Synergistic neuroprotective effects of Fingolimod and mesenchymal stem cells (MSC) in experimental autoimmune encephalomyelitis

Abstract

Fingolimod (Gilenya™) is an effective oral medication approved for relapsing-remitting multiple sclerosis (MS), albeit less effective in chronic disease. Its main mechanism of action is through peripheral immunomodulation but neuroprotective effects may also be involved. Mesenchymal stem cells (MSC) were shown to exert immunomodulatory and neurotrophic effects in the model of multiple sclerosis (experimental autoimmune encephalomyelitis-EAE). The use of combination treatments in chronic diseases such as MS, has long been advocated and may result in improvement of the beneficial effects of each one of them.We tested the in vitro effects of Fingolimod (FTY720) on MSC and the in vivo effect of such combination treatment in the model of EAE.Fingolimod did not affect in any detrimental way the basic features of MSCs and it promoted their migration and proliferation ability .Moreover, Fingolimod induced neurotrophic factors secretion and suppressed the production of pro-inflammatory cytokines from astrocytes and microglia, in vitro. In vivo, the combined treatment of FTY720 and MSC (either by the intravenous or the intra-cerebroventricular route of administration) resulted in synergistic clinical beneficial effects compared to FTY720 or MSC alone, paralleled by a significant reduction of inflammatory CNS infiltrations and of axonal loss. These data may indicate a synergism of fingolimod with MSC and may support future combinations of immunomodulatory drugs with cellular therapies for the improvement of the benefits in progressive forms of MS.