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OL Differentiation (ol + differentiation)
Selected AbstractsHuman remyelination promoting antibody inhibits apoptotic signaling and differentiation through Lyn kinase in primary rat oligodendrocytesGLIA, Issue 15 2010J. Watzlawik Abstract Purpose: Human remyelination promoting IgM mAbs target oligodendrocytes (OLs) and function in animal models of multiple sclerosis (MS). However, their mechanism of action is unknown. This study seeks to identify the cellular mechanism of action of a recombinant human IgM on OL survival. Methods: Binding of rHIgM22 to the surface of rat OLs was studied by co-localization with various markers. RHIgM22-mediated effects on apoptotic signaling in OLs, differentiation markers, and signaling molecules were detected by Western blotting and immunoprecipitation. Results: RHIgM22 co-localized with integrin ,3 but not other integrin ,-chains in OLs. Downstream of integrin ,3 we identified Src family kinase (SFK) Lyn as a key player of rHIgM22-mediated actions in OLs. Lyn immunoprecipitated in a complex together with integrin ,v,3 and PDGF,R. Lyn expression was 9-fold up-regulated and Lyn activation was 3-fold higher inrHIgM22-treated OL cultures compared with controls. RHIgM22 inhibited apoptotic signaling by greater than 10-fold reduction of caspase-3 and capsase-9 cleavage and reduced by 4-fold expression of differentiation markers MBP and MOG in OLs. SFK inhibitors PP2 and SU6656 inhibited Lyn activity and restored caspase-cleavage in OLs. A human IgM that did not promote remyelination and medium wereused as controls. Conclusions: rHIgM22 prevented apoptotic signaling andinhibited OL differentiation by Lyn implying thatIgM-mediated remyelination is due toprotection of OPC and OLs rather than promotion of OPC differentiation. © 2010 Wiley-Liss, Inc. [source] Activation of PPAR-, and PTEN cascade participates in lovastatin-mediated accelerated differentiation of oligodendrocyte progenitor cellsGLIA, Issue 14 2010Ajaib S. Paintlia Abstract Previously, we and others documented that statins including-lovastatin (LOV) promote the differentiation of oligodendrocyte progenitor cells (OPCs) and remyelination in experimental autoimmune encephalomyelitis (EAE), an multiple sclerosis (MS) model. Conversely, some recent studies demonstrated that statins negatively influence oligodendrocyte (OL) differentiation in vitro and remyelination in a cuprizone-CNS demyelinating model. Therefore, herein, we first investigated the cause of impaired differentiation of OLs by statins in vitro settings. Our observations indicated that the depletion of cholesterol was detrimental to LOV treated OPCs under cholesterol/serum-deprived culture conditions similar to that were used in conflicting studies. However, the depletion of geranylgeranyl-pp under normal cholesterol homeostasis conditions enhanced the phenotypic commitment and differentiation of LOV-treated OPCs ascribed to inhibition of RhoA-Rho kinase. Interestingly, this effect of LOV was associated with increased activation and expression of both PPAR-, and PTEN in OPCs as confirmed by various pharmacological and molecular based approaches. Furthermore, PTEN was involved in an inhibition of OPCs proliferation via PI3K-Akt inhibition and induction of cell cycle arrest at G1 phase, but without affecting their cell survival. These effects of LOV on OPCs in vitro were absent in the CNS of normal rats chronically treated with LOV concentrations used in EAE indicating that PPAR-, induction in normal brain may be tightly regulated-providing evidences that statins are therapeutically safe for humans. Collectively, these data provide initial evidence that statin-mediated activation of the PPAR-,-PTEN cascade participates in OL differentiation, thus suggesting new therapeutic-interventions for MS or related CNS-demyelinating diseases. © 2010 Wiley-Liss, Inc. [source] Regulation of development of oligodendrocytesJOURNAL OF NEUROCHEMISTRY, Issue 2002K. Ikenaka Oligodendrocyte (OL) is the myelin-forming glial cell in the central nervous system. In the spinal cord, molecular markers for OL precursor cells (OPCs), such as PDGF a-receptor (PDGFR a), are first expressed in a strictly restricted focus of the ventral ventricular lumen at E12.5 in mouse and later spread throughout the cord. To investigate how they originate from these specific regions, we used an explant culture system of E12 mouse cervical spinal cord. When we cultured the ventral and dorsal spinal cords separately, a robust increase in the number of O4+ cells was observed in the ventral fragment. This phenomenon suggests the presence of factors inhibiting OL development from dorsal spinal cord. BMP4 is secreted from dorsal spinal cord and is a strong candidate for this factor; however, it did not affect OL development in our system. Here we show that Wnt-1 and Wnt-3a, in contrast, may have a role in OL maturation. The developmental profile of wnt-1/3a gene expressions in the dorsal spinal cord showed a significant correlation with that of the dorsal activity, which was very strong at E11, and then reduced to an undetectable level by E14. When Wnt-3a was added to the dissociation culture prepared from E14 mouse ventral cervical cords, the numbers of OL decreased. b-Catenin and LEF family proteins are known to form a transcription factor complex at the down stream of Wnt signalling. OL,like differentiation of CG4 cells was inhibited by constitutively active LEF-b-Catenin, supporting the idea that Wnt signalling directly inhibits OL differentiation. [source] Agonists specific for the transcription factor PPARdelta accelerate differentiation of oligodendrocytesJOURNAL OF NEUROCHEMISTRY, Issue 2002R. P. Skoff Peroxisome proliferator activated receptors (PPARs) are transcription factors belonging to the nuclear hormone receptor superfamily that regulate key genes involved in lipid metabolism. PPAR, is ubiquitously expressed at low levels in many tissues and its function has remained elusive. However, we have shown that PPAR, is abundantly expressed in oligodendrocytes (Ols), suggesting this receptor plays a critical role in oligodendrocyte differentiation (Granneman et al. 1998 J. Neurosci. Res51, 563). We first investigated the effects of PPAR agonists on proliferation and differentiation of Ols in tissue culture. Primary glial and enriched Ol cultures were treated with ligands that specifically activate PPAR, and PPAR, (Berger et al. 1999 J. Biol. Chem. 274, 6717). PPAR, but not PPAR, agonists increased the size of OL membrane sheets within 24 h of application. The increase in membrane sheet size was mirrored by increases in MBP and PLP mRNA's. In enriched Ol cultures, the number of Ols was increased 70% with the PPAR, agonist but not the PPAR, agonist (Saluja et al. 2001 Glia33, 191). In vivo injections of PPAR, agonist into P2 and P3 mice show an increase of total macroglia in the ventral and dorsal funiculi of the spinal cord of 20,40% compared to controls. Preliminary observations suggest the Ols in agonist treated cultures are larger and more densely stained than controls. Our results show for the first time that a specific ligand for a transcription factor is capable of activating the program of Ol differentiation. Acknowledgements: Supported by NMSS. [source] | ||||||||||