Therapeutic efficacy of adipose-derived MSC in chronic experimental autoimmune encephalomyelitis

Mesenchymal stem cells (MSC) represent a promising therapeutic approach for neurological autoimmune diseases; previous studies have shown that treatment with bone marrow-derived MSC induces immune modulation and reduces disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we show that intravenous administration of adipose-derived MSC (ASC) before disease onset significantly reduces the severity of EAE and decreases spinal cord inflammation and demyelination by immune modulation. ASC preferentially home into lymphoid organs, but migrates also inside the central nervous system (CNS). Most importantly, administration of ASC in chronic established EAE significantly ameliorates the disease course and reduces both demyelination and axonal loss, and induces a Th2-type cytokine shift in T cells. Interestingly, a relevant subset of ASC expresses activated α4 integrins and adheres to inflamed brain venules in intravital microscopy experiments. Bioluminescence imaging confirms that α4 integrins control ASC accumulation in inflamed CNS. After penetration within EAE lesions, ASC induce a significant increase of the number of endogenous oligodendrocyte progenitors. As for the mechanisms responsible for such effect, we found that ASC cultures produce vascular endothelial growth factor, insulin growth factor-I, basic fibroblast growth factor, brain-derived growth factor and platelet-derived growth factor-AB both in basal condition and after inflammatory stimulus. Interestingly, these molecules are all involved in the proliferation of both oligodendrocyte precursors and ASC themselves. In conclusion, we show that ASC display clear therapeutic effect by a bimodal mechanism, by suppressing the autoimmune response in early phases of disease as well as by inducing local neuro-regeneration by activating endogenous progenitors in animals with established disease. Overall our data suggest that ASC represent a valuable tool for stem cell-based therapy in chronic inflammatory diseases of the CNS.