title: Bone morphogenetic protein signaling and olig1/2 interact to regulate the differentiation and maturation of adult oligodendrocyte precursor cells.
abstract: Promotion of remyelination is an important therapeutic strategy for the treatment of the demyelinating neurological disorders. Adult oligodendrocyte precursor cells (OPCs), which normally reside quiescently in the adult central nervous system (CNS), become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited because of the failure of adult OPCs to mature into myelinating oligodendrocytes (OLs) in the demyelinated CNS. Understanding the molecular mechanisms that regulate the differentiation of adult OPCs could lead to new therapeutic strategies to treat these disorders. In this study, we established a stable culture of adult spinal cord OPCs and developed a reliable in vitro protocol to induce their sequential differentiation. Adult OPCs expressed bone morphogenetic protein (BMP) type Ia, Ib, and II receptor subunits, which are required for BMP signal transduction. BMP2 and 4 promoted dose-dependent astrocyte differentiation of adult OPCs with concurrent suppression of OL differentiation. Treatment of OPCs with BMP2 and 4 increased ID4 expression and decreased the expression of olig1 and olig2. Overexpression of olig1 or olig2 blocked the astrocyte differentiation of adult OPCs induced by BMP2 and 4. Furthermore, overexpression of both olig1 and olig2, but not olig1 or olig2 alone, rescued OL differentiation from inhibition by BMP2 and 4. Our results demonstrated that downregulation of olig1 and olig2 is an important mechanism by which BMP2 and 4 inhibit OL differentiation of adult OPCs. These data suggest that blocking BMP signaling combined with olig1/2 overexpression could be a useful therapeutic strategy to enhance endogenous remyelination and facilitate functional recovery in CNS demyelinated disorders. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, MDR 616, 511 South Floyd Street, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Cheng
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: He
authors.forename: Mengsheng
authors.initials: M
authors.lastname: Qiu
authors.forename: Scott R
authors.initials: SR
authors.lastname: Whittemore
authors.forename: Qilin
authors.initials: Q
authors.lastname: Cao
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D006131:Growth Inhibitors; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C498633:Olig1 protein, rat; C522729:Olig2 protein, rat