title: Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination.
abstract: OBJECTIVE
  Failure of remyelination is a critical impediment to recovery in multiple sclerosis (MS). Chondroitin sulfate proteoglycans (CSPGs) have been reported to accumulate in MS lesions, and we thus examined the functional roles of CSPGs on oligodendrocyte precursor cells (OPCs), oligodendrocytes, and remyelination.
  
  
  METHODS
  We evaluated the expression of CSPGs in lysolecithin-injected mouse spinal cord, an animal model of demyelination and spontaneous remyelination. The functional impact of CSPGs on OPCs and remyelination was investigated using cultured adult murine and human OPCs and by treating demyelinated mice with xyloside to reduce the CSPG deposition that occurred following injury.
  
  
  RESULTS
  Early and robust upregulation of CSPGs following lysolecithin-induced demyelination was cleared during remyelination. In culture, CSPGs anchored onto the substratum reduced the adhesion of mouse and human OPCs and their subsequent morphological differentiation into process-bearing oligodendrocytes. Soluble CSPGs added to already adherent OPCs reduced the development of processes, whereas the acquisition of mature myelin proteins was unimpeded. Stripe assays of alternating CSPG and control substrata confirmed the nonpermissive nature of CSPGs for OPC adhesion and morphological differentiation. Enzymatic degradation of CSPGs with chondroitinase ABC was sufficient to overcome CSPG-dependent inhibition of human oligodendrocytes. Finally, in vivo xyloside treatment to reduce CSPG synthesis in lysolecithin-demyelinated mice increased numbers of OPCs and oligodendrocytes in lesions, and culminated in improved remyelination.
  
  
  CONCLUSIONS
  These results identify CSPGs as a nonpermissive substrate for OPCs and oligodendrocytes, and as a prominent impediment to remyelination. The data suggest the requirement for the neutralization of CSPGs for repair after demyelination.
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta.
authors.forename: Lorraine W
authors.initials: LW
authors.lastname: Lau
authors.forename: Michael B
authors.initials: MB
authors.lastname: Keough
authors.forename: Sarah
authors.initials: S
authors.lastname: Haylock-Jacobs
authors.forename: Rowena
authors.initials: R
authors.lastname: Cua
authors.forename: Axinia
authors.initials: A
authors.lastname: Döring
authors.forename: Scott
authors.initials: S
authors.lastname: Sloka
authors.forename: David P
authors.initials: DP
authors.lastname: Stirling
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism* / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000178:diet therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006027:Glycosides / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles; D008244:Lysophosphatidylcholines / Q000633:toxicity; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D011508:Chondroitin Sulfate Proteoglycans; D005904:Glial Fibrillary Acidic Protein; D006027:Glycosides; D007211:Indoles; D008244:Lysophosphatidylcholines; D008840:Microfilament Proteins; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; C010807:xylosides; C018588:Luxol Fast Blue MBS; D019765:Chondroitin ABC Lyase