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FTY720 modulates human oligodendrocyte progenitor process extension and survival.
Ann Neurol. 2008 Jan; 63(1):61-71.AN

Abstract

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.

INTERPRETATION

FTY720 induces time-dependent modulation of S1P receptors on human OPCs with consequent functional responses that are directly relevant for the remyelination process.

Authors+Show Affiliations

Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17918267

Citation

Miron, Veronique E., et al. "FTY720 Modulates Human Oligodendrocyte Progenitor Process Extension and Survival." Annals of Neurology, vol. 63, no. 1, 2008, pp. 61-71.
Miron VE, Jung CG, Kim HJ, et al. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol. 2008;63(1):61-71.
Miron, V. E., Jung, C. G., Kim, H. J., Kennedy, T. E., Soliven, B., & Antel, J. P. (2008). FTY720 modulates human oligodendrocyte progenitor process extension and survival. Annals of Neurology, 63(1), 61-71.
Miron VE, et al. FTY720 Modulates Human Oligodendrocyte Progenitor Process Extension and Survival. Ann Neurol. 2008;63(1):61-71. PubMed PMID: 17918267.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FTY720 modulates human oligodendrocyte progenitor process extension and survival. AU - Miron,Veronique E, AU - Jung,Cha Gyun, AU - Kim,Hye Jung, AU - Kennedy,Timothy E, AU - Soliven,Betty, AU - Antel,Jack P, PY - 2007/10/6/pubmed PY - 2008/3/13/medline PY - 2007/10/6/entrez SP - 61 EP - 71 JF - Annals of neurology JO - Ann. Neurol. VL - 63 IS - 1 N2 - 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. INTERPRETATION: FTY720 induces time-dependent modulation of S1P receptors on human OPCs with consequent functional responses that are directly relevant for the remyelination process. SN - 1531-8249 UR - https://www.unboundmedicine.com/medline/citation/17918267/FTY720_modulates_human_oligodendrocyte_progenitor_process_extension_and_survival_ L2 - https://doi.org/10.1002/ana.21227 DB - PRIME DP - Unbound Medicine ER -