首页 | 本学科首页   官方微博 | 高级检索  
   检索      


Unconjugated Bilirubin Restricts Oligodendrocyte Differentiation and Axonal Myelination
Authors:Andreia Barateiro  Veronique E Miron  Sofia D Santos  João B Relvas  Adelaide Fernandes  Charles ffrench-Constant  Dora Brites
Institution:1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal
2. MRC Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK
3. Instituto de Biologia Molecular e Celular, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal
4. Departamento de Biologia Experimental, Faculty of Medicine, University of Porto, Av. Prof. Hernani Monteiro, 4200-319, Porto, Portugal
5. Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal
Abstract:High levels of serum unconjugated bilirubin (UCB) in newborns are associated with axonal damage and glial reactivity that may contribute to subsequent neurologic injury and encephalopathy (kernicterus). Impairments in myelination and white matter damage were observed at autopsy in kernicteric infants. We have recently reported that UCB reduces oligodendrocyte progenitor cell (OPC) survival in a pure OPC in vitro proliferative culture. Here, we hypothesized that neonatal hyperbilirubinemia may also impair oligodendrocyte (OL) maturation and myelination. We used an experimental model of hyperbilirubinemia that has been shown to mimic the pathophysiological conditions leading to brain dysfunction by unbound (free) UCB. Using primary cultures of OL, we demonstrated that UCB delays cell differentiation by increasing the OPC number and reducing the number of mature OL. This finding was combined with a downregulation of Olig1 mRNA levels and upregulation of Olig2 mRNA levels. Addition of UCB, prior to or during differentiation, impaired OL morphological maturation, extension of processes and cell diameter. Both conditions reduced active guanosine triphosphate (GTP)-bound Rac1 fraction. In myelinating co-cultures of dorsal root ganglia neurons and OL, UCB treatment prior to the onset of myelination decreased oligodendroglial differentiation and the number of myelinating OL, also observed when UCB was added after the onset of myelination. In both circumstances, UCB decreased the number of myelin internodes per OL, as well as the myelin internode length. Our studies demonstrate that increased concentrations of UCB compromise myelinogenesis, thereby elucidating a potential deleterious consequence of elevated UCB.
Keywords:
本文献已被 SpringerLink 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号