FTY720 modulates human oligodendrocyte progenitor process extension and survival.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
FTY720 induces time-dependent modulation of S1P receptors on human OPCs with consequent functional responses that are directly relevant for the remyelination process.
Miron
Veronique E
VE
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Jung
Cha Gyun
CG
Kim
Hye Jung
HJ
Kennedy
Timothy E
TE
Soliven
Betty
B
Antel
Jack P
JP
D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D022081:Cell Surface Extensions / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013498:Suramin; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine