Final Activity Report Summary - RE-MYELINATION (Inflammation and de/remyelination coupling in EAE: A focus on the role of soluble TNF and receptors) Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, develops through the immunologic destruction of the myelin sheath of the Central nervous system (CNS). The adult CNS maintains the ability to self-repair by recruiting Neuronal stem and precursor cells (NPCs). When and how this process occurs and why it eventually succumbs to the destructive nature of the disease remain haunting questions in the field. Our detailed histological examination of the inflamed CNS revealed the existence of cellular niches bearing markers spanning all levels of the neural stem cell differentiation pathway. The cytoarchitecture of these niches was reminiscent of the germinal niches, where NPCs resided and supported neurogenesis and gliogenesis throughout adult life. It was therefore possible that what we observed were ectopic niches where NPCs were recruited and received signals to differentiate and become the oligodendrocytes required for tissue repair. Our goal was to identify molecular mechanisms governing such tissue repair. Tumour necrosis factor (TNF) and its receptors, namely p55TNFR and p75TNFR, are known to play a vital role in CNS pathogenesis. More specifically, p75TNFR was implicated in CNS repair and the proliferation of oligodedrocyte precursors. It was noted that p75TNFR-/- animals exhibited exacerbated EAE clinical profile with sustained motor deficits. Interestingly, in the CNS of these animals the numbers of ectopic niches was greatly reduced and the various cellular populations adopted a seemingly random spatial distribution. Real time Polymerase chain reaction (PCR) analysis of the spinal cords of diseased animals revealed the sustained upregulation of the NPC marker nestin in the absence of p75TNFR. Furthermore, we were able to grow neurospheres from the spinal cords of EAE-affected p75TNFR-/- animals but not from wild type littermates. Taken together, our data supported that, in the absence of p75TNFR, the inflamed CNS lacked a properly organised cellular microenvironment and had a sustained pool of undifferentiated NPCs. In summary, our studies shed some light on the role of p75TNFR in the repair of autoimmune demyelination. p75TNFR appeared to have a reparative role through its ability to promote NPC differentiation. We further aimed to elucidate the signalling pathway and the direct or indirect effect of p75TNFR on NPC differentiation. Such knowledge would be invaluable for the advancement of efficient stem cell therapeutic approaches for demyelinating diseases.