. This article reviews the available literature regarding the use of radiofrequency ablation, microwave ablation, and cryoablation in the treatment of metastatic disease to the liver. The published results of each of these modalities in the treatment of metastatic disease to the liver are promising, and outcomes continue to be evaluated.

  6. Homocysteine and folate deficiency sensitize oligodendrocytes to the cell death-promoting effects of a presenilin-1 mutation and amyloid beta-peptide.

    PubMed

    Pak, Kirk J; Chan, Sic L; Mattson, Mark P

    2003-01-01

    Although damage to white matter occurs in the brains of patients with Alzheimer's disease (AD), the underlying mechanisms are unknown. Recent findings suggest that individuals with elevated levels of homocysteine are at increased risk of AD. Here we show that oligodendrocytes from mice expressing a mutant form of presenilin-1 (PS1) that causes familial AD exhibit increased sensitivity to death induced by homocysteine compared to oligodendrocytes from wild-type control mice. Homocysteine also sensitized oligodendrocytes to the cytotoxicity of amyloid beta-peptide. Folate deficiency, which is known to result in elevated levels of homocysteine in vivo, also sensitized oligodendrocytes to the cell-death-promoting actions of mutant PS1 and amyloid beta-peptide. Inhibitors of poly (ADP-ribose) polymerase and p53 protected oligodendrocytes against cell death induced by homocysteine and amyloid beta-peptide, consistent with a role for a DNA-damage response in the cell death process. These findings demonstrate an adverse effect of homocysteine on oligodendrocytes, and suggest roles for homocysteine and folate deficiency in the white matter damage in AD and related neurodegenerative disorders.

  7. Analysis of iodinated contrast delivered during thermal ablation: is material trapped in the ablation zone?

    NASA Astrophysics Data System (ADS)

    Wu, Po-hung; Brace, Chris L.

    2016-08-01

    Intra-procedural contrast-enhanced CT (CECT) has been proposed to evaluate treatment efficacy of thermal ablation. We hypothesized that contrast material delivered concurrently with thermal ablation may become trapped in the ablation zone, and set out to determine whether such an effect would impact ablation visualization. CECT images were acquired during microwave ablation in normal porcine liver with: (A) normal blood perfusion and no iodinated contrast, (B) normal perfusion and iodinated contrast infusion or (C) no blood perfusion and residual iodinated contrast. Changes in CT attenuation were analyzed from before, during and after ablation to evaluate whether contrast was trapped inside of the ablation zone. Visualization was compared between groups using post-ablation contrast-to-noise ratio (CNR). Attenuation gradients were calculated at the ablation boundary and background to quantitate ablation conspicuity. In Group A, attenuation decreased during ablation due to thermal expansion of tissue water and water vaporization. The ablation zone was difficult to visualize (CNR  =  1.57  ±  0.73, boundary gradient  =  0.7  ±  0.4 HU mm-1), leading to ablation diameter underestimation compared to gross pathology. Group B ablations saw attenuation increase, suggesting that iodine was trapped inside the ablation zone. However, because the normally perfused liver increased even more, Group B ablations were more visible than Group A (CNR  =  2.04  ±  0.84, boundary gradient  =  6.3  ±  1.1 HU mm-1) and allowed accurate estimation of the ablation zone dimensions compared to gross pathology. Substantial water vaporization led to substantial attenuation changes in Group C, though the ablation zone boundary was not highly visible (boundary gradient  =  3.9  ±  1.1 HU mm-1). Our results demonstrate that despite iodinated contrast being trapped in the ablation zone, ablation visibility was

  8. Anti-MOG (Myelin Oligodendrocyte Glycoprotein)–Positive Severe Optic Neuritis with Optic Disc Ischaemia and Macular Star

    PubMed Central

    Moura, Frederico Castelo; Sato, Douglas Kazutoshi; Rimkus, Carolina Medeiros; Apóstolos-Pereira, Samira Luisa; de Oliveira, Luana Michelli; Leite, Claudia Costa; Fujihara, Kazuo; Monteiro, Mario Luiz Ribeiro; Callegaro, Dagoberto

    2015-01-01

    Abstract A 44-year-old man presented with severe right visual loss. The right fundus examination showed marked optic disc oedema associated with partial macular star. Serological blood tests for infectious agents were all negative. Serum aquaporin-4 antibody was negative but anti-MOG (myelin oligodendrocyte glycoprotein) was positive. Magnetic resonance revealed extensive lesion in right optic nerve. There was no visual improvement after intravenous therapy. Patient had no further attacks after follow-up. Optic disc oedema with macular star is found in several infectious and non-inflammatory disorders, but it has not been reported in optic neuritis (ON) associated with autoantibodies to myelin oligodendrocyte glycoprotein (anti-MOG). PMID:27928371

  9. Reactivated astrocytes as a possible source of oligodendrocyte precursors for remyelination in remitting phase of experimental autoimmune encephalomyelitis rats

    PubMed Central

    Guo, An-Chen; Chu, Takho; Liu, Xu-Qing; Su, Huan-Xing; Wu, Wu-Tian

    2016-01-01

    Multiple sclerosis (MS) is ademyelinating disease in the central nervous system (CNS). Majority of the MS patients show relapsing-remitting disease course. Evidences show that oligodendrocyte precursor cells (OPCs), which remain relatively quiescent in normal adult CNS, play a key role in the remitting phase by proliferation and remyelination. In the present study, we found that spinal cord astrocytesco-expressed progenitor cell marker and oligodendroglial lineage markers in the remittance phase in adult rat experimental autoimmune encephalomyelitis (EAE) model. We suggest that activated astrocyte could de-differentiate into OPCs and re-differentiate into mature oligodendrocytes, raising the possibility that astrocytes can be a potential source of OPCs in the adult demyelinated spinal cord. PMID:28078034

  10. Reactivated astrocytes as a possible source of oligodendrocyte precursors for remyelination in remitting phase of experimental autoimmune encephalomyelitis rats.

    PubMed

    Guo, An-Chen; Chu, Takho; Liu, Xu-Qing; Su, Huan-Xing; Wu, Wu-Tian

    2016-01-01

    Multiple sclerosis (MS) is ademyelinating disease in the central nervous system (CNS). Majority of the MS patients show relapsing-remitting disease course. Evidences show that oligodendrocyte precursor cells (OPCs), which remain relatively quiescent in normal adult CNS, play a key role in the remitting phase by proliferation and remyelination. In the present study, we found that spinal cord astrocytesco-expressed progenitor cell marker and oligodendroglial lineage markers in the remittance phase in adult rat experimental autoimmune encephalomyelitis (EAE) model. We suggest that activated astrocyte could de-differentiate into OPCs and re-differentiate into mature oligodendrocytes, raising the possibility that astrocytes can be a potential source of OPCs in the adult demyelinated spinal cord.

  11. Study of breakdown in an ablative pulsed plasma thruster

    SciTech Connect

    Huang, Tiankun; Wu, Zhiwen; Liu, Xiangyang; Xie, Kan; Wang, Ningfei; Cheng, Yue

    2015-10-15

    Breakdown in ablative pulsed plasma thrusters (APPTs) must be studied in order to design new types of APPTs and measure particular parameters. In this paper, we studied a parallel-plate ablative pulsed plasma thruster that used a coaxial semiconductor spark plug. By operating the APPT about 500 times with various capacitor voltages and electrode gaps, we measured and analyzed the voltage of the spark plug, the voltage between the electrodes, and the discharge current. These experiments revealed a time delay (∼1–10 μs) between spark plug ignition and capacitor discharge, which may affect the performance of high-pulsing-rate (>10 kHz) and double-discharge APPTs, and the measurements of some of the APPT parameters. The delay time decreased as the capacitor voltage increased, and it increased with an increasing electrode gap and increasing number of ignitions. We explain our results through a simple theoretical analysis.

  12. TRPA1 deficiency is protective in cuprizone-induced demyelination-A new target against oligodendrocyte apoptosis.

    PubMed

    Sághy, Éva; Sipos, Éva; Ács, Péter; Bölcskei, Kata; Pohóczky, Krisztina; Kemény, Ágnes; Sándor, Zoltán; Szőke, Éva; Sétáló, György; Komoly, Sámuel; Pintér, Erika

    2016-12-01

    Multiple sclerosis is a chronic inflammatory, demyelinating degenerative disease of the central nervous system. Current treatments target pathological immune responses to counteract the inflammatory processes. However, these drugs do not restrain the long-term progression of clinical disability. For this reason, new therapeutic approaches and identification of novel target molecules are needed to prevent demyelination or promote repair mechanisms. Transient Receptor Potential Ankyrin 1 (TRPA1) is a nonselective cation channel with relatively high Ca(2+) permeability. Its pathophysiological role in central nervous system disorders has not been elucidated yet. In the present study, we aimed to assess the distribution of TRPA1 in the mouse brain and reveal its regulatory role in the cuprizone-induced demyelination. This toxin-induced model, characterized by oligodendrocyte apoptosis and subsequent primary demyelination, allows us to investigate the nonimmune aspects of multiple sclerosis. We found that TRPA1 is expressed on astrocytes in the mouse central nervous system. Interestingly, TRPA1 deficiency significantly attenuated cuprizone-induced demyelination by reducing the apoptosis of mature oligodendrocytes. Our data suggest that TRPA1 regulates mitogen-activated protein kinase pathways, as well as transcription factor c-Jun and a proapoptotic Bcl-2 family member (Bak) expression resulting in enhanced oligodendrocyte apoptosis. In conclusion, we propose that TRPA1 receptors enhancing the intracellular Ca(2+) concentration modulate astrocyte functions, and influence the pro or anti-apoptotic pathways in oligodendrocytes. Inhibition of TRPA1 receptors might successfully diminish the degenerative pathology in multiple sclerosis and could be a promising therapeutic target to limit central nervous system damage in demyelinating diseases. GLIA 2016;64:2166-2180.

  13. Maintenance of the relative proportion of oligodendrocytes to axons even in the absence of BAX and BAK

    PubMed Central

    Kawai, Kumi; Itoh, Takayuki; Itoh, Aki; Horiuchi, Makoto; Wakayama, Kouji; Bannerman, Peter; Garbern, James Y.; Pleasure, David; Lindsten, Tullia

    2009-01-01

    Highly purified oligodendroglial lineage cells from mice lacking functional bax and bak genes were resistant to apoptosis after in vitro differentiation, indicating an essential role of the intrinsic apoptotic pathway in apoptosis of oligodendrocytes in the absence of neurons (axons) and other glial cells. These mice therefore provide a valuable tool with which to evaluate the significance of the intrinsic apoptotic pathway in regulating the population sizes of oligodendrocytes and oligodendroglial progenitor cells. Quantitative analysis of the optic nerves and the dorsal columns of the spinal cord revealed that the absolute numbers of mature oligodendrocytes immunolabeled for aspartoacylase, and adult glial progenitor cells expressing NG2 chondroitin sulfate proteoglycan, were increased in both white matter tracts of adult bax/bak-deficient mice, and, to a lesser extent, bax-deficient mice, except for no increase in NG2-positive progenitor cells in the dorsal columns of these strains of mutant mice. These increases in mature oligodendrocytes and progenitor cells in bax/bak-deficient mice were unexpectedly proportional to increases in numbers of axons in these white matter tracts, thus retaining the oligodendroglial lineage to axon ratios at most 1.3-fold of the physiological numbers. This contrasts to the prominent expansion in numbers of neural precursor cells in the subventricular zones of these adult mutant mice. Our study indicates that quantitative homeostatic control of the oligodendroglial lineage is distinct from that of neural precursor cells, and that other regulatory mechanism(s), in addition to apoptotic elimination through the intrinsic pathway, prevent the overproduction of highly mitotic oligodendroglial progenitor cells. PMID:20128842

  14. Different Mechanisms Regulate Expression of Zebrafish Myelin Protein Zero (P0) in Myelinating Oligodendrocytes and Its Induction following Axonal Injury*

    PubMed Central

    Bai, Qing; Parris, Ritika S.; Burton, Edward A.

    2014-01-01

    Zebrafish CNS axons regenerate robustly following injury; it is thought that CNS oligodendrocytes contribute to this response by expressing growth-promoting molecules. We characterized the mpz gene, which encodes myelin protein zero and is up-regulated in oligodendroglia following axonal injury. The 2.5-kb mpz mRNA is expressed from a single TATA box promoter. Four independent Tg(mpz:egfp) transgenic zebrafish lines, in which GFP was expressed under the mpz promoter and 10 kb of genomic 5′-flanking sequence, showed transgene expression in CNS oligodendrocytes from larval development through adulthood. Following optic nerve crush injury, the mpz:egfp transgene was strongly up-regulated in oligodendrocytes along the regenerating retinotectal projection, mirroring up-regulation of endogenous mpz mRNA. GFP-expressing oligodendroglia were significantly more abundant in the regenerating optic pathway, resulting from both transgene induction in oligodendroglial precursors and the birth of new cells. Up-regulation of the mpz:egfp transgene was not dependent on axonal regeneration, suggesting that the primary signal may be axonal loss, debris, or microglial infiltration. Deletion experiments indicated that an oligodendroglial enhancer located in the region from −6 to −10 kb with respect to the mpz transcriptional start site is dissociable from the cis-regulatory element mediating the mpz transcriptional response to axonal injury, which is located between −1 and −4 kb. These data show that different mechanisms regulate expression of zebrafish mpz in myelinating oligodendrocytes and its induction following axonal injury. The underlying molecular events could potentially be exploited to enhance axonal repair following mammalian CNS injury. The transgenic lines and cis-regulatory constructs reported here will facilitate identification of the relevant signaling pathways. PMID:25028515

  15. A complex between contactin-1 and the protein tyrosine phosphatase PTPRZ controls the development of oligodendrocyte precursor cells

    SciTech Connect

    Lamprianou, Smaragda; Chatzopoulou, Elli; Thomas, Jean-Léon; Bouyain, Samuel; Harroch, Sheila

    2013-09-23

    The six members of the contactin (CNTN) family of neural cell adhesion molecules are involved in the formation and maintenance of the central nervous system (CNS) and have been linked to mental retardation and neuropsychiatric disorders such as autism. Five of the six CNTNs bind to the homologous receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ), but the biological roles of these interactions remain unclear. We report here the cocrystal structure of the carbonic anhydrase-like domain of PTPRZ bound to tandem Ig repeats of CNTN1 and combine these structural data with binding assays to show that PTPRZ binds specifically to CNTN1 expressed at the surface of oligodendrocyte precursor cells. Furthermore, analyses of glial cell populations in wild-type and PTPRZ-deficient mice show that the binding of PTPRZ to CNTN1 expressed at the surface of oligodendrocyte precursor cells inhibits their proliferation and promotes their development into mature oligodendrocytes. Overall, these results implicate the PTPRZ/CNTN1 complex as a previously unknown modulator of oligodendrogenesis.

  16. d-LSD-induced c-Fos expression occurs in a population of oligodendrocytes in rat prefrontal cortex.

    PubMed

    Reissig, Chad J; Rabin, Richard A; Winter, Jerrold C; Dlugos, Cynthia A

    2008-03-31

    Induction of mRNA or protein for immediate-early genes, such as c-fos, is used to identify brain areas, specific cell types, and neuronal circuits that become activated in response to various stimuli including psychoactive drugs. The objective of the present study was to identify the cell types in the prefrontal cortex in which lysergic acid diethylamide (d-LSD) induces c-Fos expression. Systemic administration of d-LSD resulted in a dose-dependent increase in c-Fos immunoreactivity. Although c-Fos-positive cells were found in all cortical layers, they were most numerous in layers III, IV, and V. d-LSD-induced c-Fos immunoreactivity was found in cells co-labeled with anti-neuron-specific enolase or anti-oligodendrocyte Oligo1. The Oligo1-labeled cells had small, round bodies and nuclear diameters characteristic of oligodendrocytes. Studies using confocal microscopy confirmed colocalization of c-Fos-labeled nuclei in NeuN-labeled neurons. Astrocytes and microglia labeled with glial fibrillary acidic protein antibody and OX-42 antibody, respectively, did not display LSD-induced c-Fos expression. Pyramidal neurons labeled with anti-neurofilament antibody also did not show induction of c-Fos immunoreactivity after systemic d-LSD administration. The present study demonstrates that d-LSD induced expression of c-Fos in the prefrontal cortex occurs in subpopulations of neurons and in oligodendrocytes, but not in pyramidal neurons, astrocytes, and microglia.

  17. Laser Navigation for Radiofrequency Ablation

    SciTech Connect

    Varro, Zoltan; Locklin, Julia K. Wood, Bradford J.

    2004-09-15

    A 45-year-old male with renal cell carcinoma secondary to von-Hippel Lindau (VHL) disease presented for radiofrequency ablation (RFA) of kidney tumors. Due to his prior history of several partial nephrectomies and limited renal reserve, RFA was chosen because of its relatively nephron-sparing nature. A laser guidance device was used to help guide probe placement in an attempt to reduce procedure time and improve targeting accuracy. The device was successful at guiding needle placement, as both tumors were located with a single pass. Follow-up CT scan confirmed accurate needle placement, showing an area of coagulation necrosis covering the previously seen tumor.

  18. Possible role for cryoballoon ablation of right atrial appendage tachycardia when conventional ablation fails.

    PubMed

    Amasyali, Basri; Kilic, Ayhan

    2015-06-01

    Focal atrial tachycardia arising from the right atrial appendage usually responds well to radiofrequency ablation; however, successful ablation in this anatomic region can be challenging. Surgical excision of the right atrial appendage has sometimes been necessary to eliminate the tachycardia and prevent or reverse the resultant cardiomyopathy. We report the case of a 48-year-old man who had right atrial appendage tachycardia resistant to multiple attempts at ablation with use of conventional radiofrequency energy guided by means of a 3-dimensional mapping system. The condition led to cardiomyopathy in 3 months. The arrhythmia was successfully ablated with use of a 28-mm cryoballoon catheter that had originally been developed for catheter ablation of paroxysmal atrial fibrillation. To our knowledge, this is the first report of cryoballoon ablation without isolation of the right atrial appendage. It might also be an alternative to epicardial ablation or surgery when refractory atrial tachycardia originates from the right atrial appendage.

  19. Local Ablation for Hepatocellular Carcinoma in Taiwan

    PubMed Central

    Lin, Shi-Ming

    2013-01-01

    Hepatocellular carcinoma (HCC) is the second commonest cancer in Taiwan. The national surveillance program can detect HCC in its early stages, and various curative modalities (including surgical resection, orthotopic liver transplantation, and local ablation) are employed for the treatment of small HCC. Local ablation therapies are currently advocated for early-stage HCC that is unresectable because of co-morbidities, the need to preserve liver function, or refusal of resection. Among the various local ablation therapies, the most commonly used modalities include percutaneous ethanol injection and radiofrequency ablation (RFA); percutaneous acetic acid injection and microwave ablation are used less often. RFA is more commonly employed than other local ablative modalities in Taiwan because the technique is highly effective, minimally invasive, and requires fewer sessions. RFA is therefore advocated in Taiwan as the first-line curative therapy for unresectable HCC or even for resectable HCC. However, current RFA procedures are less effective against tumors that are in high-risk or difficult-to-ablate locations, are poorly visualized on ultrasonography (US), or are large. Recent advancements in RFA in Taiwan can resolve these issues by the creation of artificial ascites or pleural effusion, application of real-time virtual US assistance, use of combination therapy before RFA, or use of switching RF controllers with multiple electrodes. This review article provides updates on the clinical outcomes and advances in local ablative modalities (mostly RFA) for HCC in Taiwan. PMID:24159599

  20. Testing and evaluation of light ablation decontamination

    SciTech Connect

    Demmer, R.L.; Ferguson, R.L.

    1994-10-01

    This report details the testing and evaluation of light ablation decontamination. It details WINCO contracted research and application of light ablation efforts by Ames Laboratory. Tests were conducted with SIMCON (simulated contamination) coupons and REALCON (actual radioactive metal coupons) under controlled conditions to compare cleaning effectiveness, speed and application to plant process type equipment.

  1. Effective temperatures of polymer laser ablation

    NASA Astrophysics Data System (ADS)

    Furzikov, Nickolay P.

    1991-09-01

    Effective temperatures of laser ablation of certain polymers are extracted from experimental dependences of ablation depths on laser fluences. Dependence of these temperatures on laser pulse durations is established. Comparison with the known thermodestruction data shows that the effective temperature corresponds to transient thermodestruction proceeding by the statistically most probable way.

  2. Monitoring radiofrequency ablation using real-time ultrasound Nakagami imaging combined with frequency and temporal compounding techniques.

    PubMed

    Zhou, Zhuhuang; Wu, Shuicai; Wang, Chiao-Yin; Ma, Hsiang-Yang; Lin, Chung-Chih; Tsui, Po-Hsiang

    2015-01-01

    Gas bubbles induced during the radiofrequency ablation (RFA) of tissues can affect the detection of ablation zones (necrosis zone or thermal lesion) during ultrasound elastography. To resolve this problem, our previous study proposed ultrasound Nakagami imaging for detecting thermal-induced bubble formation to evaluate ablation zones. To prepare for future applications, this study (i) created a novel algorithmic scheme based on the frequency and temporal compounding of Nakagami imaging for enhanced ablation zone visualization, (ii) integrated the proposed algorithm into a clinical scanner to develop a real-time Nakagami imaging system for monitoring RFA, and (iii) investigated the applicability of Nakagami imaging to various types of tissues. The performance of the real-time Nakagami imaging system in visualizing RFA-induced ablation zones was validated by measuring porcine liver (n = 18) and muscle tissues (n = 6). The experimental results showed that the proposed algorithm can operate on a standard clinical ultrasound scanner to monitor RFA in real time. The Nakagami imaging system effectively monitors RFA-induced ablation zones in liver tissues. However, because tissue properties differ, the system cannot visualize ablation zones in muscle fibers. In the future, real-time Nakagami imaging should be focused on the RFA of the liver and is suggested as an alternative monitoring tool when advanced elastography is unavailable or substantial bubbles exist in the ablation zone.

  3. Monitoring Radiofrequency Ablation Using Real-Time Ultrasound Nakagami Imaging Combined with Frequency and Temporal Compounding Techniques

    PubMed Central

    Zhou, Zhuhuang; Wu, Shuicai; Wang, Chiao-Yin; Ma, Hsiang-Yang; Lin, Chung-Chih; Tsui, Po-Hsiang

    2015-01-01

    Gas bubbles induced during the radiofrequency ablation (RFA) of tissues can affect the detection of ablation zones (necrosis zone or thermal lesion) during ultrasound elastography. To resolve this problem, our previous study proposed ultrasound Nakagami imaging for detecting thermal-induced bubble formation to evaluate ablation zones. To prepare for future applications, this study (i) created a novel algorithmic scheme based on the frequency and temporal compounding of Nakagami imaging for enhanced ablation zone visualization, (ii) integrated the proposed algorithm into a clinical scanner to develop a real-time Nakagami imaging system for monitoring RFA, and (iii) investigated the applicability of Nakagami imaging to various types of tissues. The performance of the real-time Nakagami imaging system in visualizing RFA-induced ablation zones was validated by measuring porcine liver (n = 18) and muscle tissues (n = 6). The experimental results showed that the proposed algorithm can operate on a standard clinical ultrasound scanner to monitor RFA in real time. The Nakagami imaging system effectively monitors RFA-induced ablation zones in liver tissues. However, because tissue properties differ, the system cannot visualize ablation zones in muscle fibers. In the future, real-time Nakagami imaging should be focused on the RFA of the liver and is suggested as an alternative monitoring tool when advanced elastography is unavailable or substantial bubbles exist in the ablation zone. PMID:25658424

  4. Lung Cancer Ablation: Technologies and Techniques

    PubMed Central

    Alexander, Erica S.; Dupuy, Damian E.

    2013-01-01

    The incidence of lung cancers in 2012 is estimated to reach 226,160 new cases, with only a third of patients suitable surgical candidates. Tumor ablation has emerged as an important and efficacious treatment option for nonsurgical lung cancer patients. This localized minimally invasive therapy is best suited for small oligonodular lesions or favorably located metastatic tumors. Radiofrequency ablation has been in use for over a decade, and newer modalities including microwave ablation, cryoablation, and irreversible electroporation have emerged as additional treatment options for patients. Ablation therapies can offer patients and clinicians a repeatable and effective therapy for palliation and, in some cases, cure of thoracic malignancies. This article discusses the available technologies and techniques available for tumor ablation of thoracic malignancies including patient selection, basic aspects of procedure technique, imaging follow-up, treatment outcomes, and comparisons between various therapies. PMID:24436530

  5. Lung cancer ablation: technologies and techniques.

    PubMed

    Alexander, Erica S; Dupuy, Damian E

    2013-06-01

    The incidence of lung cancers in 2012 is estimated to reach 226,160 new cases, with only a third of patients suitable surgical candidates. Tumor ablation has emerged as an important and efficacious treatment option for nonsurgical lung cancer patients. This localized minimally invasive therapy is best suited for small oligonodular lesions or favorably located metastatic tumors. Radiofrequency ablation has been in use for over a decade, and newer modalities including microwave ablation, cryoablation, and irreversible electroporation have emerged as additional treatment options for patients. Ablation therapies can offer patients and clinicians a repeatable and effective therapy for palliation and, in some cases, cure of thoracic malignancies. This article discusses the available technologies and techniques available for tumor ablation of thoracic malignancies including patient selection, basic aspects of procedure technique, imaging follow-up, treatment outcomes, and comparisons between various therapies.

  6. Endovascular Radiofrequency Ablation for Varicose Veins

    PubMed Central

    2011-01-01

    Executive Summary Objective The objective of the MAS evidence review was to conduct a systematic review of the available evidence on the safety, effectiveness, durability and cost–effectiveness of endovascular radiofrequency ablation (RFA) for the treatment of primary symptomatic varicose veins. Background The Ontario Health Technology Advisory Committee (OHTAC) met on August 26th, 2010 to review the safety, effectiveness, durability, and cost-effectiveness of RFA for the treatment of primary symptomatic varicose veins based on an evidence-based review by the Medical Advisory Secretariat (MAS). Clinical Condition Varicose veins (VV) are tortuous, twisted, or elongated veins. This can be due to existing (inherited) valve dysfunction or decreased vein elasticity (primary venous reflux) or valve damage from prior thrombotic events (secondary venous reflux). The end result is pooling of blood in the veins, increased venous pressure and subsequent vein enlargement. As a result of high venous pressure, branch vessels balloon out leading to varicosities (varicose veins). Symptoms typically affect the lower extremities and include (but are not limited to): aching, swelling, throbbing, night cramps, restless legs, leg fatigue, itching and burning. Left untreated, venous reflux tends to be progressive, often leading to chronic venous insufficiency (CVI). A number of complications are associated with untreated venous reflux: including superficial thrombophlebitis as well as variceal rupture and haemorrhage. CVI often results in chronic skin changes referred to as stasis dermatitis. Stasis dermatitis is comprised of a spectrum of cutaneous abnormalities including edema, hyperpigmentation, eczema, lipodermatosclerosis and stasis ulceration. Ulceration represents the disease end point for severe CVI. CVI is associated with a reduced quality of life particularly in relation to pain, physical function and mobility. In severe cases, VV with ulcers, QOL has been rated to be as bad

  7. Femtosecond ablation of ultrahard materials

    NASA Astrophysics Data System (ADS)

    Dumitru, G.; Romano, V.; Weber, H. P.; Sentis, M.; Marine, W.

    Several ultrahard materials and coatings of definite interest for tribological applications were tested with respect to their response when irradiated with fs laser pulses. Results on cemented tungsten carbide and on titanium carbonitride are reported for the first time and compared with outcomes of investigations on diamond and titanium nitride. The experiments were carried out in air, in a regime of 5-8 J/cm2 fluences, using the beam of a commercial Ti:sapphire laser. The changes induced in the surface morphology were analysed with a Nomarski optical microscope, and with SEM and AFM techniques. From the experimental data and from the calculated incident energy density distributions, the damage and ablation threshold values were determined. As expected, the diamond showed the highest threshold, while the cemented tungsten carbide exhibited typical values for metallic surfaces. The ablation rates determined (under the above-mentioned experimental conditions) were in the range 0.1-0.2 μm per pulse for all the materials investigated.

  8. Ablative shielding for hypervelocity projectiles

    NASA Technical Reports Server (NTRS)

    Rucker, Michelle A. (Inventor)

    1993-01-01

    A hypervelocity projectile shield which includes a hollow semi-flexible housing fabricated from a plastic like, or otherwise transparent membrane which is filled with a fluid (gas or liquid) is presented. The housing has a inlet valve, similar to that on a tire or basketball, to introduce an ablating fluid into the housing. The housing is attached by a Velcro mount or double-sided adhesive tape to the outside surface of a structure to be protected. The housings are arrayed in a side-by-side relationship for complete coverage of the surface to be protected. In use, when a hypervelocity projectile penetrates the outer wall of a housing it is broken up and then the projectile is ablated as it travels through the fluid, much like a meteorite 'burns up' as it enters the earth's atmosphere, and the housing is deflated. The deflated housing can be easily spotted for replacement, even from a distance. Replacement is then accomplished by simply pulling a deflated housing off the structure and installing a new housing.

  9. Tumor Ablation with Irreversible Electroporation

    PubMed Central

    Al-Sakere, Bassim; André, Franck; Bernat, Claire; Connault, Elisabeth; Opolon, Paule; Davalos, Rafael V.; Rubinsky, Boris; Mir, Lluis M.

    2007-01-01

    We report the first successful use of irreversible electroporation for the minimally invasive treatment of aggressive cutaneous tumors implanted in mice. Irreversible electroporation is a newly developed non-thermal tissue ablation technique in which certain short duration electrical fields are used to permanently permeabilize the cell membrane, presumably through the formation of nanoscale defects in the cell membrane. Mathematical models of the electrical and thermal fields that develop during the application of the pulses were used to design an efficient treatment protocol with minimal heating of the tissue. Tumor regression was confirmed by histological studies which also revealed that it occurred as a direct result of irreversible cell membrane permeabilization. Parametric studies show that the successful outcome of the procedure is related to the applied electric field strength, the total pulse duration as well as the temporal mode of delivery of the pulses. Our best results were obtained using plate electrodes to deliver across the tumor 80 pulses of 100 µs at 0.3 Hz with an electrical field magnitude of 2500 V/cm. These conditions induced complete regression in 12 out of 13 treated tumors, (92%), in the absence of tissue heating. Irreversible electroporation is thus a new effective modality for non-thermal tumor ablation. PMID:17989772

  10. Simple model for ablative stabilization

    NASA Astrophysics Data System (ADS)

    Mikaelian, Karnig O.

    1992-11-01

    We present a simple analytic model for ablative stablization of the Rayleigh-Taylor instability. In this model the effect of ablation is to move the peak of the perturbations to the location of peak pressure. This mechanism enhances the density-gradient stabilization, which is effective at short wavelengths, and it also enhances the stabilization of long-wavelength perturbations due to finite shell thickness. We consider the following density profile: exponential blowoff plasma with a density gradient β, followed by a constant-density shell of thickness δt. For perturbations of arbitrary wave number k, we present an explicit expression for the growth rate γ as a function of k, β, and δt. We find that ``thick'' shells defined by β δt>=1 have γ2>=0 for any k, while ``thin'' shells defined by β δt<1 can have γ2<0 for small k, reflecting stability by proximity to the back side of the shell. We also present lasnex simulations that are in good agreement with our analytic formulas.

  11. Stellar Ablation of Planetary Atmospheres

    NASA Technical Reports Server (NTRS)

    Moore, Thomas E.; Horwitz, J. L.

    2007-01-01

    We review observations and theories of the solar ablation of planetary atmospheres, focusing on the terrestrial case where a large magnetosphere holds off the solar wind, so that there is little direct atmospheric impact, but also couples the solar wind electromagnetically to the auroral zones. We consider the photothermal escape flows known as the polar wind or refilling flows, the enhanced mass flux escape flows that result from localized solar wind energy dissipation in the auroral zones, and the resultant enhanced neutral atom escape flows. We term these latter two escape flows the "auroral wind." We review observations and theories of the heating and acceleration of auroral winds, including energy inputs from precipitating particles, electromagnetic energy flux at magnetohydrodynamic and plasma wave frequencies, and acceleration by parallel electric fields and by convection pickup processes also known as "centrifugal acceleration." We consider also the global circulation of ionospheric plasmas within the magnetosphere, their participation in magnetospheric disturbances as absorbers of momentum and energy, and their ultimate loss from the magnetosphere into the downstream solar wind, loading reconnection processes that occur at high altitudes near the magnetospheric boundaries. We consider the role of planetary magnetization and the accumulating evidence of stellar ablation of extrasolar planetary atmospheres. Finally, we suggest and discuss future needs for both the theory and observation of the planetary ionospheres and their role in solar wind interactions, to achieve the generality required for a predictive science of the coupling of stellar and planetary atmospheres over the full range of possible conditions.

  12. Oligodendrocytes Engineered With Migratory Proteins as Effective Graft Source for Cell Transplantation in Multiple Sclerosis

    PubMed Central

    De La Pena, Ike; Pabon, Mibel; Acosta, Sandra; Sanberg, Paul R.; Tajiri, Naoki; Kaneko, Yuji; Borlongan, Cesar V.

    2014-01-01

    Multiple sclerosis (MS) is characterized by widespread immunomodulatory demyelination of the central nervous system (CNS), resulting in nerve cell dysfunction. Accordingly, treatment strategies have been centered on immunodulation and remyelination, with the former primarily focused on reducing the pathology rather than enhancing myelin repair, which the latter targets. While conceding to the emerging view of heterogeneity in the pathology of MS, which precludes variations in degree of immune response (i.e., inflammation) and demyelination, the concept of enhancing myelin repair is appealing since it is likely to provide both disease-reducing and disease-inhibiting therapeutic approaches to MS. In this regard, we and several others have proposed that cell replacement therapy is an effective strategy to repair the myelin in MS. Here we hypothesize that transplantation of mouse bone marrow-derived oligodendrocytes (BMDOs) and BMDOs transfected with ephrin proteins (BMDO + ephrin), which are known to enhance cell and axonal migratory capacity, may produce therapeutic benefits in animal models of MS. PMID:24999443

  13. Identification and two-photon imaging of oligodendrocyte in CA1 region of hippocampal slices

    SciTech Connect

    Zhou Wei; Ge Wooping; Zeng Shaoqun; Duan Shumin; Luo Qingming . E-mail: qluo@mail.hust.edu.cn

    2007-01-19

    Oligodendrocyte (OL) plays a critical role in myelination and axon maintenance in central nervous system. Recent studies show that OL can also express NMDA receptors in development and pathological situations in white matter. There is still lack of studies about OL properties and function in gray matter of brain. Here we reported that some glial cells in CA1 region of rat hippocampal slices (P15-23) had distinct electrophysiological characteristics from the other glia cells in this region, while they displayed uniform properties with OL from white matter in previous report; therefore, they were considered as OL in hippocampus. By loading dye in recording pipette and imaging with two-photon laser scanning microscopy, we acquired the high spatial resolution, three-dimension images of these special cells in live slices. The OL in hippocampus shows a complex process-bearing shape and the distribution of several processes is parallel to Schaffer fiber in CA1 region. When stimulating Schaffer fiber, OL displays a long duration depolarization mediated by inward rectifier potassium channel. This suggested that the OL in CA1 region could sense the neuronal activity and contribute to potassium clearance.

  14. Role of the small GTPase Rab27a during Herpes simplex virus infection of oligodendrocytic cells

    PubMed Central

    2012-01-01

    Background The morphogenesis of herpes simplex virus type 1 (HSV-1) comprises several events, of which some are not completely understood. It has been shown that HSV-1 glycoproteins accumulate in the trans-Golgi network (TGN) and in TGN-derived vesicles. It is also accepted that HSV-1 acquires its final morphology through a secondary envelopment by budding into TGN-derived vesicles coated with viral glycoproteins and tegument proteins. Nevertheless, several aspects of this process remain elusive. The small GTPase Rab27a has been implicated in regulated exocytosis, and it seems to play a key role in certain membrane trafficking events. Rab27a also seems to be required for human cytomegalovirus assembly. However, despite the involvement of various Rab GTPases in HSV-1 envelopment, there is, to date, no data reported on the role of Rab27a in HSV-1 infection. Results Herein, we show that Rab27a colocalized with GHSV-UL46, a tegument-tagged green fluorescent protein-HSV-1, in the TGN. In fact, this small GTPase colocalized with viral glycoproteins gH and gD in that compartment. Functional analysis through Rab27a depletion showed a significant decrease in the number of infected cells and viral production in Rab27a-silenced cells. Conclusions Altogether, our results indicate that Rab27a plays an important role in HSV-1 infection of oligodendrocytic cells. PMID:23164453

  15. PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms

    PubMed Central

    Mironova, Yevgeniya A; Lenk, Guy M; Lin, Jing-Ping; Lee, Seung Joon; Twiss, Jeffery L; Vaccari, Ilaria; Bolino, Alessandra; Havton, Leif A; Min, Sang H; Abrams, Charles S; Shrager, Peter; Meisler, Miriam H; Giger, Roman J

    2016-01-01

    Proper development of the CNS axon-glia unit requires bi-directional communication between axons and oligodendrocytes (OLs). We show that the signaling lipid phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2] is required in neurons and in OLs for normal CNS myelination. In mice, mutations of Fig4, Pikfyve or Vac14, encoding key components of the PI(3,5)P2 biosynthetic complex, each lead to impaired OL maturation, severe CNS hypomyelination and delayed propagation of compound action potentials. Primary OLs deficient in Fig4 accumulate large LAMP1+ and Rab7+ vesicular structures and exhibit reduced membrane sheet expansion. PI(3,5)P2 deficiency leads to accumulation of myelin-associated glycoprotein (MAG) in LAMP1+perinuclear vesicles that fail to migrate to the nascent myelin sheet. Live-cell imaging of OLs after genetic or pharmacological inhibition of PI(3,5)P2 synthesis revealed impaired trafficking of plasma membrane-derived MAG through the endolysosomal system in primary cells and brain tissue. Collectively, our studies identify PI(3,5)P2 as a key regulator of myelin membrane trafficking and myelinogenesis. DOI: http://dx.doi.org/10.7554/eLife.13023.001 PMID:27008179

  16. Knockdown of Unconventional Myosin ID Expression Induced Morphological Change in Oligodendrocytes

    PubMed Central

    Yamazaki, Reiji; Ishibashi, Tomoko; Baba, Hiroko

    2016-01-01

    Myelin is a special multilamellar structure involved in various functions in the nervous system. In the central nervous system, the oligodendrocyte (OL) produces myelin and has a unique morphology. OLs have a dynamic membrane sorting system associated with cytoskeletal organization, which aids in the production of myelin. Recently, it was reported that the assembly and disassembly of actin filaments is crucial for myelination. However, the partner myosin molecule which associates with actin filaments during the myelination process has not yet been identified. One candidate myosin is unconventional myosin ID (Myo1d) which is distributed throughout central nervous system myelin; however, its function is still unclear. We report here that Myo1d is expressed during later stages of OL differentiation, together with myelin proteolipid protein (PLP). In addition, Myo1d is distributed at the leading edge of the myelin-like membrane in cultured OL, colocalizing mainly with actin filaments, 2′,3′-cyclic nucleotide phosphodiesterase and partially with PLP. Myo1d-knockdown with specific siRNA induces significant morphological changes such as the retraction of processes and degeneration of myelin-like membrane, and finally apoptosis. Furthermore, loss of Myo1d by siRNA results in the impairment of intracellular PLP transport. Together, these results suggest that Myo1d may contribute to membrane dynamics either in wrapping or transporting of myelin membrane proteins during formation and maintenance of myelin. PMID:27655972

  17. Localization of PPARdelta in murine central nervous system: expression in oligodendrocytes and neurons.

    PubMed

    Woods, John W; Tanen, Michael; Figueroa, David J; Biswas, Chhabi; Zycband, Emanuel; Moller, David E; Austin, Christopher P; Berger, Joel P

    2003-06-13

    The peroxisome proliferator-activated receptors (PPARs), PPARdelta, PPARgamma and PPARalpha, comprise a subclass of the supergene family of nuclear receptors. As such they are ligand-regulated transcription factors whose major effects are mediated by altering expression of target genes. PPARdelta has been shown to be ubiquitously expressed in mammals. However, its primary biological role(s) has yet to be defined. Several recent studies have demonstrated that PPARdelta is the most highly expressed PPAR isoform in the central nervous system, but ambiguity still exists as to the specific brain sub-regions and cells in which it is expressed. Here, utilizing novel, isoform-selective PPARdelta riboprobes and an anti-peptide antibody, we performed a series of in situ hybridization and immunolocalization studies to determine the distribution of PPARdelta in the central nervous system (CNS) of mice. We found that PPARdelta mRNA and protein is expressed throughout the brain, with particularly high levels in the entorhinal cortex, hypothalamus and hippocampus, and lower levels in the corpus callosum and caudate putamen. At the cellular level, PPARdelta mRNA and protein were found to be expressed in oligodendrocytes and neurons but not astrocytes. Such results suggest a role for PPARdelta in both myelination and neuronal functioning within the CNS.

  18. Neuroprotective effects of oligodendrocyte progenitor cell transplantation in premature rat brain following hypoxic-ischemic injury.

    PubMed

    Chen, Long-Xia; Ma, Si-Min; Zhang, Peng; Fan, Zi-Chuan; Xiong, Man; Cheng, Guo-Qiang; Yang, Yi; Qiu, Zi-Long; Zhou, Wen-Hao; Li, Jin

    2015-01-01

    Periventricular leukomalacia (PVL) is a common ischemic brain injury in premature infants for which there is no effective treatment. The objective of this study was to determine whether transplanted mouse oligodendrocyte progenitor cells (OPCs) have neuroprotective effects in a rat model of PVL. Hypoxia-ischemia (HI) was induced in 3-day-old rat pups by left carotid artery ligation, followed by exposure to 6% oxygen for 2.5 h. Animals were assigned to OPC transplantation or sham control groups and injected with OPCs or PBS, respectively, and sacrificed up to 6 weeks later for immunohistochemical analysis to investigate the survival and differentiation of transplanted OPCs. Apoptosis was evaluated by double immunolabeling of brain sections for caspase-3 and neuronal nuclei (NeuN), while proliferation was assessed using a combination of anti-Nestin and -bromodeoxyuridine antibodies. The expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 was examined 7 days after OPC transplantation. The Morris water maze was used to test spatial learning and memory. The results showed that transplanted OPCs survived and formed a myelin sheath, and stimulated BDNF and Bcl-2 expression and the proliferation of neural stem cells (NSC), while inhibiting HI-induced neuronal apoptosis relative to control animals. Moreover, deficits in spatial learning and memory resulting from HI were improved by OPC transplantation. These results demonstrate an important neuroprotective role for OPCs that can potentially be exploited in cell-based therapeutic approaches to minimize HI-induced brain injury.

  19. A role of Sema6A expressed in oligodendrocyte precursor cells.

    PubMed

    Okada, Atsumasa; Tomooka, Yasuhiro

    2013-02-28

    Our previous study has confirmed that the distribution of oligodendrocyte precursor cells (OPCs) is disturbed in the embryonic cerebral cortex of Plexin-A4 knockout mice, and that Sema6A is expressed in OPCs in the region. The present study examined whether Sema6A expressed in OPCs is involved in their own migration, and used a clonal FBD-102b line as OPCs model. In an in vitro migration assay, Sema6A knockdown repressed the migration of FBD-102b cells. Additionally, in co-culture, 3T3 cells ectopically expressing Plexin-A4 were segregated from 3T3 cells ectopically expressing Sema6A. When FBD-102b cells were seeded in a spot and exposed to a gradient of both Sema3A and Sema6A, dispersion of FBD-102b cells was suppressed, and Plexin-A4 knockdown in FBD-102b cells attenuated the suppressive effect of the Semaphorins. These results indicate that Sema6A expressed in OPCs is involved in their autonomous migration through ligand-receptor interaction with Plexin-A4 expressed in surrounding cells.

  20. Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior.

    PubMed

    Dries, Daniel R; Zhu, Yi; Brooks, Mieu M; Forero, Diego A; Adachi, Megumi; Cenik, Basar; West, James M; Han, Yu-Hong; Yu, Cong; Arbella, Jennifer; Nordin, Annelie; Adolfsson, Rolf; Del-Favero, Jurgen; Lu, Q Richard; Callaerts, Patrick; Birnbaum, Shari G; Yu, Gang

    2016-05-27

    The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of γ-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate γ-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessive-compulsive disorder is a distinct subtype of schizophrenia.

  1. bFGF Protects Pre-oligodendrocytes from Oxygen/Glucose Deprivation Injury to Ameliorate Demyelination.

    PubMed

    Qu, Xuebin; Guo, Rui; Zhang, Zhenzhong; Ma, Li; Wu, Xiuxiang; Luo, Mengjiao; Dong, Fuxing; Yao, Ruiqin

    2015-10-01

    One of the pathological hallmarks of periventricular white matter injury is the vulnerability of pre-oligodendrocytes (preOLs) to hypoxia-ischemia (HI). There is increasing evidence that basic fibroblast growth factor (bFGF) is an important signaling molecule for neurogenesis and neuroprotection in the central nervous system. However, it is unknown whether bFGF protects preOLs from oxygen/glucose deprivation (OGD) damage in vitro and promotes remyelination in HI-induced rats. In this present study, bFGF exerted a protective effect on myelin by increasing the myelin thickness, the number of myelinated axons, and myelin basic protein expression in the HI-induced demyelinated neonatal rat corpus callosum. In vitro, bFGF ameliorated the impaired mitochondria and cell processes induced by OGD to promote the survival of isolated O4-positive preOLs. Additionally, the expression of fibroblast growth factor receptor 3 (FGFR3) was dramatically up-regulated in the preOLs after bFGF administration in vivo and in vitro. Thus, bFGF-stimulated remyelination in HI-induced rats by protecting the preOLs from hypoxic injury, and the mechanism involved may be mediated by FGFR3.

  2. Dicer1 and miR-219 Are Required for Normal Oligodendrocyte Differentiation and Myelination

    PubMed Central

    Dugas, Jason C.; Cuellar, Trinna L.; Scholze, Anja; Ason, Brandon; Ibrahim, Adiljan; Emery, Ben; Zamanian, Jennifer L.; Foo, Lynette C.; McManus, Michael T.; Barres, Ben A.

    2010-01-01

    To investigate the role of microRNAs in regulating oligodendrocyte (OL) differentiation and myelination, we utilized transgenic mice in which microRNA processing was disrupted in OL precursor cells (OPCs) and OLs by targeted deletion of Dicer1. We found that inhibition of OPC-OL miRNA processing disrupts normal CNS myelination, and that OPCs lacking mature miRNAs fail to differentiate normally in vitro. We identified three miRNAs, miR-219, miR-138, and miR-338, that are induced 10–100x during OL differentiation; the most strongly induced of these, miR-219, is necessary and sufficient to promote OL differentiation, and partially rescues OL differentiation defects caused by total miRNA loss. miR-219 directly represses the expression of PDGFRα, Sox6, FoxJ3, and ZFP238 proteins, all of which normally help to promote OPC proliferation. Together, these findings show that miR-219 plays a critical role in coupling differentiation to proliferation arrest in the OL lineage, enabling the rapid transition from proliferating OPCs to myelinating OLs. PMID:20223197

  3. Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process.

    PubMed

    Galvao, Rui Pedro; Kasina, Anita; McNeill, Robert S; Harbin, Jordan E; Foreman, Oded; Verhaak, Roel G W; Nishiyama, Akiko; Miller, C Ryan; Zong, Hui

    2014-10-07

    How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas.

  4. Modeling bimodal vessel effects on radio and microwave frequency ablation zones.

    PubMed

    Brannan, Joseph D; Ladtkow, Casey M

    2009-01-01

    A bench liver model is presented that separates the thermal and electrical effects of large blood vessels within radio and microwave frequency ablation boundaries. The model includes a cylindrical tissue environment with a 5 mm vessel placed parallel to and 15 mm way from either a Covidien Energy-based Devices Evident MW Ablation Percutaneous Antenna or a CoolTip RF Ablation Single Electrode Kit. An array of fiber optic thermal probes is used to monitor radial temperature profile on the vessel and non-vessel sides of the ablation zone. Circulating blood exhibits higher electrical conductivity than surrounding liver tissue and provides a significant means for transport of thermal energy. Data from the thermal probes indicate key performance differentiators between MW and RF ablation modalities when they are used next to large blood vessels clarifying the difference between thermal and electrical energy sink. The results suggest RFA is susceptible to both the thermal and electrical energy sink effects of large vasculature while MWA is only susceptible to thermal sink. Ablation zone boundaries were distorted on both the vessel and non-vessel sides with RFA whereas with MWA only the vessel side is affected.

  5. Laser ablation of persistent twist cells in Drosophila: muscle precursor fate is not segmentally restricted

    NASA Technical Reports Server (NTRS)

    Farrell, E. R.; Keshishian, H.

    1999-01-01

    In Drosophila the precursors of the adult musculature arise during embryogenesis. These precursor cells have been termed Persistent Twist Cells (PTCs), as they continue to express the transcription factor Twist after that gene ceases expression elsewhere in the mesoderm. In the larval abdomen, the PTCs are associated with peripheral nerves in stereotypic ventral, dorsal, and lateral clusters, which give rise, respectively, to the ventral, dorsal, and lateral muscle fiber groups of the adult. We tested the developmental potential of the PTCs by using a microbeam laser to ablate specific clusters in larvae. We found that the ablation of a single segmental PTC cluster does not usually result in the deletion of the corresponding adult fibers of that segment. Instead, normal or near normal numbers of adult fibers can form after the ablation. Examination of pupae following ablation showed that migrating PTCs from adjacent segments are able to invade the affected segment, replenishing the ablated cells. However, the ablation of homologous PTCs in multiple segments does result in the deletion of the corresponding adult muscle fibers. These data indicate that the PTCs in an abdominal segment can contribute to the formation of muscle fibers in adjacent abdominal segments, and thus are not inherently restricted to the formation of muscle fibers within their segment of origin.

  6. Effect of excimer laser radiant exposure on uniformity of ablated corneal surface.

    PubMed

    Fantes, F E; Waring, G O

    1989-01-01

    The argon fluoride (193 nm) excimer laser is being used to change the anterior corneal curvature for correction of refractive errors. Uniformity of the surface following laser ablation may play an important role in the rate of epithelial healing and amount and type of stromal scarring. To test the effect of radiant exposure (fluence) on surface smoothness, we ablated rabbit corneas with the 193 nm argon fluoride excimer laser at nine radiant exposures from 50 to 850 mJ/cm2. A total energy of 100 J/cm2 was used for each ablation at a frequency of 1 Hz. Scanning electron microscopy demonstrated progressive improvement of surface smoothness with increasing radiant exposures. Transmission electron microscopy demonstrated no consistent increase in thickness to the surface condensate (pseudomembrane) with increasing radiant exposure. Improvement in surface quality associated with increasing radiant exposures may result from a more uniform depth of ablation per pulse in the corneal lamellae that absorb laser wavelengths differently. Radiant exposures at levels where the depth of ablation is the same regardless of increasing energy densities achieve a more uniform surface because inhomogeneities in the beam and variation in energy from pulse to pulse do not affect the ablation rate.

  7. Long term results of fast pathway ablation in atrioventricular nodal reentry tachycardia using a modified technique.

    PubMed Central

    Mehta, D.; Gomes, J. A.

    1995-01-01

    OBJECTIVE--To assess immediate and long term success of "fast" pathway catheter ablation with graded use of radiofrequency energy in patients with classic atrioventricular nodal reentrant tachycardia (AVNRT) and evaluate clinical, procedure related, and electrophysiological features affecting long term results. DESIGN--31 consecutive patients with classic AVNRT at electrophysiological study, who were candidates for radiofrequency ablation. Patients were followed for an average of 24 months after ablation. SETTING--All studies and ablations were performed in an electrophysiological laboratory under fluoroscopic guidance using standard electrophysiological techniques. INTERVENTION--Radiofrequency application was performed at the site of proximal His bundle electrogram with A:V ratio of > 1. It was started at 10 W with increment of 5 W to a maximum of 25 W at 60 s. With the onset of junctional rhythm, atrial pacing was begun in order to monitor the PR interval. Application was terminated prematurely with a non-conducted P wave, continued prolongation of the PR interval beyond 50% of the baseline, or a threefold rise in impedance. RESULTS--Successful ablation was possible in 30/31 patients (97%) with an average of seven applications (range 1-10). It was associated with significant prolongation of PR interval (P < 0.001) and AV Wenckebach cycle length (P = 0.01). Ventriculo-atrial conduction was abolished in 24/30 patients (82%) with successful ablation. Two patients developed transient complete heart block (3 and 12 min) and one persistent right branch block. Four patients had late recurrence. Presence of ventriculo-atrial block was the only electrophysiological index predictive of long term success (P = 0.01). CONCLUSIONS--Graded use of radiofrequency energy and atrial pacing to monitor PR interval decreases the risk of atrioventricular block in patients undergoing fast pathway ablation for AVNRT. Ventriculo-atrial block is predictive of long term success and should

  8. Pulsed infrared laser ablation and clinical applications

    NASA Astrophysics Data System (ADS)

    Chan, Kin Foong

    Sufficient light energy deposited in tissue can result in ablation and excessive thermal and mechanical damage to adjacent tissues. The goals of this research are to investigate the mechanisms of pulsed infrared laser ablation of tissue, to optimize laser parameters for minimizing unnecessary damage to healthy tissue, and to explore the potential of using pulsed infrared lasers for clinical applications, especially laser lithotripsy. A dual-channel optical low coherence reflectometer was implemented to measure the expansion and collapse velocities of a Q-switched Ho:YAG (λ = 2.12 μm) laser-induced cavitation in water. Cavitation wall velocities up to 11 m/s were measured with this technique, and the results were in fair agreement with those calculated from fast-flash photographic images. The dependence of ablation threshold fluence on calculus absorption was examined. Preliminary results indicated that the product of optical absorption and ablation threshold fluence, which is the heat of ablation, remained constant for a given urinary calculus type and laser pulse duration. An extended study examined the influence of optical absorption on pulsed infrared laser ablation. An analytical photothermal ablation model was applied and compared to experimental ablation results using an infrared free-electron laser at selected wavelengths between 2.12 μm and 6.45 μm Results were in good agreement with the model, and the ablation depths of urinary calculi were highly dependent upon the calculus optical absorption as well as light attenuation within the intrapulse ablation plume. An efficient wavelength for ablation corresponded to the wavelength of the Er:YAG laser (λ = 2.94 μm) suggested this laser should be examined for laser lithotripsy. Schlieren flash photography, acoustic transient measurements with a piezoelectric polyvinylidene-fluoride needle-hydrophone, mass loss measurements, and chemical analyses were employed to study the ablation mechanisms of the free

  9. Reconfigurable tapered coaxial slot antenna for hepatic microwave ablation.

    PubMed

    Malhotra, Neeru; Marwaha, Anupma; Kumar, Ajay

    2016-01-01

    Microwave ablation is rapidly being rediscovered and developed for treating many cancers of liver, lung, kidney and bone, as well as arrhythmias and other medical conditions. The microwaves ablate tissue by heating it to cytotoxic temperatures. The microwave antenna design suffers the challenges of effective coupling and penetration into body tissues, uncontrolled power deposition due to applicator construction limitations affecting uniform heating of target region, and narrowband operation leading to mismatch for many patients and detrimental heating. To meet out the requirements of wideband operation and localized lesion reconfigurable linearly tapered slot interstitial wideband antenna has been proposed for working in the 1.38 GHz to 4.31 GHz frequency band. The performance of the antenna is evaluated by using FEM-based HFSS software. The slot height and taper height are reconfigured for parametric analysis achieving maximum impedance matching and spherical ablation zone without requiring any additional adjustable structures. The tapering of the slot in coaxial antenna generates current distribution at the edges of the slot for maximizing specific absorption rate.

  10. Damage in materials following ablation by ultrashort laser pulses: A molecular-dynamics study

    SciTech Connect

    Bouilly, Delphine; Perez, Danny; Lewis, Laurent J.

    2007-11-01

    The formation of craters following femtosecond- and picosecond-pulse laser ablation in the thermal regime is studied using a generic two-dimensional numerical model based on molecular-dynamics simulations and the Lennard-Jones potential. Femtosecond pulses are found to produce very clean craters through a combination of etching of the walls and the formation of a very thin heat affected zone. Our simulations also indicate that dislocations are emitted continuously during all of the ablation process (i.e., for hundreds of ps). For picosecond pulses, we observe much thicker heat affected zones which result from melting and recrystallization following the absorption of the light. In this case also, continuous emission of dislocations--though fewer in number--takes place throughout the ablation process.

  11. On the Ablation Models of Fuel Pellets

    SciTech Connect

    Rozhansky, V.A.; Senichenkov, I.Yu.

    2005-12-15

    The neutral gas shielding model and neutral-gas-plasma shielding model are analyzed qualitatively. The main physical processes that govern the formation of the shielding gas cloud and, consequently, the ablation rate are considered. For the neutral gas shielding model, simple formulas relating the ablation rate and cloud parameters to the parameters of the pellet and the background plasma are presented. The estimates of the efficiency of neutral gas shielding and plasma shielding are compared. It is shown that the main portion of the energy flux of the background electrons is released in the plasma cloud. Formulas for the ablation rate and plasma parameters are derived in the neutral-gas-plasma shielding model. The question is discussed as to why the neutral gas shielding model describes well the ablation rate of the pellet material, although it does not take into account the ionization effects and the effects associated with the interaction of ionized particles with the magnetic field. The reason is that the ablation rate depends weakly on the energy flux of hot electrons; as a result, the attenuation of this flux by the electrostatic shielding and plasma shielding has little effect on the ablation rate. This justifies the use of the neutral gas shielding model to estimate the ablation rate (to within a factor of about 2) over a wide range of parameters of the pellet and the background plasma.

  12. [Indications for catheter ablation of ventricular tachycardia].

    PubMed

    Deneke, T; Israel, C W; Krug, J; Nentwich, K; Müller, P; Mügge, A; Schade, A

    2013-09-01

    Ventricular tachyarrhythmias (VT) can cause sudden cardiac death. This can be prevented by an implantable cardioverter-defibrillator (ICD) but approximately 25% of patients with an ICD develop electrical storm (≥ 3 VTs within 24 hours) during the course of 4-5 years. This is a life-threatening event even in the presence of an ICD, particularly if incessant VT is present, and may significantly deteriorate the patient's psychological state if multiple shocks are discharged. Catheter ablation of VT has developed into a standard procedure in many specialized electrophysiology centers. Patients with hemodynamically stable and unstable VT are amendable to substrate-based ablation strategies. Catheter ablation can be performed as emergency procedure in patients with electrical storm as well as electively in patients with monomorphic VT stored in ICD memory. In patients with ischemic or non-ischemic cardiomyopathy, VT ablation is complementary to ICD implantation and can reduce the number of ventricular arrhythmia episodes and shocks and should be performed early. In patients with electrical storm, catheter ablation can acutely achieve rhythm stabilization and may improve prognosis in the long term. Further indications for catheter ablation exist in patients with idiopathic VT where catheter ablation represents a curative therapy, and in patients with symptomatic or asymptomatic frequent premature ventricular beats which may improve prognosis in patients with heart failure and cardiac resynchronization therapy.

  13. Analysis of infrared laser tissue ablation

    NASA Astrophysics Data System (ADS)

    McKenzie, Gordon P.; Timmerman, Brenda H.; Bryanston-Cross, Peter J.

    2005-04-01

    The mechanisms involved in infrared laser tissue ablation are studied using a free electron laser (FELIX) in order to clarify whether the increased ablation efficiency reported in literature for certain infrared wavelengths is due to a wavelength effect or to the specific pulse structure of the lasers that are generally used in these studies. Investigations are presented of ablation of vitreous from pigs" eyes using several techniques including protein gel electrophoresis and ablation plume visualization. The ablation effects of three different infrared wavelengths are compared: 3 mm, which is currently in clinical surgical use, and the wavelengths associated with the amide I and amide II bands, i.e. 6.2 mm and 6.45mm, respectively. The results suggest a different ablation mechanism to be in operation for each studied wavelength, thus indicating that the generally reported increased ablation efficiency in the 6-6.5 micron range is due to the wavelength rather than the typical free electron laser pulse structure.

  14. Thermal therapy, Part III: ablation techniques.

    PubMed

    Habash, Riadh W Y; Bansal, Rajeev; Krewski, Daniel; Alhafid, Hafid T

    2007-01-01

    Ablative treatments are gaining increasing attention as an alternative to standard surgical therapies, especially for patients with contraindication or those who refuse open surgery. Thermal ablation is used in clinical applications mainly for treating heart arrhythmias, benign prostate hyperplasia, and nonoperable liver tumors; there is also increasing application to other organ sites, including the kidney, lung, and brain. Potential benefits of thermal ablation include reduced morbidity and mortality in comparison with standard surgical resection and the ability to treat nonsurgical patients. The purpose of this review is to outline and discuss the engineering principles and biological responses by which thermal ablation techniques can provide elevation of temperature in organs within the human body. Because of the individual problems associated with each type of treatment, a wide range of ablation techniques have evolved including cryoablation as well as ultrasound, radiofrequency (RF), microwave, and laser ablation. Aspects of each ablation technique, including mechanisms of action, equipment required, selection of eligible patients, treatment techniques, and patient outcomes are presented, along with a discussion of limitations of the techniques and future research directions.

  15. Early snowmelt decreases ablation period carbon uptake in a high elevation, subalpine forest, Niwot Ridge, Colorado, USA

    NASA Astrophysics Data System (ADS)

    Winchell, T. S.; Molotch, N. P.; Barnard, D. M.

    2015-12-01

    The snow ablation period is a time of great potential for carbon uptake in high-elevation, subalpine forests. During this period, water availability associated with snowmelt promotes photosynthetic carbon uptake, while snow cover diminishes carbon losses from soil respiration. Although the ablation period can be as short as two weeks, as much as 30% of the total seasonal carbon uptake can occur during this period. Varying ablation period dynamics, however, can result in varying rates of carbon uptake during this integral uptake period. We use fifteen years of observational climate flux and snow water equivalent (SWE) data for a subalpine forest in the Colorado Rocky Mountains to analyze carbon uptake trends during the annual ablation period. Specifically, we focus on how the timing of peak SWE affects carbon uptake during the ablation period. We find that when the snowmelt period occurs one month earlier than average, the forest experiences an ablation period mean air temperature of 2.7° C, approximately 5° C colder than an ablation period that occurs one month later than average. This early, colder atmospheric condition leads to daytime carbon uptake rates that are 2.5 gC/m2/day less than the later, warmer period, which results in 47 gC/m2 less ablation period carbon uptake. As most climate models project peak SWE to occur earlier under various warming scenarios, we can expect to see a trend of less carbon uptake during future ablation periods. We expect to see a decrease in total growing season carbon uptake if the post-snowmelt period is unable to compensate for the decrease in ablation period carbon uptake.

  16. Thermal protection system ablation sensor

    NASA Technical Reports Server (NTRS)

    Gorbunov, Sergey (Inventor); Martinez, Edward R. (Inventor); Scott, James B. (Inventor); Oishi, Tomomi (Inventor); Fu, Johnny (Inventor); Mach, Joseph G. (Inventor); Santos, Jose B. (Inventor)

    2011-01-01

    An isotherm sensor tracks space vehicle temperatures by a thermal protection system (TPS) material during vehicle re-entry as a function of time, and surface recession through calibration, calculation, analysis and exposed surface modeling. Sensor design includes: two resistive conductors, wound around a tube, with a first end of each conductor connected to a constant current source, and second ends electrically insulated from each other by a selected material that becomes an electrically conductive char at higher temperatures to thereby complete an electrical circuit. The sensor conductors become shorter as ablation proceeds and reduced resistance in the completed electrical circuit (proportional to conductor length) is continually monitored, using measured end-to-end voltage change or current in the circuit. Thermocouple and/or piezoelectric measurements provide consistency checks on local temperatures.

  17. Radiofrequency Ablation: A Nursing Perspective

    PubMed Central

    Locklin, Julia K.; Wood, Bradford J.

    2008-01-01

    Radiofrequency ablation (RFA) has emerged as a safe and predictable technology for treating certain patients with cancer who otherwise have few treatment options. Nurses need to be familiar with all phases of the RFA procedure to create an optimal environment for patients. This article offers a brief review of the RFA procedure and nurses' responsibilities in caring for these patients. Before RFA, nurses should focus on patient education and aggressive hydration. During the procedure, nurses can prevent injury by placing grounding pads appropriately, monitoring vital signs, and medicating patients as needed. After RFA, nurses should assess the skin puncture site, provide adequate pain relief, and, again, hydrate patients. Nurses who care appropriately for RFA recipients may help to improve patient outcomes and make an otherwise frightening procedure more comfortable. PMID:15973845

  18. Ablation of idiopathic ventricular tachycardia.

    PubMed

    Schreiber, Doreen; Kottkamp, Hans

    2010-09-01

    Idiopathic ventricular arrhythmias occur in patients without structural heart disease. They can arise from a variety of specific areas within both ventricles and in the supravalvular regions of the great arteries. Two main groups need to be differentiated: arrhythmias from the outflow tract (OT) region and idiopathic left ventricular, so-called fascicular, tachycardias (ILVTs). OT tachycardia typically originates in the right ventricular OT, but may also occur in the left ventricular OT, particularly in the sinuses of Valsalva or the anterior epicardium or the great cardiac vein. Activation mapping or pace mapping for the OT regions and mapping of diastolic potentials in ILVTs are the mapping techniques that are typically used. The ablation of idiopathic ventricular arrhythmias is highly successful, associated with only rare complications. Newly recognized entities of idiopathic ventricular tachycardias are those originating in the papillary muscles and in the atrioventricular annular regions.

  19. Nanosecond laser ablation of gold nanoparticle films

    SciTech Connect

    Ko, Seung H.; Choi, Yeonho; Hwang, David J.; Grigoropoulos, Costas P.; Chung, Jaewon; Poulikakos, Dimos

    2006-10-02

    Ablation of self-assembled monolayer protected gold nanoparticle films on polyimide was explored using a nanosecond laser. When the nanoparticle film was ablated and subsequently thermally sintered to a continuous film, the elevated rim structure by the expulsion of molten pool could be avoided and the ablation threshold fluence was reduced to a value at least ten times lower than the reported threshold for the gold film. This could be explained by the unusual properties of nanoparticle film such as low melting temperature, weak bonding between nanoparticles, efficient laser energy deposition, and reduced heat loss. Finally, submicron lines were demonstrated.

  20. IR laser ablation of dental enamel

    NASA Astrophysics Data System (ADS)

    Fried, Daniel

    2000-03-01

    An overview of the basic mechanisms of IR laser ablation of dental enamel is presented. Enamel is a highly structured tissue consisting of an heterogeneous distribution of water, mineral, protein and lipid. Absorption bands of water and carbonated hydroxyapatite can be selectively targeted from 2.7 to 11-micrometer via several laser wavelengths. Mechanistic differences in the nature of ablation and the varying surface morphology produced can be explained by the microstructure of the tissue. Suggested criteria for the choice of the optimum laser parameters for clinical use, the influence of plasma shielding and the role of exogenous water on the mechanism of ablation are discussed.

  1. Diamond Ablators for Inertial Confinement Fusion

    SciTech Connect

    Biener, J; Mirkarimi, P B; Tringe, J W; Baker, S L; Wang, Y M; Kucheyev, S O; Teslich, N E; Wu, K J; Hamza, A V; Wild, C; Woerner, E; Koidl, P; Bruehne, K; Fecht, H

    2005-06-21

    Diamond has a unique combination of physical properties for the inertial confinement fusion ablator application, such as appropriate optical properties, high atomic density, high yield strength, and high thermal conductivity. Here, we present a feasible concept to fabricate diamond ablator shells. The fabrication of diamond capsules is a multi-step process, which involves diamond chemical vapor deposition on silicon mandrels followed by polishing, microfabrication of holes, and removing of the silicon mandrel by an etch process. We also discuss the pros and cons of coarse-grained optical quality and nanocrystalline chemical vapor deposition diamond films for the ablator application.

  2. Radiofrequency Ablation of Persistent Atrial Fibrillation

    PubMed Central

    Hussein, Ayman A.; Saliba, Walid I.; Barakat, Amr; Bassiouny, Mohammed; Chamsi-Pasha, Mohammed; Al-Bawardy, Rasha; Hakim, Ali; Tarakji, Khaldoun; Baranowski, Bryan; Cantillon, Daniel; Dresing, Thomas; Tchou, Patrick; Martin, David O.; Varma, Niraj; Bhargava, Mandeep; Callahan, Thomas; Niebauer, Mark; Kanj, Mohamed; Chung, Mina; Natale, Andrea; Lindsay, Bruce D.; Wazni, Oussama M.

    2017-01-01

    Background Various ablation strategies of persistent atrial fibrillation (PersAF) have had disappointing outcomes, despite concerted clinical and research efforts, which could reflect progressive atrial fibrillation–related atrial remodeling. Methods and Results Two-year outcomes were assessed in 1241 consecutive patients undergoing first-time ablation of PersAF (2005–2012). The time intervals between the first diagnosis of PersAF and the ablation procedures were determined. Patients had echocardiograms and measures of B-type natriuretic peptide and C-reactive protein before the procedures. The median diagnosis-to-ablation time was 3 years (25th–75th percentiles 1–6.5). With longer diagnosis-to-ablation time (based on quartiles), there was a significant increase in recurrence rates in addition to an increase in B-type natriuretic peptide levels (P=0.01), C-reactive protein levels (P<0.0001), and left atrial size (P=0.03). The arrhythmia recurrence rates over 2 years were 33.6%, 52.6%, 57.1%, and 54.6% in the first, second, third, and fourth quartiles, respectively (Pcategorical<0.0001). In Cox Proportional Hazard analyses, B-type natriuretic peptide levels, C-reactive protein levels, and left atrial size were associated with arrhythmia recurrence. The diagnosis-to-ablation time had the strongest association with the ablation outcomes which persisted in multivariable Cox analyzes (hazard ratio for recurrence per +1Log diagnosis-to-ablation time 1.27, 95% confidence interval 1.14–1.43; P<0.0001; hazard ratio fourth versus first quartile 2.44, 95% confidence interval 1.68–3.65; Pcategorical<0.0001). Conclusions In patients with PersAF undergoing ablation, the time interval between the first diagnosis of PersAF and the catheter ablation procedure had a strong association with the ablation outcomes, such as shorter diagnosis-to-ablation times were associated with better outcomes and in direct association with markers of atrial remodeling. PMID:26763227

  3. Ablation of pulmonary malignancy: current status.

    PubMed

    Pua, Bradley B; Thornton, Raymond H; Solomon, Stephen B

    2010-08-01

    Since the first reported use of radiofrequency ablation of the lung in 2000, the field of image-guided lung ablation has received a considerable amount of attention. Survival studies have demonstrated the potential utility of thermal ablation in the treatment of patients with early-stage primary and limited secondary pulmonary tumors with promising results. Diagnostic imaging studies have advanced the understanding of the expected immediate postablation appearance of treated lesions, leading the way for early detection of local tumor progression. These survival studies and the expected imaging follow-up of these patients are reviewed herein.

  4. Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro.

    PubMed

    Franco-Pons, Neus; Tomàs, Jordi; Roig, Bárbara; Auladell, Carme; Martorell, Lourdes; Vilella, Elisabet

    2009-05-01

    The discoidin domain receptor (DDR1) is highly expressed in oligodendrocytes during the neurodevelopmental myelination process and is genetically associated to schizophrenia. In this study, we aimed to further assess the involvement of DDR1 in both remyelination and oligodendrocyte differentiation. In the mouse model of demyelination-remyelination induced by oral administration of cuprizone, in situ hybridization showed an upregulation of the DDR1 gene in three different white matter areas (corpus callosum, dorsal fornix, and external capsule) during the remyelination period. Moreover, real time reverse transcriptase polymerase chain reaction showed that the increase in DDR1 messenger RNA (mRNA) was strongly correlated with the number of DDR1-positive cells in the corpus callosum (Spearman coefficient = 0.987, P = 0.013). Cells positive for DDR1 mRNA were also positive for oligodendrocyte markers (OLIG2, carnosine, and APC) but not for markers of oligodendrocyte precursors (NG2), myelin markers (CNPase), microglia (CD11b), or reactive glia (GFAP). Differentiation of a human oligodendroglial cell line, HOG16, was associated with an increase in mRNA expression of DDR1 and several myelin proteins (MBP and MOBP) but not other proteins (APC and CNPase). Here, we demonstrate that DDR1 is upregulated in vitro and in vivo when oligodendrocyte myelinating machinery is activated. Further studies are needed to identify the specific molecular pathway.

  5. PDGF-alpha receptor and myelin basic protein mRNAs are not coexpressed by oligodendrocytes in vivo: a double in situ hybridization study in the anterior medullary velum of the neonatal rat.

    PubMed

    Butt, A M; Hornby, M F; Ibrahim, M; Kirvell, S; Graham, A; Berry, M

    1997-01-01

    Platelet-derived growth factor (PDGF) is a growth-regulatory dimer with A and B subunits. PDGF-AA, acting via PDGF receptors of the alpha-unit subtype (PDGF-alphaR), is implicated in the differentiation of oligodendrocyte precursors and in the survival of newly formed oligodendrocytes, which gradually lose expression of PDGF-alphaR. However, it is unclear whether terminally differentiated oligodendrocytes express PDGF-alphaR in vivo. To address this question, and to help clarify the role of PDGF-AA in late oligodendrocyte differentiation, we have used double in situ hybridization with digoxigenin- and fluorescein-labeled riboprobes to relate PDGF-alphaR mRNA and myelin basic protein (MBP) mRNA expression in the isolated intact anterior medullary velum (AMV) of rats ages Postnatal Day (P) 10-12 and P30-32. In parallel experiments, AMV were immunolabeled with the oligodendrocyte-specific monoclonal antibody Rip to provide information on oligodendrocyte development and the extent of myelination. At P10, the AMV contained tracts in which axons ranged from unmyelinated to fully myelinated, whereas myelination was complete in P30-32 AMV. The first oligodendrocytes to express MBP mRNA or Rip were promyelinating oligodendrocytes, which had a "star-burst" morphology and had not yet begun to form myelin sheaths. As myelination proceeded, MBP mRNA became dispersed throughout oligodendrocyte units, comprising cell somata, processes, and internodal myelin sheaths. By P30-32, MBP mRNA had been redistributed to the myelin sheaths only, reflecting a change in the site of protein synthesis in mature myelinated axon tracts. At no stage of oligodendrocyte differentiation did we observe cellular coexpression of mRNA for PDGFalphaR and MBP. Our results indicated that oligodendrocytes lost the expression of PDGFalphaR prior to gaining that of myelin gene products, and preclude an action of PDGF-AA on Rip+/MBP+ star-burst promyelinating oligodendrocytes. The spatial and temporal

  6. Effect of sample storage conditions on Er:YAG laser ablation of enamel, dentin, and bone

    NASA Astrophysics Data System (ADS)

    Selting, Wayne J.

    2007-02-01

    Samples of bone, dentin and enamel were stored in distilled water, 10% neutral buffered formalin, 70% ethyl alcohol or 6% sodium hypochlorite solutions for fifteen days. Other samples were stored in the same solutions for 36 hours and then transferred to distilled water for the remainder of the fifteen day period. Finally, samples than had been stored dry for up to 5 years were rehydrated and ablated. All enamel specimens appeared unaffected by the storage conditions. Dentin samples were very significantly affected by all storage methods. Bone samples were affected by most storage conditions. Samples stored in sodium hypochlorite had as much as a 100 percent increase in ablation rate. Surprisingly, dry stored samples that were reconstituted for 36 hours ablated at virtually the same rate as those stored in distilled water. None of the storage conditions studied produced ablation rates that mirrored in vivo ablation. Sterilization by autoclave is the only reliable and safe method studied but cannot be used on teeth with amalgam fillings for safety reasons. Teeth with fillings should be stored in 10% neutral bufferred formalin for a minimum of one week.

  7. Laser ablation deposition of superconducting Bi-Sr-Ca-Cu-O thin films on zirconia-buffered crystalline quartz

    SciTech Connect

    Bohandy, J.; Agostinelli, E.; Kim, B.F.; Green, W.J.; Phillips, T.E.; Adrian, F.J.; Moorjani, K.

    1989-06-01

    Thin films of Bi-Sr-Ca-Cu-O have been deposited on crystalline quartz substrates by laser ablation. Without a buffer layer, superconducting regions exist in the films as detected by magnetically modulated microwave absorption. However, with a 1000-A zirconia buffer layer, also deposited by laser ablation, continuous, superconducting thin films were obtained. It is shown that both annealing temperature and annealing time greatly affect the film quality.

  8. Brain-derived neurotrophic factor deficiency restricts proliferation of oligodendrocyte progenitors following cuprizone-induced demyelination.

    PubMed

    Tsiperson, Vladislav; Huang, Yangyang; Bagayogo, Issa; Song, Yeri; VonDran, Melissa W; DiCicco-Bloom, Emanuel; Dreyfus, Cheryl F

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that through its neurotrophic tyrosine kinase, receptor, type 2 (TrkB) receptor, increases 5-bromo-2-deoxyuridine incorporation in oligodendrocyte progenitor cells (OPCs) in culture. Roles in vivo are less well understood; however, increases in numbers of OPCs are restricted in BDNF+/- mice following cuprizone-elicited demyelination. Here, we investigate whether these blunted increases in OPCs are associated with changes in proliferation. BDNF+/+ and BDNF+/- mice were fed cuprizone-containing or control feed. To assess effects on OPC numbers, platelet-derived growth factor receptor alpha (PDGFRα)+ or NG2+ cells were counted. To monitor DNA synthesis, 5-ethynyl-2'-deoxyuridine (EdU) was injected intraperitoneally and colocalized with PDGFRα+ cells. Alternatively, proliferating cell nuclear antigen (PCNA) was colocalized with PDGFRα or NG2. Labeling indices were determined in the BDNF+/+ and BDNF+/- animals. After 4 or 5 weeks of control feed, BDNF+/- mice exhibit similar numbers of OPCs compared with BDNF+/+ animals. The labeling indices for EdU and PCNA also were not significantly different, suggesting that neither the DNA synthesis phase (S phase) nor the proliferative pool size was different between genotypes. In contrast, when mice were challenged by cuprizone for 4 or 5 weeks, increases in OPCs observed in BDNF+/+ mice were reduced in the BDNF+/- mice. This difference in elevations in cell number was accompanied by decreases in EdU labeling and PCNA labeling without changes in cell death, indicating a reduction in the DNA synthesis and the proliferative pool. Therefore, levels of BDNF influence the proliferation of OPCs resulting from a demyelinating lesion.

  9. Reactive Oxygen Species Derived from NOX3 and NOX5 Drive Differentiation of Human Oligodendrocytes

    PubMed Central

    Accetta, Roberta; Damiano, Simona; Morano, Annalisa; Mondola, Paolo; Paternò, Roberto; Avvedimento, Enrico V.; Santillo, Mariarosaria

    2016-01-01

    Reactive oxygen species (ROS) are signaling molecules that mediate stress response, apoptosis, DNA damage, gene expression and differentiation. We report here that differentiation of oligodendrocytes (OLs), the myelin forming cells in the CNS, is driven by ROS. To dissect the OL differentiation pathway, we used the cell line MO3-13, which display the molecular and cellular features of OL precursors. These cells exposed 1–4 days to low levels of H2O2 or to the protein kinase C (PKC) activator, phorbol-12-Myristate-13-Acetate (PMA) increased the expression of specific OL differentiation markers: the specific nuclear factor Olig-2, and Myelin Basic Protein (MBP), which was processed and accumulated selectively in membranes. The induction of differentiation genes was associated with the activation of ERK1-2 and phosphorylation of the nuclear cAMP responsive element binding protein 1 (CREB). PKC mediates ROS-induced differentiation because PKC depletion or bis-indolyl-maleimide (BIM), a PKC inhibitor, reversed the induction of differentiation markers by H2O2. H2O2 and PMA increased the expression of membrane-bound NADPH oxidases, NOX3 and NOX5. Selective depletion of these proteins inhibited differentiation induced by PMA. Furthermore, NOX5 silencing down regulated NOX3 mRNA levels, suggesting that ROS produced by NOX5 up-regulate NOX3 expression. These data unravel an elaborate network of ROS-generating enzymes (NOX5 to NOX3) activated by PKC and necessary for differentiation of OLs. Furthermore, NOX3 and NOX5, as inducers of OL differentiation, represent novel targets for therapies of demyelinating diseases, including multiple sclerosis, associated with impairment of OL differentiation. PMID:27313511

  10. Infectious Mononucleosis Triggers Generation of IgG Auto-Antibodies against Native Myelin Oligodendrocyte Glycoprotein

    PubMed Central

    Kakalacheva, Kristina; Regenass, Stephan; Wiesmayr, Silke; Azzi, Tarik; Berger, Christoph; Dale, Russell C.; Brilot, Fabienne; Münz, Christian; Rostasy, Kevin; Nadal, David; Lünemann, Jan D.

    2016-01-01

    A history of infectious mononucleosis (IM), symptomatic primary infection with the Epstein Barr virus, is associated with the development of autoimmune diseases and increases the risk to develop multiple sclerosis. Here, we hypothesized that immune activation during IM triggers autoreactive immune responses. Antibody responses towards cellular antigens using a HEp-2 based indirect immunofluorescence assay and native myelin oligodendrocyte glycoprotein (MOG) using a flow cytometry-based assay were determined in 35 patients with IM and in 23 control subjects. We detected frequent immunoglobulin M (IgM) reactivity to vimentin, a major constituent of the intermediate filament family of proteins, in IM patients (27/35; 77%) but rarely in control subjects (2/23; 9%). IgG autoantibodies binding to HEp-2 cells were absent in both groups. In contrast, IgG responses to native MOG, present in up to 40% of children with inflammatory demyelinating diseases of the central nervous system (CNS), were detectable in 7/35 (20%) patients with IM but not in control subjects. Normalization of anti-vimentin IgM levels to increased total IgM concentrations during IM resulted in loss of significant differences for anti-vimentin IgM titers. Anti-MOG specific IgG responses were still detectable in a subset of three out of 35 patients with IM (9%), even after normalization to increased total IgG levels. Vimentin-specific IgM and MOG-specific IgG responses decreased following clinical resolution of acute IM symptoms. We conclude from our data that MOG-specific memory B cells are activated in subset of patients with IM. PMID:26907324

  11. Infectious Mononucleosis Triggers Generation of IgG Auto-Antibodies against Native Myelin Oligodendrocyte Glycoprotein.

    PubMed

    Kakalacheva, Kristina; Regenass, Stephan; Wiesmayr, Silke; Azzi, Tarik; Berger, Christoph; Dale, Russell C; Brilot, Fabienne; Münz, Christian; Rostasy, Kevin; Nadal, David; Lünemann, Jan D

    2016-02-12

    A history of infectious mononucleosis (IM), symptomatic primary infection with the Epstein Barr virus, is associated with the development of autoimmune diseases and increases the risk to develop multiple sclerosis. Here, we hypothesized that immune activation during IM triggers autoreactive immune responses. Antibody responses towards cellular antigens using a HEp-2 based indirect immunofluorescence assay and native myelin oligodendrocyte glycoprotein (MOG) using a flow cytometry-based assay were determined in 35 patients with IM and in 23 control subjects. We detected frequent immunoglobulin M (IgM) reactivity to vimentin, a major constituent of the intermediate filament family of proteins, in IM patients (27/35; 77%) but rarely in control subjects (2/23; 9%). IgG autoantibodies binding to HEp-2 cells were absent in both groups. In contrast, IgG responses to native MOG, present in up to 40% of children with inflammatory demyelinating diseases of the central nervous system (CNS), were detectable in 7/35 (20%) patients with IM but not in control subjects. Normalization of anti-vimentin IgM levels to increased total IgM concentrations during IM resulted in loss of significant differences for anti-vimentin IgM titers. Anti-MOG specific IgG responses were still detectable in a subset of three out of 35 patients with IM (9%), even after normalization to increased total IgG levels. Vimentin-specific IgM and MOG-specific IgG responses decreased following clinical resolution of acute IM symptoms. We conclude from our data that MOG-specific memory B cells are activated in subset of patients with IM.

  12. Characterization of acid-sensing ion channel expression in oligodendrocyte-lineage cells.

    PubMed

    Feldman, Daniel H; Horiuchi, Makoto; Keachie, Krista; Mccauley, Erica; Bannerman, Peter; Itoh, Aki; Itoh, Takayuki; Pleasure, David

    2008-08-15

    Acid-sensing ion channels (ASICs) are widely expressed in neurons, where they serve in pain and mechanical sensation, and contribute to learning and memory. Six ASIC subunit proteins form homo- or heteromeric channel complexes with distinct physiological properties. Of such complexes, only monomeric ASIC1a channels are Ca2+ permeable. Prior pharmacologic and genetic studies have shown that ASIC1a channel inactivation markedly diminishes CNS susceptibility to ischemic damage. Here, we characterize ASIC expression in oligodendrocyte lineage cells (OLC) by molecular, electrophysiological, calcium imaging, and immunofluorescence techniques. ASIC1a, ASIC2a, and ASIC4 mRNAs were expressed in cultured rat OLC, with steady-state levels of each of these mRNAs several-fold higher in oligodendroglial progenitors than in mature oligodendroglia. ASIC transcripts were also detected in brain white matter, and ASIC1a protein expression was detected in white matter oligodendroglia. Inactivating, proton-gated, amiloride-sensitive OLC currents were detected by whole-cell voltage clamp. These currents showed profound tachyphylaxis with slow recovery, and were predominantly blocked by psalmotoxin, indicating that homomeric ASIC1a comprised a large fraction of functional ASIC in the cultured OLC. ASIC activation substantially depolarized OLC plasma membrane in current clamp studies, and elicited transient elevations in intracellular Ca2+ in imaging studies. Thus, OLC ASIC1a channels provide a means by which an acid shift in CNS extracellular pH, by diminishing plasma membrane potential and increasing Ca2+ permeability, can activate OLC signaling pathways, and may contribute to OLC vulnerability to CNS ischemia.

  13. CNS Schwann cells display oligodendrocyte precursor-like potassium channel activation and antigenic expression in vitro.

    PubMed

    Kegler, Kristel; Imbschweiler, Ilka; Ulrich, Reiner; Kovermann, Peter; Fahlke, Christoph; Deschl, Ulrich; Kalkuhl, Arno; Baumgärnter, Wolfgang; Wewetzer, Konstantin

    2014-06-01

    Central nervous system (CNS) injury triggers production of myelinating Schwann cells from endogenous oligodendrocyte precursors (OLPs). These CNS Schwann cells may be attractive candidates for novel therapeutic strategies aiming to promote endogenous CNS repair. However, CNS Schwann cells have been so far mainly characterized in situ regarding morphology and marker expression, and it has remained enigmatic whether they display functional properties distinct from peripheral nervous system (PNS) Schwann cells. Potassium channels (K+) have been implicated in progenitor and glial cell proliferation after injury and may, therefore, represent a suitable pharmacological target. In the present study, we focused on the function and expression of voltage-gated K+ channels Kv(1-12) and accessory β-subunits in purified adult canine CNS and PNS Schwann cell cultures using electrophysiology and microarray analysis and characterized their antigenic phenotype. We show here that K+ channels differed significantly in both cell types. While CNS Schwann cells displayed prominent K D-mediated K+ currents, PNS Schwann cells elicited K(D-) and K(A-type) K+ currents. Inhibition of K+ currents by TEA and Ba2+ was more effective in CNS Schwann cells. These functional differences were not paralleled by differential mRNA expression of Kv(1-12) and accessory β-subunits. However, O4/A2B5 and GFAP expressions were significantly higher and lower, respectively, in CNS than in PNS Schwann cells. Taken together, this is the first evidence that CNS Schwann cells display specific properties not shared by their peripheral counterpart. Both Kv currents and increased O4/A2B5 expression were reminiscent of OLPs suggesting that CNS Schwann cells retain OLP features during maturation.

  14. Extracellular Vesicles from Vascular Endothelial Cells Promote Survival, Proliferation and Motility of Oligodendrocyte Precursor Cells

    PubMed Central

    Kurachi, Masashi; Mikuni, Masahiko; Ishizaki, Yasuki

    2016-01-01

    We previously examined the effect of brain microvascular endothelial cell (MVEC) transplantation on rat white matter infarction, and found that MVEC transplantation promoted remyelination of demyelinated axons in the infarct region and reduced apoptotic death of oligodendrocyte precursor cells (OPCs). We also found that the conditioned medium (CM) from cultured MVECs inhibited apoptosis of cultured OPCs. In this study, we examined contribution of extracellular vesicles (EVs) contained in the CM to its inhibitory effect on OPC apoptosis. Removal of EVs from the CM by ultracentrifugation reduced its inhibitory effect on OPC apoptosis. To confirm whether EVs derived from MVECs are taken up by cultured OPCs, we labeled EVs with PKH67, a fluorescent dye, and added them to OPC cultures. Many vesicular structures labeled with PKH67 were found within OPCs immediately after their addition. Next we examined the effect of MVEC-derived EVs on OPC behaviors. After 2 days in culture with EVs, there was significantly less pyknotic and more BrdU-positive OPCs when compared to control. We also examined the effect of EVs on motility of OPCs. OPCs migrated longer in the presence of EVs when compared to control. To examine whether these effects on cultured OPCs are shared by EVs from endothelial cells, we prepared EVs from conditioned media of several types of endothelial cells, and tested their effects on cultured OPCs. EVs from all types of endothelial cells we examined reduced apoptosis of OPCs and promoted their motility. Identification of the molecules contained in EVs from endothelial cells may prove helpful for establishment of effective therapies for demyelinating diseases. PMID:27403742

  15. Interleukin (IL)-8 immunoreactivity of injured axons and surrounding oligodendrocytes in traumatic head injury.

    PubMed

    Hayashi, Takahito; Ago, Kazutoshi; Nakamae, Takuma; Higo, Eri; Ogata, Mamoru

    2016-06-01

    Interleukin (IL)-8 has been suggested to be a positive regulator of myelination in the central nervous system, in addition to its principal role as a chemokine for neutrophils. Immunostaining for beta-amyloid precursor protein (AβPP) is an effective tool for detecting traumatic axonal injury, although AβPP immunoreactivity can also indicate axonal injury due to hypoxic causes. In this study, we examined IL-8 and AβPP immunoreactivity in sections of corpus callosum obtained from deceased patients with blunt head injury and from equivalent control tissue. AβPP immunoreactivity was detected in injured axons, such as axonal bulbs and varicose axons, in 24 of 44 head injury cases. These AβPP immunoreactive cases had survived for more than 3h. The AβPP immunostaining pattern can be classified into two types: traumatic (Pattern 1) and non-traumatic (Pattern 2) axonal injuries, which we described previously [Hayashi et al. Int. J. Legal Med. 129 (2015) 1085-1090]. Three of 44 control cases also showed AβPP immunoreactive injured axons as Pattern 2. In contrast, IL-8 immunoreactivity was detected in 7 AβPP immunoreactive and in 2 non-AβPP immunoreactive head injury cases, but was not detected in any of the 44 control cases, including the 3 AβPP immunoreactive control cases. The IL-8 immunoreactive cases had survived from 3 to 24 days, whereas those cases who survived less than 3 days (n=29) and who survived 90 days (n=1) were not IL-8 immunoreactive. Moreover, IL-8 was detected as Pattern 1 axons only. In addition, double immunofluorescence analysis showed that IL-8 is expressed by oligodendrocytes surrounding injured axons. In conclusion, our results suggest that immunohistochemical detection of IL-8 may be useful as a complementary diagnostic marker of traumatic axonal injury.

  16. Multiple kinase pathways regulate voltage-dependent Ca++ influx and migration in oligodendrocyte precursor cells

    PubMed Central

    Paez, PM; Fulton, DJ; Spreur, V; Handley, V; Campagnoni, AT

    2010-01-01

    It is becoming increasingly clear that voltage-operated Ca++ channels (VOCCs) play a fundamental role in the development of oligodendrocyte progenitor cells (OPCs). Since direct phosphorylation by different kinases is one of the most important mechanisms involved in VOCC modulation, the aim of this study was to evaluate the participation of serine-threonine (Ser/Thr) kinases and tyrosine kinases (TK) on Ca++ influx mediated by VOCCs in OPCs. Calcium imaging revealed that OPCs exhibited Ca++ influx following plasma membrane depolarization via L-type VOCCs. Furthermore, VOCC-mediated Ca++ influx declined with OPC differentiation, indicating that VOCCs are developmentally regulated in OPCs. PKC activation significantly increased VOCC activity in OPCs, while PKA activation produced the opposite effect. The results also indicated that OPC morphological changes induced by PKC activation were partially mediated by VOCCs. Our data clearly suggest that TKs exert an activating influence on VOCC function in OPCs. Furthermore, using the PDGF response as a model to probe the role of TK receptors (TKr) on OPCs Ca++ uptake, we found that TKr activation potentiated Ca++ influx after membrane depolarization. Interestingly, this TKr modulation of VOCCs appeared to be essential for the PDGF enhancement of OPC migration rate, since cell motility was completely blocked by TKr antagonists, as well as VOCC inhibitors, in migration assays. The present study strongly demonstrates that PKC and TKrs enhance Ca++ influx induced by depolarization in OPCs, while PKA has an inhibitory effect. These kinases modulate voltage-operated Ca++ uptake in OPCs and participate in the modulation of process extension and migration. PMID:20445068

  17. Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia

    PubMed Central

    McMillan, Corey T.; Suh, EunRan; Powers, John; Rascovsky, Katya; Wood, Elisabeth M.; Toledo, Jon B.; Arnold, Steven E.; Lee, Virginia M.-Y.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Grossman, Murray

    2014-01-01

    Objective: To determine the prognostic utility of tauopathy-associated single nucleotide polymorphisms (SNPs) in sporadic behavioral-variant frontotemporal dementia (bvFTD). Methods: Eighty-one patients with sporadic bvFTD were genotyped for tauopathy-associated SNPs at rs8070723 (microtubule-associated protein tau [MAPT]) and rs1768208 (myelin-associated oligodendrocyte basic protein [MOBP]). We performed a retrospective case-control study comparing age at onset and disease duration between carriers of ≥1 polymorphism allele and noncarriers for these SNPs. Subanalyses were performed for autopsied subgroups with tauopathy (n = 20) and TDP-43 proteinopathy (n = 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n = 37). Results: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA+) had a shorter median disease duration (TC/TT = 5.5 years, CC = 9.5 years; p = 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies (p = 0.04) but not with TDP-43 proteinopathies (p > 0.1). By comparison, polymorphisms at rs8070723 (MAPT) had no effect on disease duration (p > 0.1), although carriers of protective allele (G) in rs8070723 had a younger median age at onset (AG/GG = 54.5 years, AA = 58 years; p < 0.01). MOBP RA+ patients had increased radial diffusivity in the superior corona radiata and midbrain, and reduced fractional anisotropy in the superior corona radiata as well as superior and inferior longitudinal fasciculi compared with noncarriers (p < 0.01). Conclusions: The rs1768208 risk polymorphism in MOBP may have prognostic value in bvFTD. MOBP RA+ patients have more severe white matter degeneration in bvFTD that may contribute to shorter disease duration. Future studies are needed to help confirm these findings. PMID:24994843

  18. Use of a circular mapping and ablation catheter for ablation of atypical right ventricular outflow tract arrhythmia.

    PubMed

    Katritsis, Demosthenes G; Giazitzoglou, Eleftherios; Paxinos, George

    2010-02-01

    A new technique for ablation of persistent ectopic activity with atypical electrocardiographic characteristics at the vicinity of the right ventricular outflow tract is described. A new circular mapping and ablation catheter initially designed for pulmonary vein ablation was used. Abolition of ectopic activity was achieved with minimal fluoroscopy and ablation times.

  19. Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF).

    PubMed

    Rittchen, Sonja; Boyd, Amanda; Burns, Alasdair; Park, Jason; Fahmy, Tarek M; Metcalfe, Su; Williams, Anna

    2015-07-01

    Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination. Impact statement Nanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS.

  20. Laser ablation in analytical chemistry - A review

    SciTech Connect

    Russo, Richard E.; Mao, Xianglei; Liu, Haichen; Gonzalez, Jhanis; Mao, Samuel S.

    2001-10-10

    Laser ablation is becoming a dominant technology for direct solid sampling in analytical chemistry. Laser ablation refers to the process in which an intense burst of energy delivered by a short laser pulse is used to sample (remove a portion of) a material. The advantages of laser ablation chemical analysis include direct characterization of solids, no chemical procedures for dissolution, reduced risk of contamination or sample loss, analysis of very small samples not separable for solution analysis, and determination of spatial distributions of elemental composition. This review describes recent research to understand and utilize laser ablation for direct solid sampling, with emphasis on sample introduction to an inductively coupled plasma (ICP). Current research related to contemporary experimental systems, calibration and optimization, and fractionation is discussed, with a summary of applications in several areas.

  1. Nanoscale ablation through optically trapped microspheres

    NASA Astrophysics Data System (ADS)

    Fardel, Romain; McLeod, Euan; Tsai, Yu-Cheng; Arnold, Craig B.

    2010-10-01

    The ability to directly create patterns with size scales below 100 nm is important for many applications where the production or repair of high resolution and density features is needed. Laser-based direct-write methods have the benefit of being able to quickly and easily modify and create structures on existing devices, but ablation can negatively impact the overall technique. In this paper we show that self-positioning of near-field objectives through the optical trap assisted nanopatterning (OTAN) method allows for ablation without harming the objective elements. Small microbeads are positioned in close proximity to a substrate where ablation is initiated. Upon ablation, these beads are temporarily displaced from the trap but rapidly return to the initial position. We analyze the range of fluence values for which this process occurs and find that there exists a critical threshold beyond which the beads are permanently ejected.

  2. Physical processes of laser tissue ablation

    NASA Astrophysics Data System (ADS)

    Furzikov, Nickolay P.

    1991-05-01

    The revised ablation model applicable to homogeneous tissues is presented. It is based on the thermal mechanism and involves the instability of the laserinduced evaporation (thermodestruction) front the growth of the surface ripple structure the interference of the laser wave and of the surface wave arising by diffraction on the ripples Beer''s law violation the pulsed thermodestruction of the organic structural component the tissue water boiling and gas dynamic expansion of the resulting products into the surrounding medium which is followed by the shock wave formation. The UV and IR ablation schemes were implemented and compared to the corneal ablation experiments. The initial ablation pressure and temperature are given restored from the timeofflight measurements of the supersonic expansion of the product. 1.

  3. Evolving Ablative Therapies for Hepatic Malignancy

    PubMed Central

    Hochwald, Steven N.

    2014-01-01

    The liver is a common site for both primary and secondary malignancy. Hepatic resection and transplantation are the two treatment modalities that have been shown to achieve complete cure, but only 10 to 20% of patients are candidates for these treatments. For the remaining patients, tumor ablation has emerged as the most promising alternative modality. In addition to providing local control and improving survival outcomes, tumor ablation also helps to down stage patients for potential curative treatments, both alone as well as in combination with other treatments. While tumor ablation can be achieved in multiple ways, the introduction of newer ablative techniques has shifted the focus from palliation to potentially curative treatment. Because the long-term safety and survival benefits are not substantive at present, it is important that we strive to evaluate the results from these studies using appropriate comparative outcome methodologies. PMID:24877069

  4. Thermal Ablation Modeling for Silicate Materials

    NASA Technical Reports Server (NTRS)

    Chen, Yih-Kanq

    2016-01-01

    A general thermal ablation model for silicates is proposed. The model includes the mass losses through the balance between evaporation and condensation, and through the moving molten layer driven by surface shear force and pressure gradient. This model can be applied in the ablation simulation of the meteoroid and the glassy ablator for spacecraft Thermal Protection Systems. Time-dependent axisymmetric computations are performed by coupling the fluid dynamics code, Data-Parallel Line Relaxation program, with the material response code, Two-dimensional Implicit Thermal Ablation simulation program, to predict the mass lost rates and shape change. The predicted mass loss rates will be compared with available data for model validation, and parametric studies will also be performed for meteoroid earth entry conditions.

  5. Pharmacological Tests in Atrial Fibrillation Ablation

    PubMed Central

    Gourraud, Jean-Baptiste; Andrade, Jason G; Macle, Laurent

    2016-01-01

    The invasive management of atrial fibrillation (AF) has been considerably changed by the identification of major sites of AF initiation and/or maintenance within the pulmonary vein antra. Percutaneous catheter ablation of these targets has become the standard of care for sustained maintenance of sinus rhythm. Long-term failure of ablation is related to an inability to create a durable transmural lesion or to identify all of the non-pulmonary vein arrhythmia triggers. Pharmacological challenges during catheter ablation have been suggested to improve outcomes in both paroxysmal and persistent AF. Herein we review the mechanism and evidence for the use of pharmacological adjuncts during the catheter ablation of AF. PMID:28116081

  6. Microwave Tissue Ablation: Biophysics, Technology and Applications

    PubMed Central

    2010-01-01

    Microwave ablation is an emerging treatment option for many cancers, cardiac arrhythmias and other medical conditions. During treatment, microwaves are applied directly to tissues to produce rapid temperature elevations sufficient to produce immediate coagulative necrosis. The engineering design criteria for each application differ, with individual consideration for factors such as desired ablation zone size, treatment duration, and procedural invasiveness. Recent technological developments in applicator cooling, power control and system optimization for specific applications promise to increase the utilization of microwave ablation in the future. This article will review the basic biophysics of microwave tissue heating, provide an overview of the design and operation of current equipment, and outline areas for future research for microwave ablation. PMID:21175404

  7. Indications and options for endometrial ablation.

    PubMed

    2008-11-01

    Endometrial ablation is an effective therapeutic option for the management of menorrhagia in properly selected patients. Hysteroscopic and non-hysteroscopic techniques offer similar rates of symptom relief and patient satisfaction.

  8. Percutaneous ablation of malignant thoracic tumors.

    PubMed

    Ghaye, B

    2013-01-01

    Lung cancer is the leading cause of death related to cancer. Fifteen to thirty percent of patients with a localized lung cancer are actually inoperable as they present with poor general condition, limited cardiopulmonary function, or a too high surgical risk. Therefore, minimally invasive treatments are needed and percutaneous ablation seems an attractive option. Thermal ablation can be performed by delivering heat (radiofrequency, microwave, laser) or cold (cryotherapy) through a needle inserted into the tumor under CT guidance. The ideal lesion is less than 2 or 3 cm in diameter. Success of percutaneous thermal ablation appears to be close to those of surgery for localized lung cancer. Nevertheless studies are still needed to definitely assess the role of ablation compared to other emerging techniques, as stereotactic radiotherapy as well as potential synergy with other treatments.

  9. Flexible Ablators: Applications and Arcjet Testing

    NASA Technical Reports Server (NTRS)

    Arnold, James O.; Venkatapathy, Ethiraj; Beck, Robin A S.; Mcguire, Kathy; Prabhu, Dinesh K.; Gorbunov, Sergey

    2011-01-01

    Flexible ablators were conceived in 2009 to meet the technology pull for large, human Mars Exploration Class, 23 m diameter hypersonic inflatable aerodynamic decelerators. As described elsewhere, they have been recently undergoing initial technical readiness (TRL) advancement by NASA. The performance limits of flexible ablators in terms of maximum heat rates, pressure and shear remain to be defined. Further, it is hoped that this emerging technology will vastly expand the capability of future NASA missions involving atmospheric entry systems. This paper considers four topics of relevance to flexible ablators: (1) Their potential applications to near/far term human and robotic missions (2) Brief consideration of the balance between heat shield diameter, flexible ablator performance limits, entry vehicle controllability and aft-body shear layer impingement of interest to designers of very large entry vehicles, (3) The approach for developing bonding processes of flexible ablators for use on rigid entry bodies and (4) Design of large arcjet test articles that will enable the testing of flexible ablators in flight-like, combined environments (heat flux, pressure, shear and structural tensile loading). Based on a review of thermal protection system performance requirements for future entry vehicles, it is concluded that flexible ablators have broad applications to conventional, rigid entry body systems and are enabling to large deployable (both inflatable and mechanical) heat shields. Because of the game-changing nature of flexible ablators, it appears that NASA's Office of the Chief Technologist (OCT) will fund a focused, 3-year TRL advancement of the new materials capable of performance in heat fluxes in the range of 200-600 W/sq. cm. This support will enable the manufacture and use of the large-scale arcjet test designs that will be a key element of this OCT funded activity.

  10. Resonant laser ablation: mechanisms and applications

    SciTech Connect

    Anderson, J.E.; Allen, T.M.; Garrett, A.W.; Gill, C.G.; Hemberger, P.H.; Kelly, P.B.; Nogar, N.S.

    1996-10-01

    We report on aspects of resonant laser ablation (RLA) behavior for a number of sample types: metals, alloys, thin films, zeolites and soil. The versatility of RLA is demonstrated, with results on a variety of samples and in several mass spectrometers. In addition, the application to depth profiling of thin films is described; absolute removal rates and detection limits are also displayed. A discussion of possible mechanisms for low-power ablation is presented.

  11. Percutaneous ablation of colorectal lung metastases

    PubMed Central

    Solomon, Stephen B.

    2015-01-01

    Lung metastasectomy can prolong survival in patients with metastatic colorectal carcinoma. Thermal ablation offers a potential solution with similar reported survival outcomes. It has minimal effect on pulmonary function, or quality of life, can be repeated, and may be considered more acceptable to patients because of the associated shorter hospital stay and recovery. This review describes the indications, technique, reported outcomes, complications and radiologic appearances after thermal ablation of colorectal lung metastases. PMID:26697202

  12. Co-culture of oligodendrocytes and neurons can be used to assess drugs for axon regeneration in the central nervous system

    PubMed Central

    Gang, Lin; Yao, Yu-chen; Liu, Ying-fu; Li, Yi-peng; Yang, Kai; Lu, Lei; Cheng, Yuan-chi; Chen, Xu-yi; Tu, Yue

    2015-01-01

    We present a novel in vitro model in which to investigate the efficacy of experimental drugs for the promotion of axon regeneration in the central nervous system. We co-cultured rat hippocampal neurons and cerebral cortical oligodendrocytes, and tested the co-culture system using a Nogo-66 receptor antagonist peptide (NEP1–40), which promotes axonal growth. Primary cultured oligodendrocytes suppressed axonal growth in the rat hippocampus, but NEP1–40 stimulated axonal growth in the co-culture system. Our results confirm the validity of the neuron-oligodendrocyte co-culture system as an assay for the evaluation of drugs for axon regeneration in the central nervous system. PMID:26692858

  13. Laser Ablated Carbon Nanodots for Light Emission.

    PubMed

    Reyes, Delfino; Camacho, Marco; Camacho, Miguel; Mayorga, Miguel; Weathers, Duncan; Salamo, Greg; Wang, Zhiming; Neogi, Arup

    2016-12-01

    The synthesis of fluorescent carbon dots-like nanostructures (CNDs) obtained through the laser ablation of a carbon solid target in liquid environment is reported. The ablation process was induced in acetone with laser pulses of 1064, 532, and 355 nm under different irradiation times. Close-spherical amorphous CNDs with sizes between 5 and 20 nm, whose abundance strongly depends on the ablation parameters were investigated using electron microscopy and was confirmed using absorption and emission spectroscopies. The π- π* electronic transition at 3.76 eV dominates the absorption for all the CNDs species synthesized under different irradiation conditions. The light emission is most efficient due to excitation at 3.54 eV with the photoluminescence intensity centered at 3.23 eV. The light emission from the CNDs is most efficient due to ablation at 355 nm. The emission wavelength of the CNDs can be tuned from the near-UV to the green wavelength region by controlling the ablation time and modifying the ablation and excitation laser wavelength.

  14. Pulsed HF laser ablation of dentin

    NASA Astrophysics Data System (ADS)

    Papagiakoumou, Eirini I.; Papadopoulos, Dimitris N.; Makropoulou, Mersini I.; Khabbaz, Maruan G.; Serafetinides, Alexander A.

    2005-03-01

    The interaction of a TEA (Transversally Excited Atmospheric pressure) corona preionized oscillator double amplifier HF (hydrogen fluoride) laser beam with dentin tissue is reported. Pulses of 39 ns in the wavelength range of 2.65-3.35 μm and output energies in the range of 10-45 mJ, in a predominantly TEM00 beam were used to interact with dentin tissue. Ablation experiments were conducted with the laser beam directly focused on the tissue. Several samples of freshly extracted human teeth were used, cut longitudinally in facets of about 1mm thick and stored in phosphate buffered saline after being cleaned from the soft tissue remains. The experimental data (ablation thresholds, ablation rates) are discussed with respect to the ablation mechanism(s). Adequate tissue removal was observed and the ablation behavior was, in the greates part of the available fluences, almost linear. From the microscopic examination of teh samples, in a scanning electron microscope (SEM), the irradiated surfaces displayed oval craters (reflecting the laser beam shape) with absence of any melting or carbonization zone. It is suggested that the specific laser removes hard tissue by a combined photothermal and plasma mediated ablation mechanism, leaving a surface free from thermal damage and with a well-shaped crater.

  15. [Catheter ablation of atrial fibrillation: Health Technology Assessment Report from the Italian Association of Arrhythmology and Cardiac Pacing (AIAC)].

    PubMed

    Themistoclakis, Sakis; Tritto, Massimo; Bertaglia, Emanuele; Berto, Patrizia; Bongiorni, Maria Grazia; Catanzariti, Domenico; De Fabrizio, Giuseppe; De Ponti, Roberto; Grimaldi, Massimo; Pandozi, Claudio; Tondo, Claudio; Gulizia, Michele

    2011-11-01

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and significantly impact patients' quality of life, morbidity and mortality. The number of affected patients is expected to increase as well as the costs associated with AF management, mainly driven by hospitalizations. Over the last decade, catheter ablation techniques targeting pulmonary vein isolation have demonstrated to be effective in treating AF and preventing AF recurrence. This Health Technology Assessment report of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) aims to define the current role of catheter ablation of AF in terms of effectiveness, efficiency and appropriateness. On the basis of an extensive review of the available literature, this report provides (i) an overview of the epidemiology, clinical impact and socio-economic burden of AF; (ii) an evaluation of therapeutic options other than catheter ablation of AF; and (iii) a detailed presentation of clinical outcomes and cost-benefit ratio associated with catheter ablation. The costs of catheter ablation of AF in Italy were obtained using a bottom-up analysis of a resource utilization survey of 52 hospitals that were considered a representative sample, including 4 Centers that contributed with additional unit cost information in a separate questionnaire. An analysis of budget impact was also performed to evaluate the impact of ablation on the management costs of AF. Results of this analysis show that (1) catheter ablation is effective, safe and superior to antiarrhythmic drug therapy in maintaining sinus rhythm; (2) the cost of an ablation procedure in Italy typically ranges from €8868 to €9455, though current reimbursement remains insufficient, covering only about 60% of the costs; (3) the costs of follow-up are modest (about 8% of total costs); (4) assuming an adjustment of reimbursement to the real cost of an ablation procedure and a 5-10% increase in the annual rate of ablation procedures, after

  16. Myocardial tissue ablation by single high-energy laser pulses for ELR and TMR

    NASA Astrophysics Data System (ADS)

    Theisen, Dirk; Brinkmann, Ralf; Stubbe, Hans-Martin; Birngruber, Reginald

    1999-02-01

    The objective of this study is to compare the ablation sites induced by two different laser and application systems for myocardial laser revascularization. One system used was an 800 W CO2 laser, which is clinically established for transmyocardial laser revascularization (TMR). The second system was a self-designed Holmium laser emitting single high energy pulses for the minimal invasive approach of endocardial laser revascularization (ELR), whereby the laser light is transmitted via optical fiber into the left ventricle to ablate the myocardial channels from the inside. The laser energy was applied to Polyacrylamide (PAA) as transparent tissue phantom and in water as blood phantom. The ablation dynamics were investigated by high speed flash photography recording a picture series of a single event. Reperfused ex- vivo porcine hearts were treated to quantify differences in the thermal-mechanical damage ranges by polarization light microscopy. Ablation dynamics in water revealed oscillatory changes of the axial length of the steam bubbles between 3 mm and 12 mm during the CO2 laser pulse. For the Holmium laser pulse a maximal axial and lateral length of 5 mm was observed. The lateral dimensions of the bubbles were maximal 1 mm with the CO2- and 3.5 mm with the Holmium laser system. In PAA bubbles also collapse during the laser pulse which affects the size of the ablated channels. Using 12 J Holmium laser pulses for ablation of PAA, channel depths around 7 mm were found. Single Holmium laser pulses demonstrate ablations comparable in size and thermal- mechanical collateral damage to those achieved with the standard CO2 laser. The results are very encouraging for single pulse ELR and demonstrate the potential of a catheter based minimal invasive procedure for laser heart reperfusion.

  17. Seeing the Invisible: Revealing Atrial Ablation Lesions Using Hyperspectral Imaging Approach

    PubMed Central

    Muselimyan, Narine; Swift, Luther M.; Asfour, Huda; Chahbazian, Tigran; Mazhari, Ramesh; Mercader, Marco A.; Sarvazyan, Narine A.

    2016-01-01

    Background Currently, there are limited means for high-resolution monitoring of tissue injury during radiofrequency ablation procedures. Objective To develop the next generation of visualization catheters that can reveal irreversible atrial muscle damage caused by ablation and identify viability gaps between the lesions. Methods Radiofrequency lesions were placed on the endocardial surfaces of excised human and bovine atria and left ventricles of blood perfused rat hearts. Tissue was illuminated with 365nm light and a series of images were acquired from individual spectral bands within 420-720nm range. By extracting spectral profiles of individual pixels and spectral unmixing, the relative contribution of ablated and unablated spectra to each pixel was then displayed. Results of spectral unmixing were compared to lesion pathology. Results RF ablation caused significant changes in the tissue autofluorescence profile. The magnitude of these spectral changes in human left atrium was relatively small (< 10% of peak fluorescence value), yet highly significant. Spectral unmixing of hyperspectral datasets enabled high spatial resolution, in-situ delineation of radiofrequency lesion boundaries without the need for exogenous markers. Lesion dimensions derived from hyperspectral imaging approach strongly correlated with histological outcomes. Presence of blood within the myocardium decreased the amplitude of the autofluorescence spectra while having minimal effect on their overall shapes. As a result, the ability of hyperspectral imaging to delineate ablation lesions in vivo was not affected. Conclusions Hyperspectral imaging greatly increases the contrast between ablated and unablated tissue enabling visualization of viability gaps at clinically relevant locations. Data supports the possibility for developing percutaneous hyperspectral catheters for high-resolution ablation guidance. PMID:27930718

  18. Dust ablation in Pluto's atmosphere

    NASA Astrophysics Data System (ADS)

    Horanyi, Mihaly; Poppe, Andrew; Sternovsky, Zoltan

    2016-04-01

    Based on measurements by dust detectors onboard the Pioneer 10/11 and New Horizons spacecraft the total production rate of dust particles born in the Edgeworth Kuiper Belt (EKB) has been be estimated to be on the order of 5 ṡ 103 kg/s in the approximate size range of 1 - 10 μm. Dust particles are produced by collisions between EKB objects and their bombardment by both interplanetary and interstellar dust particles. Dust particles of EKB origin, in general, migrate towards the Sun due to Poynting-Robertson drag but their distributions are further sculpted by mean-motion resonances as they first approach the orbit of Neptune and later the other planets, as well as mutual collisions. Subsequently, Jupiter will eject the vast majority of them before they reach the inner solar system. The expected mass influx into Pluto atmosphere is on the order of 200 kg/day, and the arrival speed of the incoming particles is on the order of 3 - 4 km/s. We have followed the ablation history as function of speed and size of dust particles in Pluto's atmosphere, and found that volatile rich particles can fully sublimate due to drag heating and deposit their mass in narrow layers. This deposition might promote the formation of the haze layers observed by the New Horizons spacecraft. This talk will explore the constraints on the composition of the dust particles by comparing the altitude of the deposition layers to the observed haze layers.

  19. Radiofrequency Ablation Beyond the Liver

    PubMed Central

    Neeman, Ziv; Wood, Bradford J.

    2008-01-01

    Radiofrequency ablation (RFA) has begun to show promise for extrahepatic indications. Although much of the reported work on image-guided RFA of liver neoplasms is quite promising, it is even earlier in the evaluation and validation process for extrahepatic RFA, with few short-term and no long-term studies reported. Although there are much more data for liver RFA with almost 3,000 cases reported in the literature, there are a number of ongoing investigations of RFA for tumors in the kidney, lung, bone, breast, bone, and adrenal gland. Debulking and pain control with RFA present palliative options becoming increasingly popular weapons in the interventionalist's oncology arsenal. Metastatic disease with a wide variety of primary histologies in a myriad of locations may be treated with RFA after a careful consideration of the risk-to-benefit ratio balance. The RFA technique can be slightly different outside the liver. Specifically, differing dielectric tissue characteristics may markedly alter the RFA treatment. Each different RFA system has a unique risk and advantage profile. Extrahepatic indications and contraindications will be suggested. Treatment tips and the unique complications and considerations will be introduced for some of the more common extrahepatic locations. PMID:12524646

  20. Plans and status of the Beryllium ablator campaign on NIF

    NASA Astrophysics Data System (ADS)

    Kline, J. L.; Yi, S. A.; Simakov, A. N.; Wilson, D. C.; Olson, R. E.; Krasheninnikova, N. S.; Kyrala, G. A.; Perry, T. S.; Batha, S. H.; Dewald, E. L.; Edwards, M. J.; MacKinnon, A. J.; Meezan, N. B.

    2014-10-01

    Beryllium has long been known to have excellent properties for indirectly driven ICF implosions including enhanced ablation pressure, implosion velocity, and mass ablation rate. The high ablation velocity leads to stabilization of ablative hydrodynamic instabilities and higher ablation pressures. Recent ``high foot'' experiments have shown ablative Rayleigh-Taylor to be a leading cause of degraded performance for ICF implosions. While Beryllium ablators have these advantages, there are also risks associated with Beryllium target designs. A campaign is underway to design and to test these advantages for comparison with other ablator options and determine which provides the best path forward for ICF. Experiments using Beryllium ablators are expected to start in the late summer of 2014. This presentation will discuss the status of the experiments and layout the plans/goals for the campaign. This work is supported by the US DOE.

  1. Percutaneous Microwave Ablation of Renal Angiomyolipomas

    SciTech Connect

    Cristescu, Mircea; Abel, E. Jason; Wells, Shane Ziemlewicz, Timothy J.; Hedican, Sean P.; Lubner, Megan G. Hinshaw, J. Louis Brace, Christopher L. Lee, Fred T.

    2016-03-15

    PurposeTo evaluate the safety and efficacy of US-guided percutaneous microwave (MW) ablation in the treatment of renal angiomyolipoma (AML).Materials and MethodsFrom January 2011 to April 2014, seven patients (5 females and 2 males; mean age 51.4) with 11 renal AMLs (9 sporadic type and 2 tuberous sclerosis associated) with a mean size of 3.4 ± 0.7 cm (range 2.4–4.9 cm) were treated with high-powered, gas-cooled percutaneous MW ablation under US guidance. Tumoral diameter, volume, and CT/MR enhancement were measured on pre-treatment, immediate post-ablation, and delayed post-ablation imaging. Clinical symptoms and creatinine were assessed on follow-up visits.ResultsAll ablations were technically successful and no major complications were encountered. Mean ablation parameters were ablation power of 65 W (range 60–70 W), using 456 mL of hydrodissection fluid per patient, over 4.7 min (range 3–8 min). Immediate post-ablation imaging demonstrated mean tumor diameter and volume decreases of 1.8 % (3.4–3.3 cm) and 1.7 % (27.5–26.3 cm{sup 3}), respectively. Delayed imaging follow-up obtained at a mean interval of 23.1 months (median 17.6; range 9–47) demonstrated mean tumor diameter and volume decreases of 29 % (3.4–2.4 cm) and 47 % (27.5–12.1 cm{sup 3}), respectively. Tumoral enhancement decreased on immediate post-procedure and delayed imaging by CT/MR parameters, indicating decreased tumor vascularity. No patients required additional intervention and no patients experienced spontaneous bleeding post-ablation.ConclusionOur early experience with high-powered, gas-cooled percutaneous MW ablation demonstrates it to be a safe and effective modality to devascularize and decrease the size of renal AMLs.

  2. A systematic review of surgical ablation versus catheter ablation for atrial fibrillation

    PubMed Central

    Kearney, Katherine; Stephenson, Rowan; Phan, Kevin; Chan, Wei Yen; Huang, Min Yin

    2014-01-01

    Background Atrial fibrillation (AF) is an increasingly prevalent condition in the ageing population, with significantly associated morbidity and mortality. Surgical and catheter ablative strategies both aim to reduce mortality and morbidity through freedom from AF. This review consolidates all currently available comparative data to evaluate these two interventions. Methods A systematic search was conducted across MEDLINE, PubMed, Embase, Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews from January 2000 until August 2013. All studies were critically appraised and only those directly comparing surgical and catheter ablation were included. Results Seven studies were deemed suitable for analysis according to the inclusion criteria. Freedom from AF was significantly higher in the surgical ablation group versus the catheter ablation group at 6-month, 12-month and study endpoint follow-up periods. Subgroup analysis demonstrated similar trends, with higher freedom from AF in the surgical ablation group for paroxysmal AF patients. The incidence of pacemaker implantation was higher, while no difference in stroke or cardiac tamponade was demonstrated for the surgical versus catheter ablation groups. Conclusions Current evidence suggests that epicardial ablative strategies are associated with higher freedom from AF, higher pacemaker implantation rates and comparable neurological complications and cardiac tamponade incidence to catheter ablative treatment. Other complications and risks were poorly reported, which warrants further randomized controlled trials (RCTs) of adequate power and follow-up duration. PMID:24516794

  3. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

    PubMed Central

    2011-01-01

    Background Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved. Results We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to

  4. Gene expression abnormalities and oligodendrocyte deficits in the internal capsule in schizophrenia.

    PubMed

    Kerns, David; Vong, Ghe S; Barley, Kevin; Dracheva, Stella; Katsel, Pavel; Casaccia, Patrizia; Haroutunian, Vahram; Byne, William

    2010-07-01

    Deficits in the expression of oligodendrocyte (Ol) and myelin genes have been described in numerous brain regions in schizophrenia (SZ) in association with abnormalities of cell cycle markers. We have previously reported a SZ-associated decrease in the expression of genes expressed after, but not prior to, the terminal differentiation of Ols in the posterior limb of the internal capsule (ICp). This pattern of deficits could reflect a failure of Ol precursors to exit the cell cycle and differentiate to meet the demands imposed by the high rate of apoptosis among myelinating Ols. Here we explore this hypothesis using quantitative real time PCR to examine the mRNA expression of additional genes in the ICp of the previously examined sample of 14 subjects with SZ and 15 normal controls (NCs). The genes examined in the present study were chosen because they are associated with particular phases of the cell cycle (CCND1, CCND2, p21(Cip1), p27(Kip1), and p57(Kip2)), with DNA replication and repair (PCNA), apoptosis (CASP3), or the Notch signaling pathway (JAG1, HES1, HES5, andDTX1). The Notch pathway influences whether Ol precursors continue to proliferate or exit the cell cycle. We also determined the densities of Ols in the ICp. Genes associated with maintenance of the cell cycle tended to exhibit increased expression levels in SZ relative to NCs and to be negatively correlated with the expression levels of the previously assessed mature Ol genes. In contrast, genes associated with cell cycle arrest tended to show the opposite pattern (decreased expression in SZ and positive correlations with mature Ol genes). CASP3 and PCNA expression levels were significantly decreased in SZ and positively correlated with mature Ol genes, suggesting that myelinating Ols may turnover more rapidly in normal controls than in subjects with SZ. JAG1 expression was significantly increased in SZ and exhibited positive correlations with mediators of the canonical Notch pathway but negative

  5. Transmission of 1064 nm laser radiation during ablation with an ultra-short pulse laser (USPL) system

    NASA Astrophysics Data System (ADS)

    Schelle, Florian; Meister, Jörg; Oehme, Bernd; Frentzen, Matthias

    2012-01-01

    During ablation of oral hard tissue with an USPL system a small amount of the incident laser power does not contribute to the ablation process and is being transmitted. Partial transmission of ultra-short laser pulses could potentially affect the dental pulp. The aim of this study was to assess the transmission during ablation and to deduce possible risks for the patient. The study was performed with an Nd:YVO4 laser, emitting pulses with a duration of 8 ps at a wavelength of 1064 nm. A repetition rate of 500 kHz and an average power of 9 W were chosen to achieve high ablation efficiency. A scanner system created square cavities with an edge length of 1 mm. Transmission during ablation of mammoth ivory and dentin slices with a thickness of 2 mm and 5 mm was measured with a power meter, placed directly beyond the samples. Effects on subjacent blood were observed by ablating specimens placed in contact to pork blood. In a separate measurement the temperature increase during ablation was monitored using an infrared camera. The influence of transmission was assessed by tuning down the laser to the corresponding power and then directly irradiating the blood. Transmission during ablation of 2 mm specimens was about 7.7% (ivory) and 9.6% (dentin) of the incident laser power. Ablation of specimens directly in contact to blood caused coagulation at longer irradiation times (t~18s). Direct irradiation of blood with the transmitted power provoked bubbling and smoke formation. Temperature measurements identified heat generation as the main reason for the observed coagulation.

  6. Investigation of low-cost ablative heat shield fabrication for space shuttles

    NASA Technical Reports Server (NTRS)

    Chandler, H. H.

    1972-01-01

    Improvements in the processes and design to reduce the manufacturing costs for low density ablative panels for the space shuttle are discussed. The areas that were studied included methods of loading honeycomb core, alternative reinforcement concepts, and the use of reusable subpanels. A review of previous studies on the fabrication of low-cost ablative panels and on permissible defects that do not affect thermal performance was conducted. Considerable differences in the quoted prices for ablative panels, even though the various contractors had reported similar fabrication times were discovered. How these cost differences arise from different estimating criteria and which estimating assumptions and other costs must be included in order to arrive at a realistic price are discussed.

  7. An overview of energy sources in clinical use for the ablation of atrial fibrillation.

    PubMed

    Comas, George M; Imren, Yildirim; Williams, Mathew R

    2007-01-01

    Recent years have seen many developments in the field of alternative energy sources for arrhythmia surgery. The impetus behind these advances is to replace the traditional, "cut-and-sew" Cox maze III procedure with lesion sets that are simpler, shorter, and safer but just as effective. There is demand for technology to make continuous, linear, transmural ablations reliably with a versatile energy source via an epicardial approach. This would make minimally invasive endoscopic surgical ablation of atrial fibrillation (AF) without cardiopulmonary bypass and with a closed chest feasible. These advances would shorten cardio-pulmonary bypass and improve outcomes in patients having surgical ablation and concomitant cardiac surgery. This review summarizes the technology behind alternative energy sources used to treat AF. Alternative energy sources include hypothermic sources (cryoablation) and hyperthermic sources (radiofrequency, microwave, laser, ultrasound). For each source, the biophysical background, mode of tissue injury, factors affecting lesion size, and advantages and complications are discussed.

  8. Protocol to Isolate a Large Amount of Functional Oligodendrocyte Precursor Cells from the Cerebral Cortex of Adult Mice and Humans

    PubMed Central

    Medina-Rodríguez, Eva María; Arenzana, Francisco Javier; Bribián, Ana; de Castro, Fernando

    2013-01-01

    During development, oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), a cell type that is a significant proportion of the total cells (3-8%) in the adult central nervous system (CNS) of both rodents and humans. Adult OPCs are responsible for the spontaneous remyelination that occurs in demyelinating diseases like Multiple Sclerosis (MS) and they constitute an interesting source of cells for regenerative therapy in such conditions. However, there is little data regarding the neurobiology of adult OPCs isolated from mice since an efficient method to isolate them has yet to be established. We have designed a protocol to obtain viable adult OPCs from the cerebral cortex of different mouse strains and we have compared its efficiency with other well-known methods. In addition, we show that this protocol is also useful to isolate functional OPCs from human brain biopsies. Using this method we can isolate primary cortical OPCs in sufficient quantities so as to be able to study their survival, maturation and function, and to facilitate an evaluation of their utility in myelin repair. PMID:24303061

  9. Myelin-oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex

    SciTech Connect

    Pham-Dinh, D.; Dautigny, A. ); Mattei, M.G.; Roeckel, N. ); Nussbaum, J.H.; Roussel, G. ); Pontarotti, P. ); Mather, I.H. ); Artzt, K. ); Lindahl, K.F. )

    1993-09-01

    Myelin/oligodendrocyte glycoprotein (MOG) is found on the surface of myelinating oligodendrocytes and external lamellae of myelin sheaths in the central nervous system, and it is target antigen in experimental autoimmune encephalomyelitis and multiple sclerosis. The authors have isolated bovine, mouse, and rat MOG cDNA clones and shown that the developmental pattern of MOG expression in the rat central nervous system coincides with the late stages of myelination. The amino-terminal, extracellular domain of MOG has characteristics of an immunoglobulin variable domain and is 46% and 41% identical with the amino terminus of bovine butyrophilin (expressed in the lactating mammary gland) and B-G antigens of the chicken major histocompatibility complex (MHC), respectively; these proteins thus form a subset of the immunoglobulin superfamily. The homology between MOG and B-G extends beyond their structure and genetic mapping to their ability to induce strong antibody responses and has implications for the role of MOG in pathological, autoimmune conditions. The authors colocalized the MOG and BT genes to the human MHC on chromosome 6p21.3-p22. The mouse MOG gene was mapped to the homologous band C of chromosome 17, within the M region of the mouse MHC. 38 refs., 6 figs.

  10. Transplantation of PDGF-AA-Overexpressing Oligodendrocyte Precursor Cells Promotes Recovery in Rat Following Spinal Cord Injury.

    PubMed

    Yao, Zong-Feng; Wang, Ying; Lin, Yu-Hong; Wu, Yan; Zhu, An-You; Wang, Rui; Shen, Lin; Xi, Jin; Qi, Qi; Jiang, Zhi-Quan; Lü, He-Zuo; Hu, Jian-Guo

    2017-01-01

    Our previous study showed that Schwann cells (SCs) promote survival, proliferation and migration of co-transplanted oligodendrocyte progenitor cells (OPCs) and neurological recovery in rats with spinal cord injury (SCI). A subsequent in vitro study confirmed that SCs modulated OPC proliferation and migration by secreting platelet-derived growth factor (PDGF)-AA and fibroblast growth factor-2 (FGF)-2. We also found that PDGF-AA stimulated OPC proliferation and their differentiation into oligodendrocytes (OLs) at later stages. We therefore speculated that PDGF-AA administration can exert the same effect as SC co-transplantation in SCI repair. To test this hypothesis, in this study we investigated the effect of transplanting PDGF-AA-overexpressing OPCs in a rat model of SCI. We found that PDGF-AA overexpression in OPCs promoted their survival, proliferation, and migration and differentiation into OLs in vivo. OPCs overexpressing PDGF-AA were also associated with increased myelination and tissue repair after SCI, leading to the recovery of neurological function. These results indicate that PDGF-AA-overexpressing OPCs may be an effective treatment for SCI.

  11. Transplantation of PDGF-AA-Overexpressing Oligodendrocyte Precursor Cells Promotes Recovery in Rat Following Spinal Cord Injury

    PubMed Central

    Yao, Zong-Feng; Wang, Ying; Lin, Yu-Hong; Wu, Yan; Zhu, An-You; Wang, Rui; Shen, Lin; Xi, Jin; Qi, Qi; Jiang, Zhi-Quan; Lü, He-Zuo; Hu, Jian-Guo

    2017-01-01

    Our previous study showed that Schwann cells (SCs) promote survival, proliferation and migration of co-transplanted oligodendrocyte progenitor cells (OPCs) and neurological recovery in rats with spinal cord injury (SCI). A subsequent in vitro study confirmed that SCs modulated OPC proliferation and migration by secreting platelet-derived growth factor (PDGF)-AA and fibroblast growth factor-2 (FGF)-2. We also found that PDGF-AA stimulated OPC proliferation and their differentiation into oligodendrocytes (OLs) at later stages. We therefore speculated that PDGF-AA administration can exert the same effect as SC co-transplantation in SCI repair. To test this hypothesis, in this study we investigated the effect of transplanting PDGF-AA-overexpressing OPCs in a rat model of SCI. We found that PDGF-AA overexpression in OPCs promoted their survival, proliferation, and migration and differentiation into OLs in vivo. OPCs overexpressing PDGF-AA were also associated with increased myelination and tissue repair after SCI, leading to the recovery of neurological function. These results indicate that PDGF-AA-overexpressing OPCs may be an effective treatment for SCI. PMID:28377695

  12. Insulin-like growth factor-I-stimulated Akt phosphorylation and oligodendrocyte progenitor cell survival require cholesterol-enriched membranes.

    PubMed

    Romanelli, Robert J; Mahajan, Kedar R; Fulmer, Clifton G; Wood, Teresa L

    2009-11-15

    Previously we showed that insulin-like growth factor-I (IGF-I) promotes sustained phosphorylation of Akt in oligodendrocyte progenitor cells (OPCs) and that Akt phosphorylation is required for survival of these cells. The direct mechanisms, however, by which IGF-I promotes Akt phosphorylation are currently undefined. Recently, cholesterol-enriched membranes (CEMs) have been implicated in regulation of growth factor-mediated activation of the PI3K/Akt pathway and survival of mature oligodendrocytes; however, less is know about their role in OPC survival. In the present study, we investigate the role of CEMs in IGF-I-mediated Akt phosphorylation and OPC survival. We report that acute disruption of membrane cholesterol with methyl-beta-cyclodextrin results in altered OPC morphology and inhibition of IGF-I-mediated Akt phosphorylation. We also report that long-term inhibition of cholesterol biosynthesis with 25-hydroxycholesterol blocks IGF-I stimulated Akt phosphorylation and cell survival. Moreover, we show that the PI3K regulatory subunit, p85, Akt, and the IGF-IR are sequestered within cholesterol-enriched fractions in steady-state stimulation of the IGF-IR and that phosphorylated Akt and IGF-IR are present in cholesterol-enriched fractions with IGF-I stimulation. Together, the results of these studies support a role for CEMs or "lipid rafts" in IGF-I-mediated Akt phosphorylation and provide a better understanding of the mechanisms by which IGF-I promotes OPC survival.

  13. Initiation of Oligodendrocyte Progenitor Cell Migration by a PDGF-A Activated Extracellular Regulated Kinase (ERK) Signaling Pathway

    PubMed Central

    Frost, Emma E.; Zhou, ZhiCheng; Krasnesky, Kimberley; Armstrong, Regina C.

    2009-01-01

    During CNS development, oligodendrocyte progenitor (OP) cells migrate from germinal zones to presumptive white matter tracts to generate myelinating oligodendrocytes. In vitro and in vivo studies indicate that platelet-derived growth factor-A (PDGF-A) is a potent chemoattractant for OP cells and important for normal distribution throughout the developing CNS. However, PDGF-A does not localize in concentration gradients corresponding to OP migratory pathways, as would be expected for a chemoattractant to direct migration. Therefore, the mechanism by which PDGF-A regulates OP distribution remains to be clarified. Here we show that PDGF-A induces OP migration and continuous exposure to PDGF-A is not required to maintain migration. Using pharmacological inhibitors, we show that a self-sustaining extracellular-regulated-kinase signaling pathway drives OP migration for up to 72 hours after the initial PDGF stimulus. These findings indicate PDGF-A may act to mobilize OP cells that then respond to distinct directional signals to distribute appropriately within the CNS. PMID:18512152

  14. Regulation of serum response factor by miRNA-200 and miRNA-9 modulates oligodendrocyte progenitor cell differentiation

    PubMed Central

    Buller, Benjamin; Chopp, Michael; Ueno, Yuji; Zhang, Li; Zhang, Rui Lan; Morris, Daniel; Zhang, Yi; Zhang, Zheng Gang

    2012-01-01

    Serum response factor (SRF) is a transcription factor that transactivates actin associated genes, and has been implicated in oligodendrocyte (OL) differentiation. To date, it has not been investigated in cerebral ischemia. We investigated the dynamics of SRF expression after stroke in vivo and the role of SRF in oligodendrocyte differentiation in vitro. Using immunohistochemistry, we found that SRF was upregulated in OLs and OL precursor cells (OPCs) after stroke. Moreover, upregulation of SRF was concurrent with downregulation of the microRNAs (miRNAs) miR-9 and the miR-200 family in the ischemic white matter region, the corpus callosum. Inhibition of SRF activation by CCG-1423, a specific inhibitor of SRF function, blocked OPCs from differentiating into OLs. Over-expression of miR-9 and miR-200 in cultured OPCs suppressed SRF expression and inhibited OPC differentiation. Moreover, co-expression of miR-9 and miR-200 attenuated activity of a luciferase reporter assay containing the Srf 3′ untranslated region (UTR). Collectively, this study is the first to show that stroke upregulates SRF expression in OPCs and OLs, and that SRF levels are mediated by miRNAs and regulate OPC differentiation. PMID:22907787

  15. Online monitoring of nanoparticles formed during nanosecond laser ablation

    NASA Astrophysics Data System (ADS)

    Nováková, Hana; Holá, Markéta; Vojtíšek-Lom, Michal; Ondráček, Jakub; Kanický, Viktor

    2016-11-01

    The particle size distribution of dry aerosol originating from laser ablation of glass material was monitored simultaneously with Laser Ablation - Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) analysis and two aerosol spectrometers - Fast Mobility Particle Sizer (FMPS) and Aerodynamic Particle Sizer (APS). The unique combination of LA-ICP-MS and FMPS offers the possibility of measuring the particle size distribution every 1 s of the ablation process in the size range of 5.6-560 nm. APS extends the information about particle concentration in the size range 0.54-17 μm. Online monitoring of the dry aerosol was performed for two ablation modes (spot and line with a duration of 80 s) with a 193 nm excimer laser system, using the glass reference material NIST 610 as a sample. Different sizes of laser spot for spot ablation and different scan speeds for line ablation were tested. It was found that the FMPS device is capable of detecting changes in particle size distribution at the first pulses of spot laser ablation and is suitable for laser ablation control simultaneously with LA-ICP-MS analysis. The studied parameters of laser ablation have an influence on the resulting particle size distribution. The line mode of laser ablation produces larger particles during the whole ablation process, while spot ablation produces larger particles only at the beginning, during the ablation of the intact layer of the ablated material. Moreover, spot ablation produces more primary nano-particles (in ultrafine mode size range < 100 nm) than line ablation. This effect is most probably caused by a reduced amount of large particles released from the spot ablation crater. The larger particles scavenge the ultrafine particles during the line ablation mode.

  16. Improvements of deep vein reflux following radiofrequency ablation for saphenous vein incompetence.

    PubMed

    Kim, Suh Min; Jung, In Mok; Chung, Jung Kee

    2017-02-01

    Objectives The aim of this study was to describe the changes of deep vein reflux after radiofrequency ablation for great saphenous vein incompetence. Method The data on 139 limbs which were treated with radiofrequency ablation for great saphenous vein incompetence were prospectively collected and reviewed. Results Deep vein reflux was present in 43 of 139 limbs (30.9%). There were no significant differences in the rate of successful closure, the incidence of procedure-related complications, and the improvements of symptoms and quality of life between the limbs with or without deep vein reflux. With a mean follow-up of 5.9 months, the peak reflux velocity and duration of reflux were improved in all limbs with deep vein reflux and it was completely corrected in 13 limbs (30.2%) after radiofrequency ablation. Conclusions The presence of deep vein reflux does not affect the treatment outcomes of radiofrequency ablation for great saphenous vein incompetence and is improved in all patients. Deep vein reflux is not a barrier to performing radiofrequency ablation.

  17. Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome.

    PubMed

    Xu, Meiyu; Kobets, Andrew; Du, Jung-Chieh; Lennington, Jessica; Li, Lina; Banasr, Mounira; Duman, Ronald S; Vaccarino, Flora M; DiLeone, Ralph J; Pittenger, Christopher

    2015-01-20

    Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼ 5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved ∼ 50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or d-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS.

  18. Tracking Perfluorocarbon Nanoemulsion Delivery by 19F MRI for Precise High Intensity Focused Ultrasound Tumor Ablation

    PubMed Central

    Shin, Soo Hyun; Park, Eun-Joo; Min, Changki; Choi, Sun Il; Jeon, Soyeon; Kim, Yun-Hee; Kim, Daehong

    2017-01-01

    Perfluorocarbon nanoemulsions (PFCNEs) have recently been undergoing rigorous study to investigate their ability to improve the therapeutic efficacy of tumor ablation by high intensity focused ultrasound (HIFU). For precise control of PFCNE delivery and thermal ablation, their accumulation and distribution in a tumor should be quantitatively analyzed. Here, we used fluorine-19 (19F) magnetic resonance imaging (MRI) to quantitatively track PFCNE accumulation in a tumor, and analyzed how intra-tumoral PFCNE quantities affect the therapeutic efficacy of HIFU treatment. Ablation outcomes were assessed by intra-voxel incoherent motion analysis and bioluminescent imaging up to 14 days after the procedure. Assessment of PFCNE delivery and treatment outcomes showed that 2-3 mg/mL of PFCNE in a tumor produces the largest ablation volume under the same HIFU insonation conditions. Histology showed varying degrees of necrosis depending on the amount of PFCNE delivered. 19F MRI promises to be a valuable platform for precisely guiding PFCNE-enhanced HIFU ablation of tumors. PMID:28255351

  19. Contact pulsed Nd:YAG ablation of human dentin: ablation rates and tissue effects

    NASA Astrophysics Data System (ADS)

    Harris, David M.; Yessik, Michael J.

    1994-09-01

    Dentin from freshly extracted human teeth was exposed to flashlamp pumped Nd:YAG pulses (100 microsecond(s) duration, 50 - 200 mJ/pulse) delivered through a flat cut fiberoptic in contact with the dentin surface. Ablation depth and volume were measured optically and confirmed with electron microscope morphometrics. Ablation depth increased with force applied at the fiber tip up to 5 - 10 g. Above this ablation depths were insensitive to applied force. Craters made in dental stone were deeper and narrower than those made in normal dentin. Ablation depths per pulse and volumes per pulse decrease as the number of pulses increase. This is more prominent for 200 mJ pulses. At 60 mJ the ablation depths are the same from 10 to 100 Hz repetition rates, although qualitative changes (collateral damage) are greater at higher repetition rates. A progressive increase in collateral damage is seen from the 1st through the 200th pulse.

  20. Radioiodine Remnant Ablation: A Critical Review

    PubMed Central

    Bal, Chandra Sekhar; Padhy, Ajit Kumar

    2015-01-01

    Radioiodine remnant ablation (RRA) is considered a safe and effective method for eliminating residual thyroid tissue, as well as microscopic disease if at all present in thyroid bed following thyroidectomy. The rationale of RRA is that in the absence of thyroid tissue, serum thyroglobulin (Tg) measurement can be used as an excellent tumor marker. Other considerations are like the presence of significant remnant thyroid tissue makes detection and treatment of nodal or distant metastases difficult. Rarely, microscopic disease in the thyroid bed if not ablated, in the future, could be a source of anaplastic transformation. On the other hand, microscopic tumor emboli in distant sites could be the cause of distant metastasis too. The ablation of remnant tissue would in all probability eliminate these theoretical risks. It may be noted that all these are unproven contentious issues except postablation serum Tg estimation that could be a good tumor marker for detecting early biochemical recurrence in long-term follow-up strategy. Radioactive iodine is administered as a form of “adjuvant therapy” for remnant ablation. There have been several reports with regard to the administered dose for remnant ablation. The first report of a prospective randomized clinical trial was published from India by a prospective randomized study conducted at the All India Institute of Medical Sciences, New Delhi in the year 1996. The study reported that increasing the empirical 131I initial dose to more than 50 mCi results in plateauing of the dose-response curve and thus, conventional high-dose remnant ablation needs critical evaluation. Recently, two important studies were published: One from French group and the other from UK on a similar line. Interestingly, all three studies conducted in three different geographical regions of the world showed exactly similar conclusion. The new era of low-dose remnant ablation has taken a firm scientific footing across the continents. PMID:26420983

  1. Photoacoustic characterization of radiofrequency ablation lesions

    NASA Astrophysics Data System (ADS)

    Bouchard, Richard; Dana, Nicholas; Di Biase, Luigi; Natale, Andrea; Emelianov, Stanislav

    2012-02-01

    Radiofrequency ablation (RFA) procedures are used to destroy abnormal electrical pathways in the heart that can cause cardiac arrhythmias. Current methods relying on fluoroscopy, echocardiography and electrical conduction mapping are unable to accurately assess ablation lesion size. In an effort to better visualize RFA lesions, photoacoustic (PA) and ultrasonic (US) imaging were utilized to obtain co-registered images of ablated porcine cardiac tissue. The left ventricular free wall of fresh (i.e., never frozen) porcine hearts was harvested within 24 hours of the animals' sacrifice. A THERMOCOOLR Ablation System (Biosense Webster, Inc.) operating at 40 W for 30-60 s was used to induce lesions through the endocardial and epicardial walls of the cardiac samples. Following lesion creation, the ablated tissue samples were placed in 25 °C saline to allow for multi-wavelength PA imaging. Samples were imaged with a VevoR 2100 ultrasound system (VisualSonics, Inc.) using a modified 20-MHz array that could provide laser irradiation to the sample from a pulsed tunable laser (Newport Corp.) to allow for co-registered photoacoustic-ultrasound (PAUS) imaging. PA imaging was conducted from 750-1064 nm, with a surface fluence of approximately 15 mJ/cm2 maintained during imaging. In this preliminary study with PA imaging, the ablated region could be well visualized on the surface of the sample, with contrasts of 6-10 dB achieved at 750 nm. Although imaging penetration depth is a concern, PA imaging shows promise in being able to reliably visualize RF ablation lesions.

  2. Catheter Ablation of Fascicular Ventricular Tachycardia

    PubMed Central

    Liu, Yaowu; Fang, Zhen; Yang, Bing; Kojodjojo, Pipin; Chen, Hongwu; Ju, Weizhu; Cao, Kejiang; Chen, Minglong

    2015-01-01

    Background— Fascicular ventricular tachycardia (FVT) is a common form of sustained idiopathic left ventricular tachycardia with an Asian preponderance. This study aimed to prospectively investigate long-term clinical outcomes of patients undergoing ablation of FVT and identify predictors of arrhythmia recurrence. Methods and Results— Consecutive patients undergoing FVT ablation at a single tertiary center were enrolled. Activation mapping was performed to identify the earliest presystolic Purkinje potential during FVT that was targeted by radiofrequency ablation. Follow-up with clinic visits, ECG, and Holter monitoring was performed at least every 6 months. A total of 120 consecutive patients (mean age, 29.3±12.7 years; 82% men; all patients with normal ejection fraction) were enrolled. FVT involved left posterior fascicle and left anterior fascicle in 118 and 2 subjects, respectively. VT was noninducible in 3 patients, and ablation was acutely successful in 117 patients. With a median follow-up of 55.7 months, VT of a similar ECG morphology recurred in 17 patients, and repeat procedure confirmed FVT recurrence involving the same fascicle. Shorter VT cycle length was the only significant predictor of FVT recurrence (P=0.03). Six other patients developed new-onset upper septal FVT that was successfully ablated. Conclusions— Ablation of FVT guided by activation mapping is associated with a single procedural success rate without the use of antiarrhythmic drugs of 80.3%. Arrhythmia recurrences after an initially successful ablation were caused by recurrent FVT involving the same fascicle in two thirds of patients or new onset of upper septal FVT in the remainder. PMID:26386017

  3. Subsurface ablation of atherosclerotic plaque using ultrafast laser pulses

    PubMed Central

    Lanvin, Thomas; Conkey, Donald B.; Frobert, Aurelien; Valentin, Jeremy; Goy, Jean-Jacques; Cook, Stéphane; Giraud, Marie-Noelle; Psaltis, Demetri

    2015-01-01

    We perform subsurface ablation of atherosclerotic plaque using ultrafast pulses. Excised mouse aortas containing atherosclerotic plaque were ablated with ultrafast near-infrared (NIR) laser pulses. Optical coherence tomography (OCT) was used to observe the ablation result, while the physical damage was inspected in histological sections. We characterize the effects of incident pulse energy on surface damage, ablation hole size, and filament propagation. We find that it is possible to ablate plaque just below the surface without causing surface damage, which motivates further investigation of ultrafast ablation for subsurface atherosclerotic plaque removal. PMID:26203381

  4. Subsurface ablation of atherosclerotic plaque using ultrafast laser pulses.

    PubMed

    Lanvin, Thomas; Conkey, Donald B; Frobert, Aurelien; Valentin, Jeremy; Goy, Jean-Jacques; Cook, Stéphane; Giraud, Marie-Noelle; Psaltis, Demetri

    2015-07-01

    We perform subsurface ablation of atherosclerotic plaque using ultrafast pulses. Excised mouse aortas containing atherosclerotic plaque were ablated with ultrafast near-infrared (NIR) laser pulses. Optical coherence tomography (OCT) was used to observe the ablation result, while the physical damage was inspected in histological sections. We characterize the effects of incident pulse energy on surface damage, ablation hole size, and filament propagation. We find that it is possible to ablate plaque just below the surface without causing surface damage, which motivates further investigation of ultrafast ablation for subsurface atherosclerotic plaque removal.

  5. New tumor ablation techniques for cancer treatment (microwave, electroporation).

    PubMed

    de Baere, T; Deschamps, F

    2014-01-01

    Since the introduction of radiofrequency ablation (RFA) for the treatment of liver tumors at the end of the 1990s, indications for local ablation techniques have been extended to other organs, in particular, the lungs, kidneys and bones. These techniques have also been improved, in particular to try and overcome the limitations of radiofrequency techniques, especially the significant decrease in complete ablation rates for tumors larger than 3cm and tumors that are contiguous to vessels larger than 3mm. Microwave ablation is a rapidly developing thermal ablation technique similar to RFA but with numerous differences. Electroporation, a non-thermal ablation technique with other possibilities, is in earlier stages of clinical development.

  6. pERK1/2 Peripheral Recruitment and Filopodia Protrusion Augment Oligodendrocyte Progenitor Cell Migration: Combined Effects of PDGF-A and Fibronectin.

    PubMed

    Tripathi, Ashutosh; Parikh, Zalak S; Vora, Parvez; Frost, Emma E; Pillai, Prakash P

    2017-03-01

    Oligodendrocyte progenitor cell (OPC) migration is critical for effective myelination of the central nervous system. Not only during normal myelination but also during remyelination, the growth factors (GFs) and extracellular matrix (ECM) protein affect the OPC migration. Studies showed the altered levels of GFs and ECM in the demyelinating lesions. In our earlier studies, we have shown that the effect of platelet-derived growth factor alpha (PDGF-A) on OPC migration is dose- and time-dependent. In that we have shown that the physiological concentration (1 ng/ml) of PDGF-A was unable to induce OPC migration at transient exposure (30 min). However, the involvement of ECM in the regulation of PDGF-A mediated OPC migration was not clear. In the present study, we have used fibronectin (FN) as ECM. PDGF-A and FN have similar and overlapping intracellular signaling pathways including the extracellular regulated kinases 1 and 2 (ERK1/2). Here we demonstrate how physiological concentration of PDGF-A combines with FN to augment OPC migration in vitro. The present study is first of its kind to show the importance of the synergistic effects of PDGF-A and FN on peripheral recruitment of phosphorylated/activated ERK1/2 (pERK1/2), actin-pERK1/2 co-localization, and filopodia formation, which are essential for the enhanced OPC migration. These findings were further confirmed by ERK1/2 inhibition studies, using the pharmacological inhibitor U0126. An understanding of these complex interactions may lead to additional strategies for transplanting genetically modified OPCs to repair widespread demyelinated lesions.

  7. Repeated Radiofrequency Ablation Combined With Ablated Lesion Elimination and Transarterial Chemoembolization Improves the Outcome of Solitary Huge Hepatocellular Carcinomas 10 cm or Larger

    PubMed Central

    Ke, Shan; Gao, Jun; Kong, Jian; Ding, Xue-Mei; Niu, Hai-Gang; Xin, Zong-Hai; Ning, Chun-Min; Guo, Shi-Gang; Li, Xiao-Long; Zhang, Long; Dong, Yong-Hong; Sun, Wen-Bing

    2016-01-01

    Abstract This study investigated the effectiveness of a new strategy, repeated radiofrequency (RF) ablation combined with ablated lesion elimination following transarterial chemoembolization (TACE)/transarterial embolization (TAE), for solitary huge hepatocellular carcinoma (SHHCC) 10 cm or larger. From July 2008 to October 2015, 39 consecutive patients with SHHCC were screened. Of these, 12 were treated with TACE/TAE and repeated RF ablation (TACE/TAE + RF ablation group) and the remaining 27 patients were treated with the aforementioned new strategy (new strategy group). Local tumor progression (LTP)-free survival, intrahepatic distant recurrence (IDR)-free survival, and overall survival (OS) rates were obtained using the Kaplan–Meier method. Univariate and multivariate analyses were performed on several clinicopathological variables to identify factors affecting long-term outcome and intrahepatic recurrence. Correlation analysis was also performed. The 1-, 2-, and 3-year LTP-free survival rates and OS rates were significantly higher in the new strategy group than in the TACE/TAE + RF ablation group (82.9% vs 58.3%, 73.9% vs 29.2%, 18.5% vs 9.7%, P = 0.002; 92.0% vs 75.0%, 8