Abstract
Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and axonal loss throughout the central nervous system. Most of the previous studies that have been conducted to evaluate the efficacy of mesenchymal stem cells (MSCs) have utilized immune models such as experimental autoimmune encephalomyelitis (EAE). However, with this experimental setting, it is not clear whether the MSCs exert the functional improvement via an indirect consequence of MSC-mediated immunomodulation or via a direct replacement of the lost cells, paracrine actions, and/or an enhancement of endogenous repair. This study is the first to demonstrate the capability of intravenously injected bone marrow-derived MSCs (BM-MSCs) to migrate, engraft, and improve the demyelination in the non-immune cuprizone model of MS. The ultrastructural analysis conducted in this study revealed that the observed histological improvement was due to both reduced demyelination and enhanced remyelination. However, the detected remyelination was not graft-derived as no differentiation of the transplanted cells towards the oligodendroglial phenotype was detected. In addition, the transplanted cells modulated the glial response and reduced apoptosis. These results suggest that the therapeutic potential of BM-MSCs for MS is not only dependent on their immunosuppressive and immunomodulatory nature but also on their ability to enhance endogenous repair and induce oligo/neuroprotection. Proving the efficacy of BM-MSCs in a non-immune model of MS and evaluating the underlying mechanisms should enrich our knowledge of how these cells exert their beneficial effects and may eventually help us to enhance and maintain an efficacious and sustainable cell therapy for MS.