Fingolimod Enhances Oligodendrocyte Differentiation of Transplanted Human Induced Pluripotent Stem Cell-Derived Neural Progenitors

Abstract

Multiple sclerosis (MS) is an autoimmune disease which affects myelin in the central nervous system (CNS) and leads to serious disability. Currently available treatments for MS mainly suppress the immune system. Regenerative medicine-based approaches attempt to increase myelin repair by targeting endogenous progenitors or transplanting stem cells or their derivatives. Fingolimod exerts anti-inflammatory effects and directly affects neural cells. In this study we assessed the effect of fingolimod on transplanted human induced pluripotent stem cell derived neural progenitors (hiPSC-NPs). hiPSC-NPs were labeled by green fluorescence protein (GFP) and transplanted into the corpus callosum of mice which were chronically demyelinated after cuprizone (CPZ) feedings for 10 weeks. The animals received fingolimod from 1 day prior to NPs transplantation via gavage as well as daily intraperitoneal cyclosporine A from 2 days before cell transplantation until the time of sampling. At either 7 or 21 days after NPs transplantation, the animals were sacrificed and their brains were histologically evaluated for the number of transplanted cells and their fate. In the animals treated with fingolimod, we observed higher numbers of NPs within the injection site compared to the animals who did not receive fingolimod showing that hiPSC- NPs were more efficiently differentiated to the oligodendrocyte lineage. These data have suggested that repetitive treatment with fingolimod, beside its anti-inflammatory effect, may enhance the survival and differentiation of transplanted NPs to oligodendrocyte lineage cells to participate in myelin repair.