FTY720 modulates human oligodendrocyte progenitor process extension and survival
Article first published online: 4 OCT 2007
Copyright © 2007 American Neurological Association
Annals of Neurology
Volume 63, Issue 1, pages 61–71, January 2008
How to Cite
Miron, V. E., Jung, C. G., Kim, H. J., Kennedy, T. E., Soliven, B. and Antel, J. P. (2008), FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol., 63: 61–71. doi: 10.1002/ana.21227
- Issue published online: 29 JAN 2008
- Article first published online: 4 OCT 2007
- Manuscript Accepted: 3 AUG 2007
- Manuscript Revised: 29 JUN 2007
- Manuscript Received: 6 APR 2007
- Foundation of the Multiple Sclerosis Society of Canada
- Fondation de Reserche en Sante du Quebec
- Natural Sciences and Engineering Research Council of Canada
- Canadian Institutes of Health Research
- National Institute of Neurological Disorders and Stroke. Grant Number: R21 NS049014
- National MS Society
FTY720, a sphingosine-1-phosphate (S1P) receptor agonist that crosses the blood–brain barrier, is a potential immuno-therapy for multiple sclerosis. Our objective was to assess the effect of FTY720 on process extension, differentiation, and survival of human oligodendrocyte progenitor cells (OPCs), and link the functional effects with S1P receptor expression and signaling.
Functional assays and receptor expression studies were conducted on A2B5+ OPCs derived from the human fetal central nervous system. Cells were treated with physiologically relevant concentrations of the active phosphorylated form of FTY720. S1P receptor/signaling modulators were used to elucidate the basis of the FTY720-induced functional responses.
Short-term (1 day) FTY720 treatment caused initial process retraction that was reversed by uncoupling S1P3 and 5 from their G protein using suramin, and with a Rho-kinase inhibitor H1152. Retraction was associated with RhoA-mediated cytoskeletal signaling and with inhibition of OPC differentiation into more mature phenotypes. Continued FTY720 treatment (2 days) induced process extension and enhanced cell survival associated with increased extracellular signal-regulated kinases 1 and 2 phosphorylation, mimicked with the S1P1-specific agonist SEW2871, but not reversed with suramin. Quantitative real-time polymerase chain reaction showed that FTY720 induced reciprocal and cyclic modulation of S1P1 and S1P5 messenger RNA levels. The observed initial downregulation of S1P5 and subsequently of S1P1 messenger RNA supports functional responses being mediated sequentially by S1P5- and later S1P1-associated signaling.
FTY720 induces time-dependent modulation of S1P receptors on human OPCs with consequent functional responses that are directly relevant for the remyelination process. Ann Neurol 2007