Synergistic neuroprotective effects of Fingolimod and mesenchymal stem cells (MSC) in experimental autoimmune encephalomyelitis.

Fingolimod (Gilenya™) is an effective oral medication approved for relapsing-remitting multiple sclerosis (MS), albeit less effective in chronic disease. Its main mechanism of action is through peripheral immunomodulation but neuroprotective effects may also be involved. Mesenchymal stem cells (MSC) were shown to exert immunomodulatory and neurotrophic effects in the model of multiple sclerosis (experimental autoimmune encephalomyelitis-EAE). The use of combination treatments in chronic diseases such as MS, has long been advocated and may result in improvement of the beneficial effects of each one of them. We tested the in vitro effects of Fingolimod (FTY720) on MSC and the in vivo effect of such combination treatment in the model of EAE. Fingolimod did not affect in any detrimental way the basic features of MSCs and it promoted their migration and proliferation ability .Moreover, Fingolimod induced neurotrophic factors secretion and suppressed the production of pro-inflammatory cytokines from astrocytes and microglia, in vitro. In vivo, the combined treatment of FTY720 and MSC (either by the intravenous or the intra-cerebroventricular route of administration) resulted in synergistic clinical beneficial effects compared to FTY720 or MSC alone, paralleled by a significant reduction of inflammatory CNS infiltrations and of axonal loss. These data may indicate a synergism of fingolimod with MSC and may support future combinations of immunomodulatory drugs with cellular therapies for the improvement of the benefits in progressive forms of MS.

Neuralized mesenchymal stem cells (NMSC) exhibit phenotypical, and biological evidence of neuronal transdifferentiation and suppress EAE more effectively than unmodified MSC.

In the last decade several studies employing stem cells-based therapies have been investigated as an optional treatment for multiple sclerosis. Several preclinical and few clinical studies tested the efficacy of mesenchymal stem cells as a potent candidate for such therapies. Here we suggest the option of "neuralization" of classical mesenchymal stem cells as a cellular structure that resembles neural stem cells as well as there differentiation by a unique procedure towards terminally differentiated neural cells suggesting that this cell population may be appropriate for clinical application in the CNS. We investigated whether neuralized MSC (NMSC) could promote repair and recovery after injection into mice with EAE. Injection of NMSC and differentiated NMSC starting at the onset of the chronic phase of disease improved neurological function compared to controls as well as compared to naïve MSC. Injection of NMSC and mainly differentiated correlated with a reduction in the inflammation as well as in the axonal loss/damage and reduced area of demyelination. These observations suggest that NMSC and differentiated NMSC may suggest a more potent cell-based therapy that naïve MSC in the treatment arsenal of multiple sclerosis.

Long and short multifunicular projections of sacral neurons are activated by sensory input to produce locomotor activity in the absence of supraspinal control.

Afferent input from load and joint receptors has been shown to reactivate the central pattern generators for locomotion (CPGs) in spinal cord injury patients and thereby improve their motor function and mobility. Elucidation of the pathways interposed between the afferents and CPGs is critical for the determination of the capacity of sensory input to activate the CPGs when the continuity of the white matter tracts is impaired following spinal cord injury. Using electrophysiological recordings, confocal imaging studies of spinal neurons and surgical manipulations of the white matter, we show that the capacity of sacrocaudal afferent (SCA) input to produce locomotor activity in isolated rat spinal cords depends not only on long ascending pathways, but also on recruitment of sacral proprioneurons interposed between the second order neurons and the hindlimb CPGs. We argue that large heterogeneous populations of second-order and proprioneurons whose crossed and uncrossed axons project rostrally through the ventral, ventrolateral/lateral and dorsolateral white matter funiculi contribute to the generation of the rhythm by the stimulated sacrocaudal input. The complex organization and multiple projection patterns of these populations enable the sacrocaudal afferent input to activate the CPGs even if the white matter pathways are severely damaged. Further studies are required to clarify the mechanisms involved in SCA-induced locomotor activity and assess its potential use for the rescue of lost motor functions after spinal cord injury.