title: Reduced inflammation accompanies diminished myelin damage and repair in the NG2 null mouse spinal cord.
abstract: BACKGROUND
  Multiple sclerosis (MS) is a demyelinating disease in which blood-derived immune cells and activated microglia damage myelin in the central nervous system. While oligodendrocyte progenitor cells (OPCs) are essential for generating oligodendrocytes for myelin repair, other cell types also participate in the damage and repair processes. The NG2 proteoglycan is expressed by OPCs, pericytes, and macrophages/microglia. In this report we investigate the effects of NG2 on these cell types during spinal cord demyelination/remyelination.
  
  
  METHODS
  Demyelinated lesions were created by microinjecting 1% lysolecithin into the lumbar spinal cord. Following demyelination, NG2 expression patterns in wild type mice were studied via immunostaining. Immunolabeling was also used in wild type and NG2 null mice to compare the extent of myelin damage, the kinetics of myelin repair, and the respective responses of OPCs, pericytes, and macrophages/microglia. Cell proliferation was quantified by studies of BrdU incorporation, and cytokine expression levels were evaluated using qRT-PCR.
  
  
  RESULTS
  The initial volume of spinal cord demyelination in wild type mice is twice as large as in NG2 null mice. However, over the ensuing 5 weeks there is a 6-fold improvement in myelination in wild type mice, versus only a 2-fold improvement in NG2 null mice. NG2 ablation also results in reduced numbers of each of the three affected cell types. BrdU incorporation studies reveal that reduced cell proliferation is an important factor underlying NG2-dependent decreases in each of the three key cell populations. In addition, NG2 ablation reduces macrophage/microglial cell migration and shifts cytokine expression from a pro-inflammatory to anti-inflammatory phenotype.
  
  
  CONCLUSIONS
  Loss of NG2 expression leads to decreased proliferation of OPCs, pericytes, and macrophages/microglia, reducing the abundance of all three cell types in demyelinated spinal cord lesions. As a result of these NG2-dependent changes, the course of demyelination and remyelination in NG2 null mice differs from that seen in wild type mice, with both myelin damage and repair being reduced in the NG2 null mouse. These studies identify NG2 as an important factor in regulating myelin processing, suggesting that therapeutic targeting of the proteoglycan might offer a means of manipulating cell behavior in demyelinating diseases.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. kkucharo@sanfordburnham.org
authors.forename: Karolina
authors.initials: K
authors.lastname: Kucharova
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Chang
authors.forename: Andrej
authors.initials: A
authors.lastname: Boor
authors.forename: Voon Wee
authors.initials: VW
authors.lastname: Yong
authors.forename: William B
authors.initials: WB
authors.lastname: Stallcup
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D012038:Regeneration / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008244:Lysophosphatidylcholines; D008840:Microfilament Proteins; D011509:Proteoglycans; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D000099216:Chondroitin Sulfate Proteoglycan 4; C491049:Aif1 protein, mouse
references.citation: Stem Cell Rev Rep. 2010 Dec;6(4):500-6
references.pmid: 20665128
references.citation: Neuron. 1997 Jul;19(1):197-203
references.pmid: 9247275
references.citation: Expert Rev Neurother. 2010 Mar;10(3):441-57
references.pmid: 20187865
references.citation: Nat Rev Immunol. 2003 Jan;3(1):23-35
references.pmid: 12511873
references.citation: Brain. 2010 Oct;133(10):2983-98
references.pmid: 20855416
references.citation: J Neurosci. 2011 Jan 19;31(3):1069-80
references.pmid: 21248132
references.citation: J Neurosci Res. 2002 Sep 15;69(6):826-36
references.pmid: 12205676
references.citation: Biochem Soc Trans. 1989 Apr;17(2):280-3
references.pmid: 2753204
references.citation: J Neurol Sci. 1977 Aug;33(1-2):31-43
references.pmid: 903788
references.citation: J Cell Biol. 2007 Jul 2;178(1):155-65
references.pmid: 17591920
references.citation: J Neurosci. 2000 Mar 15;20(6):2218-28
references.pmid: 10704497
references.citation: J Histochem Cytochem. 2008 Mar;56(3):295-303
references.pmid: 18040080
references.citation: Neuroscience. 1999;92(1):83-95
references.pmid: 10392832
references.citation: Neuroscience. 2010 Mar 10;166(1):185-94
references.pmid: 20006679
references.citation: J Neural Transm (Vienna). 2010 Aug;117(8):907-17
references.pmid: 20571836
references.citation: J Neurol Sci. 2004 Feb 15;217(2):125-30
references.pmid: 14706213
references.citation: J Cell Sci. 1972 Mar;10(2):535-46
references.pmid: 5018033
references.citation: Mult Scler. 1998 Jun;4(3):162-8
references.pmid: 9762667
references.citation: J Neurosci. 2007 Oct 3;27(40):10714-21
references.pmid: 17913905
references.citation: Curr Top Microbiol Immunol. 2008;318:193-212
references.pmid: 18219819
references.citation: Angiogenesis. 2004;7(3):269-76
references.pmid: 15609081
references.citation: J Neuropathol Exp Neurol. 1997 Nov;56(11):1191-201
references.pmid: 9370229
references.citation: J Neurosci Res. 2008 Jul;86(9):1972-80
references.pmid: 18438913
references.citation: Mult Scler. 2011 Jan;17(1):2-15
references.pmid: 20813772
references.citation: Curr Opin Neurobiol. 2006 Oct;16(5):515-21
references.pmid: 16962768
references.citation: Glia. 2000 Mar;30(1):92-104
references.pmid: 10696148
references.citation: Neuroscience. 2010 Jan 20;165(2):386-94
references.pmid: 19878709
references.citation: Mol Biol Cell. 2004 Aug;15(8):3580-90
references.pmid: 15181153
references.citation: Stem Cells Dev. 2011 Dec;20(12):2065-76
references.pmid: 21299379
references.citation: J Neurocytol. 2002 Jul-Aug;31(6-7):437-55
references.pmid: 14501215
references.citation: Neuroscientist. 2010 Aug;16(4):408-20
references.pmid: 20817918
references.citation: J Biol Chem. 2004 Dec 31;279(53):55262-70
references.pmid: 15504744
references.citation: Dev Dyn. 2001 Oct;222(2):218-27
references.pmid: 11668599
references.citation: Cell Stem Cell. 2008 Sep 11;3(3):301-13
references.pmid: 18786417
references.citation: J Biol Chem. 1999 Jun 11;274(24):16831-7
references.pmid: 10358027
references.citation: Prog Brain Res. 2009;175:453-64
references.pmid: 19660673
references.citation: Dev Biol. 2010 Aug 15;344(2):1035-46
references.pmid: 20599895
references.citation: J Neuroimmunol. 2009 Apr 30;209(1-2):6-15
references.pmid: 19233483
references.citation: Neuroscientist. 2002 Dec;8(6):586-95
references.pmid: 12467380
references.citation: Neurology. 2001 Aug 28;57(4):681-5
references.pmid: 11524479
references.citation: Ment Retard Dev Disabil Res Rev. 2006;12(2):85-96
references.pmid: 16807909
references.citation: Exp Neurol. 2005 Apr;192(2):299-309
references.pmid: 15755547
references.citation: Science. 2004 Dec 17;306(5704):2111-5
references.pmid: 15604411
references.citation: Nat Rev Neurosci. 2002 Sep;3(9):705-14
references.pmid: 12209119
references.citation: J Cell Sci. 1999 Mar;112 ( Pt 6):905-15
references.pmid: 10036240
references.citation: Cell Adh Migr. 2008 Jul-Sep;2(3):192-201
references.pmid: 19262111
references.citation: Clin Neurol Neurosurg. 2006 Mar;108(3):241-4
references.pmid: 16388896
references.citation: J Neurocytol. 2002 Jul-Aug;31(6-7):551-65
references.pmid: 14501223
references.citation: Neurosci Lett. 2010 Feb 5;470(1):65-70
references.pmid: 20036712
references.citation: Glia. 1999 Mar;26(1):84-91
references.pmid: 10088675
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4355-9
references.pmid: 19255448
references.citation: J Neurocytol. 2002 Jul-Aug;31(6-7):423-35
references.pmid: 14501214
references.citation: Cell Stem Cell. 2008 Sep 11;3(3):229-30
references.pmid: 18786406
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11062-7
references.pmid: 20534485
references.citation: Nat Neurosci. 2004 Jan;7(1):24-32
references.pmid: 14661022
references.citation: Biochim Biophys Acta. 2011 Feb;1812(2):184-93
references.pmid: 20887785
references.citation: J Neurosci Res. 2000 Sep 1;61(5):471-9
references.pmid: 10956416