title: Myelin inhibits oligodendroglial maturation and regulates oligodendrocytic transcription factor expression.
abstract: Myelin loss is a hallmark of multiple sclerosis (MS) and promoting central nervous system myelin repair has become a major therapeutic target. Despite the presence of oligodendrocytes precursors cells (OPCs) in chronic lesions of MS, remyelination often fails. The mechanism underlying this failure of remyelination remains unknown, but it is hypothesized that environmental cues act to inhibit the maturation/differentiation of oligodendroglia, preventing remyelination. The rate of CNS remyelination is correlated to the speed of phagocytosis of myelin debris, which is present following demyelination and trauma. Thus, myelin debris could inhibit CNS remyelination. Here, we demonstrate that OPCs cultured on myelin were robustly inhibited in their maturation, as characterized by the decreased expression of immature and mature oligodendrocytes markers, the impaired production of myelin gene products, as well as their stalled morphological complexity relative to OPCs cultured on a control substrate. OPCs in contact with myelin stopped proliferating and decreased the expression of OPC markers to a comparable degree as cells grown on a control substrate. The expression of two transcription factors known to prevent OPC differentiation and maturation were increased in cells that were in contact with myelin: inhibitor of differentiation family (ID) members 2 and 4. Overexpression of ID2 and ID4 in OPCs was previously reported to decrease the percentage of cells expressing mature oligodendrocyte markers. However, knockdown of ID2 and/or ID4 in OPCs did not increase oligodendroglial maturation on or off of myelin, suggesting that contact with myelin regulates additional regulatory elements.
authors.affiliation: ICORD (International Collaboration on Repair Discoveries), Blusson Spinal Cord Centre, Vancouver, British Columbia, Canada.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Plemel
authors.forename: Sohrab B
authors.initials: SB
authors.lastname: Manesh
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Sparling
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tetzlaff
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism; D039902:Multipotent Stem Cells; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D019081:O Antigens / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
chemical_list: C497451:Id2 protein, rat; C490126:Id4 protein, rat; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D004676:Myelin Basic Protein; D019081:O Antigens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571339:Cnp protein, rat
keywords: myelin; oligodendrocyte; oligodendrocyte precursor cell; remyelination; transcription factor