Discussion
neurodegeneration, neuroaxonal loss
NEURODEGENERATION
To our knowledge, STEMS is the first phase 1 clinical trial assessing the safety and maximum tolerated dose of intrathecally transplanted In terms of safety, neither AEs of grade 3 or higher possibly related to the procedure, nor AEs definitely related to Despite pRNFL thickness being considered a potential biomarker of neuroaxonal loss, representing a reliable objective tool to assess novel neuroprotective therapies in PMSMRI brain and GM volume measurements represent neurodegeneration biomarkers in patients with MSCSF immunological and proteomic analyses were performed at baseline and 3 months after transplantation. We found an upregulation of some trophic factors (that is, GDNF, VEGF-C and SCF) and immune-related molecules (that is, FAS ligand and IL-10) and the downregulation of some pro-inflammatory chemokines, such as IL-8. Although we cannot exclude that our results might have been biased by the concomitant immunomodulatory treatments, it is possible to hypothesize that transplanted We also found an upregulation of cytokines and chemokines, such as IL-15 and GM-CSF. Although pro-inflammatory in nature, these molecules have been also shown to exert pro-regenerative functions. IL-15 regulates NPC proliferation/differentiation, and its deficiency leads to an impaired generation of neuroblasts in the subventricular zone (SVZ)–rostral migratory stream axisMoreover, our proteomic analysis supports a possible pro-regenerative role of Our previously published preclinical results clearly demonstrated that cells might retain viability and keep exerting their bystander effect even months after transplantation. However, we cannot speculate on how long the cells remain viable and potentially efficacious because the study design (with few timepoints and no long-term follow up) did not allow for CSF samples to be obtained beyond 3 months after transplantation. Moreover, the positive result of the microchimeric assay in one patient - one of three who received the highest dose of cells - though of interest, has only a descriptive value and could represent a cue for subsequent studies.In conclusion, our study showed that 