title: Role of p38MAPK in S1P receptor-mediated differentiation of human oligodendrocyte progenitors.
abstract: FTY720 is a sphingosine 1-phosphate receptor (S1PR) modulator used as a daily therapy to reduce disease activity in the relapsing form of multiple sclerosis (MS). FTY720 readily accesses the CNS. Previous studies have shown that phosphorylated FTY720 (FTY720-p) enhances oligodendrocyte progenitor cell (OPC) survival, differentiation, and remyelination following experimentally induced demyelination in rodents. To elucidate the underlying mechanism, human fetal OPCs alone or in co-culture with rat dorsal root ganglia neurons (DRGN) were treated daily with FTY720-p, a condition that desensitizes cellular responses to S1P, the natural ligand of S1PR. In co-cultures, FTY720-p and S1P given daily or every three days increased the number of O1/MBP double positive cells and axonal ensheathment. In cultures composed of PDGFRα-antibody selected cells alone, daily application of FTY720-p also increased the number of O4/GC double positive cells. At an early time point (day 2), FTY720-p activated ERK1/2, CREB and p38MAPK in O4-positive cells, as well as in β-III Tubulin positive neurons and GFAP positive astrocytes. In later cultures (day 6), FTY720-p activated p38MAPK in O4 positive cells, p38MAPK and ERK1/2 in neurons, and p38MAPK, ERK1/2 and CREB in astrocytes. A MEK inhibitor (U0126) prevented the differentiation of OPCs into O4-positive cells, while a p38MAPK inhibitor (PD169316) blocked progression into O4-positive and into GC-positive stages of differentiation. Our results demonstrate that FTY720-p, under conditions that model daily clinical use, can act directly on OPCs to impact differentiation, and also indirectly via neurons and astrocytes by activating ERK1/2 and p38MAPK.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Qiao Ling
authors.initials: QL
authors.lastname: Cui
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
authors.forename: Guillermina
authors.initials: G
authors.lastname: Almazan
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
mesh_terms: D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000502:physiology; D000068876:Fingolimod Hydrochloride; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D011409:Propylene Glycols / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: FTY720/fingolimod; human oligodendrocyte progenitor cell differentiation; myelination; p38 MAP kinase