Discussion
axonal injury, neuroinflammation, inflammation, astrocytosis, demyelination
CREST, INFLAMMATION, EAE, INFLAMMATION, ASTROCYTOSIS, DEMYELINATION
In the cuprizone model, where demyelination is induced without major involvement of the adaptive immune system, our study showed increased levels of myelin in mice treated with BM-MSCs compared to those that received saline. This finding suggests a myelin-protective effect for BM-MSCs. However, no such effect was found with SHED, and there was no impact on numbers of mature oligodendrocytes or axonal injury. Inflammation, characterized by microglial activation was lower in both BM-MSCs and SHED, whereas SHED also showed lower astrocyte activation relative to mice treated with saline, suggesting that both BM-MCS and SHED may reduce the innate immune activation within the CNS induced by cuprizone.Our findings are in opposition to another study, which did not find any positive effects on myelin or inflammation of neither intravenously nor intranasally injected MSCs in a cuprizone model [Our findings of a positive effect of BM-MSCs in the cuprizone model are in conformity with another study where murine BM-MSCs were injected intraperitoneally in both cuprizone and EAE mice [SHED showed decreased inflammation and astrocytosis in the cuprizone model as compared to saline. To the best of our knowledge, SHED have not been tested in cuprizone mice previously. SHED are derived from the normal dental pulp and originate from the cranial neural crest. These cells exhibit neural stem cell markers and secrete a variety of neurotrophic growth factors that are thought to have great neuroprotective potential [Our findings may have important implications for patients with MS, especially for patients with progressive MS. The cuprizone model shares many important characteristics of progressive MS, including the progressive clinical worsening with demyelination and activation of innate immune cells in the brain, i.e. the microglia and astrocytes [There are some limitations of the present study. We used BM-MSCs and SHED from one healthy donor. As these cell populations have been shown to be heterogenous, we cannot rule out that this may have affected the results, also in comparison with other studies as previously mentioned. However, the stemness and cell characteristics of both populations were confirmed prior to the experiment. In addition, we only used a NOGO-A antibody for oligodendrocytes in the cuprizone experiment. NOGO-A is a well-suited marker for mature oligodendrocytes. Ideally, we should also have used a marker for OPCs to elucidate the mechanisms behind the positive effects of BM-MSCs on myelin abundance. Also, behavorial tests, such as the rotarod test, could have given information to the effect of MSCs on motor performance and thereby possibly supporting the histological findings. A strength of the study is the implementation of a blinded, randomized design and use of a well established model for demyelination.In conclusion, we showed that both BM-MCSs and SHED reduced neuroinflammation in the cuprizone model, whereas BM-MSCs were associated with increased myelin. These findings suggest a neuroprotective effect of BM-MSCs and SHED in a toxic MS model without substantial involvement of the adaptive immune system.