Fingolimod induces the transition to a nerve regeneration promoting Schwann cell phenotype

Exp Neurol. 2015 Sep;271:25-35. doi: 10.1016/j.expneurol.2015.05.002. Epub 2015 May 7.

Abstract

Successful regeneration of injured peripheral nerves is mainly attributed to the plastic behavior of Schwann cells. Upon loss of axons, these cells trans-differentiate into regeneration promoting repair cells which provide trophic support to regrowing axons. Among others, activation of cJun was revealed to be involved in this process, initiating the stereotypic pattern of Schwann cell phenotype alterations during Wallerian degeneration. Nevertheless, the ability of Schwann cells to adapt and therefore the nerve's potential to regenerate can be limited in particular after long term denervation or in neuropathies leading to incomplete regeneration only and thus emphasizing the need for novel therapeutic approaches. Here we stimulated primary neonatal and adult rat Schwann cells with Fingolimod/FTY720P and investigated its impact on the regeneration promoting phenotype. FTY720P activated a number of de-differentiation markers including cJun and interfered with maturation marker and myelin expression. Functionally, FTY720P treated Schwann cells upregulated growth factor expression and these cells enhanced dorsal root ganglion neurite outgrowth on inhibitory substrates. Our results therefore provide strong evidence that FTY720P application supports the generation of a repair promoting cellular phenotype and suggest that Fingolimod could be used as treatment for peripheral nerve injuries and diseases.

Keywords: Axon outgrowth; Gilenya®; Glia; Myelin; Neuropathy; Peripheral nerve regeneration; Trans-differentiation; cJun.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Culture Media, Conditioned / pharmacology
  • Cyclic AMP / metabolism
  • Cyclin-Dependent Kinase Inhibitor p57 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p57 / genetics
  • Embryo, Mammalian
  • Fingolimod Hydrochloride / pharmacology*
  • Ganglia, Spinal / cytology
  • Gene Expression Regulation, Developmental / drug effects*
  • Immunosuppressive Agents / pharmacology*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Myelin Sheath / genetics
  • Myelin Sheath / metabolism
  • Nerve Regeneration / drug effects*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Rats
  • Rats, Wistar
  • Schwann Cells / chemistry
  • Schwann Cells / drug effects*
  • Schwann Cells / physiology*
  • Signal Transduction / drug effects

Substances

  • Culture Media, Conditioned
  • Cyclin-Dependent Kinase Inhibitor p57
  • Immunosuppressive Agents
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Cyclic AMP
  • Fingolimod Hydrochloride