Role of p38MAPK in S1P receptor-mediated differentiation of human oligodendrocyte progenitors

Glia. 2014 Aug;62(8):1361-75. doi: 10.1002/glia.22688. Epub 2014 May 9.

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.

Keywords: FTY720/fingolimod; human oligodendrocyte progenitor cell differentiation; myelination; p38 MAP kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Coculture Techniques
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / physiology
  • Fingolimod Hydrochloride
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiology
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Myelin Sheath / drug effects
  • Myelin Sheath / physiology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / physiology
  • Neurogenesis / drug effects
  • Neurogenesis / physiology*
  • Oligodendroglia / drug effects
  • Oligodendroglia / physiology*
  • Propylene Glycols / pharmacology*
  • Rats, Sprague-Dawley
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptors, Lysosphingolipid / agonists
  • Receptors, Lysosphingolipid / metabolism*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • Sphingosine-1-Phosphate Receptors
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Immunosuppressive Agents
  • Propylene Glycols
  • Receptors, Lysosphingolipid
  • S1PR1 protein, human
  • Sphingosine-1-Phosphate Receptors
  • Receptor, Platelet-Derived Growth Factor alpha
  • p38 Mitogen-Activated Protein Kinases
  • Fingolimod Hydrochloride
  • Sphingosine