Neuroinflammatory signals enhance the immunomodulatory and neuroprotective properties of multipotent adult progenitor cells

Abstract

Introduction: Stem cell-based therapies are currently widely explored as a tool to treat neuroimmune diseases. MAPC (Multipotent Adult Progenitor Cells) have been suggested to have strong immunomodulatory and neuroprotective properties in several experimental models. In this study, we investigate whether MAPC are of therapeutic interest for neuroinflammatory disorders such as multiple sclerosis (MS), by evaluating their capacities to modulate crucial pathological features and gain insights in the molecular pathways involved. Methods: Rat MAPC (rMAPC) were treated with combinations of pro-inflammatory cytokines that are closely associated with neuroinflammatory conditions, a process called licensing. mRNA expression of immunomodulatory molecules, chemokines and chemokine receptors was investigated. The migratory potential of licensed rMAPC towards a broad spectrum of chemokines was tested in a Transwell assay. Furthermore, the effect of licensing on the ability of rMAPC to attract and suppress the proliferation of encephalitogenic T cells was assessed. Finally, neuroprotective properties of rMAPC were determined in the context of protection from oxidative stress of oligodendrocytes. Therefore, rMAPC were incubated with conditioned medium of OLN93 cells subjected to sub-lethal doses of hydrogen peroxide (H2O2) and the gene expression of neurotrophic factors was assessed. Results: After licensing, a wide variety of immunomodulatory molecules and chemokines, including Nitric Oxide synthase (iNOS) and fractalkine, was up-regulated by rMAPC. The migratory properties of rMAPC towards various chemokines were also altered. In addition, rMAPC were found to inhibit antigen specific T cell proliferation and this suppressive effect was further enhanced after pro-inflammatory treatment. This phenomenon was partially mediated through iNOS or cyclooxygenase-2 (COX-2). Activated rMAPC secreted factors that led to attraction of myelin specific T cells. Finally, exposure of rMAPC to in vitro simulated neurodegenerative environment induced the up-regulation of mRNA levels of vascular endothelial growth factor (VEGF) and ciliary neurotrophic factor (CNTF). Factors secreted by rMAPC in response to this environment partially protected OLN93 cells from H2O2 induced cell death. Conclusions: rMAPC possess immune modulatory and neuroprotective properties which are enhanced in response to neuroinflammatory signals. These findings thereby warrant further research to evaluate MAPC transplantation as a therapeutic approach in diseases with an immunological and neurodegenerative component such as MS.